Hypertension recent issues

Nighttime Activity Influences the Evaluation of Ambulatory Blood Pressure Monitoring [Letters to the Editor]

Nagy, G., Nagy, C. B. — Wed, 18 Nov 2009 13:33:27 PST

Response to Nighttime Activity Influences the Evaluation of Ambulatory Blood Pressure Monitoring [Letters to the Editor]

Agarwal, R. — Wed, 18 Nov 2009 13:33:27 PST

MicroRNAs and Beyond: The Heart Reveals Its Treasures [Brief Reviews]

Schroen, B., Heymans, S. — Wed, 18 Nov 2009 13:33:25 PST

Renal Denervation as a Therapeutic Approach for Hypertension: Novel Implications for an Old Concept [Brief Reviews]

Wed, 18 Nov 2009 13:33:25 PST

Both the Toolset and Motivation Are Needed for Lasting Change [Editorial Commentaries]

Taler, S. J. — Wed, 18 Nov 2009 13:33:25 PST

Hypertension, Growth, and Skeletal Maturation in the Young: A New Look at an Old Idea [Editorial Commentaries]

Flynn, J. T. — Wed, 18 Nov 2009 13:33:25 PST

Moderate Exercise Decreases Inflammation and Oxidative Stress in Hypertension: But What Are the Mechanisms? [Editorial Commentaries]

Briones, A. M., Touyz, R. M. — Wed, 18 Nov 2009 13:33:25 PST

Does Junk Food Lead to Heart Failure?: Importance of Dietary Macronutrient Composition in Hypertension [Editorial Commentaries]

Stanley, W. C., Shah, K. B., Essop, M. F. — Wed, 18 Nov 2009 13:33:26 PST

Mineralocorticoid Receptors in Myocardial Infarction [Editorial Commentaries]

Stier, C. T. — Wed, 18 Nov 2009 13:33:26 PST

Arteriosclerosis and Atherosclerosis: Guilty by Association [Editorial Commentaries]

Wilkinson, I. B., McEniery, C. M., Cockcroft, J. R. — Wed, 18 Nov 2009 13:33:26 PST

Truncated Prorenin Comes Up ... Short [Editorial Commentaries]

Reudelhuber, T. L. — Wed, 18 Nov 2009 13:33:26 PST

Does Prorenin Exert Angiotensin-Independent Effects In Vivo? [Editorial Commentaries]

Danser, A.H. J. — Wed, 18 Nov 2009 13:33:26 PST

Mammalian Target of Rapamycin: MasTOR Mediator of Cellular Changes in Pathological States? [Editorial Commentaries]

McNicholas, C. M., Berecek, K. H. — Wed, 18 Nov 2009 13:33:26 PST

Adenosine2A Receptors and Epoxyeicosatrienoic Acids: A Recipe for Salt and Blood Pressure Regulation [Editorial Commentaries]

Imig, J. D. — Wed, 18 Nov 2009 13:33:26 PST

Hypertension Improvement Project: Randomized Trial of Quality Improvement for Physicians and Lifestyle Modification for Patients [Original Articles]

Wed, 18 Nov 2009 13:33:26 PST

Despite widely publicized hypertension treatment guidelines for physicians and lifestyle recommendations for patients, blood pressure control rates remain low. In community-based primary care clinics, we performed a nested, 2x2 randomized, controlled trial of physician intervention versus control and/or patient intervention versus control. Physician intervention included internet-based training, self-monitoring, and quarterly feedback reports. Patient intervention included 20 weekly group sessions followed by 12 monthly telephone counseling contacts and focused on weight loss, Dietary Approaches to Stop Hypertension dietary pattern, exercise, and reduced sodium intake. The primary outcome was change in systolic blood pressure at 6 months. Eight primary care practices (32 physicians) were randomized to physician intervention or control groups. Within those practices, 574 patients were randomized to patient intervention or control groups. Patient mean age was 60 years, 61% were women, and 37% were black. Blood pressure data were available for 91% of patients at 6 months. The main effect of physician intervention on systolic blood pressure at 6 months, adjusted for baseline pressure, was 0.3 mm Hg (95% CI: –1.5 to 2.2; P=0.72). The main effect of the patient intervention was –2.6 mm Hg (95% CI: –4.4 to –0.7; P=0.01). The interaction of the 2 interventions was significant (P=0.03); the largest impact was observed with the combination of physician and patient intervention (–9.7±12.7 mm Hg). Differences between treatment groups did not persist at 18 months. Combined physician and patient interventions lowers blood pressure; future research should focus on enhancing effectiveness and sustainability of these interventions.

Accelarated Skeletal Maturation in Children With Primary Hypertension [Original Articles]

Wed, 18 Nov 2009 13:33:26 PST

It is hypothesized that primary hypertension (PH) is a disorder with origins in childhood linked to, at least in part, aberrations of growth and maturation processes. To evaluate the possible relation between the rate of biological maturity and development of PH, bone age (BA) assessments on the basis of dual x-ray absorptiometry–derived hand scans were performed in 54 newly diagnosed children and adolescents with PH and 54 healthy controls matched for body mass index (BMI), age and sex. Chronological age (CA), body height (in centimeters), body weight (in kilograms), BMI (in kilograms per meter squared), and blood pressure were assessed. Healthy controls had a mean BA of 14.7±2.3 years that was not significantly different from their mean CA of 14.2±2.1 years. In the PH group, the BA of 16.0±2.0 years was higher by 1.9±0.9 years compared with their CA of 14.1±2.0 years (P<0.0001). The magnitude of acceleration of skeletal maturation (BA-CA) and its prevalence (88.9%) were significantly higher in PH compared with BMI-matched controls (37.0%; ²=31.4; P<0.0001). BA-CA values of PH patients were higher by 1.24 years in normal weight (P<0.0001), 1.80 years in overweight (P<0.01), and 1.40 years in obese (P<0.0001) subgroups of BMI z score–matched controls. Stepwise regression revealed that predictors of blood pressure status from normotension through prehypertension stages 1 and 2 of hypertension were BA-CA (β=0.530; P<0.0.001), height (β=–0.379; P<0.01), and CA (β=0.298; P<0.05; R²=0.43). In conclusion, irrespective of BMI, advanced biological maturation should be considered as an independent marker for the development of hypertension.

Preservation of Intracellular Renin Expression Is Insufficient to Compensate for Genetic Loss of Secreted Renin [Original Articles]

Xu, D., Borges, G. R., Grobe, J. L., Pelham, C. J., Yang, B., Sigmund, C. D. — Wed, 18 Nov 2009 13:33:26 PST

The primary product of the renin gene is preprorenin. A signal peptide sorts renin to the secretory pathway in juxtaglomerular cells where it is released into the circulation to initiate the renin-angiotensin system cascade. In the brain, transcription of renin occurs from an alternative promoter encoding an mRNA starting with a new first exon (exon 1b). Exon 1b initiating transcripts skip over the classical first exon (exon 1a) containing the initiation codon for preprorenin. Exon 1b transcripts are predicted to use a highly conserved initiation codon within exon 2, producing renin, which should remain intracellular, because it lacks the signal peptide. To evaluate the roles of secreted and intracellular renin, we took advantage of the organization of the renin locus to generate a secreted renin (sRen)-specific knockout, which preserves intracellular renin expression. Expression of sRen mRNA was ablated in the brain and kidney, whereas intracellular renin mRNA expression was preserved in fetal and adult brains. We noted a developmental shift from the expression of sRen mRNA in the fetal brain to intracellular renin mRNA in the adult brain. Homozygous sRen knockout mice exhibited very poor survival at weaning. The survivors exhibited renal lesions, low hematocrit, an inability to generate a concentrated urine, decreased arterial pressure, and impaired aortic contraction. These results suggest that preservation of intracellular renin expression in the brain is not sufficient to compensate for a loss of sRen, and sRen plays a pivotal role in renal development and function, survival, and the regulation of arterial pressure.

Prorenin Contributes to Angiotensin Peptide Formation in Transgenic Rats With Rat Prorenin Expression Targeted to the Liver [Original Articles]

Campbell, D. J., Karam, H., Menard, J., Bruneval, P., Mullins, J. J. — Wed, 18 Nov 2009 13:33:26 PST

We reported previously that targeted expression of rat prorenin to the liver under the control of the human 1-antitrypsin promoter increased plasma prorenin levels by several-hundred–fold in male transgenic rats and caused cardiac hypertrophy, severe renal lesions, and myocardial fibrosis by 20 weeks of age, despite normal blood pressure. We examined the evolution of the phenotype of male transgenic rats over 12 months and the effects of binephrectomy on the renin-angiotensin (Ang) system. Plasma prorenin levels were >1000-fold higher than in wild type littermates, whereas plasma and renal Ang II levels were no different from wild-type (WT) levels, and kidney renin levels were suppressed in transgenic rats. In contrast to our earlier report, transgenic rats had increased systolic blood pressure at 3 to 12 months of age, and only modest renal lesions and myocardial fibrosis were evident after 6 months of age. Binephrectomy reduced plasma renin activity and concentration and prorenin levels by 50% to 80% and Ang II levels by 90% in WT rats. By contrast, binephrectomy increased plasma renin activity and concentration and prorenin levels by 52.0-, 13.0-, and 5.8-fold, respectively, without change in Ang II levels in transgenic rats. We conclude that, in the animals studied in this report, elevated prorenin levels did not cause renal lesions or myocardial fibrosis during the first 6 months of age. Ang peptide formation consequent to the increased prorenin levels prevented reduction of Ang II levels after binephrectomy and was likely to have contributed to hypertension, cardiac hypertrophy, and suppression of kidney renin levels in these transgenic rats.

Protection of Angiotensin II-Induced Vascular Hypertrophy in Vascular Smooth Muscle-Targeted Receptor Activity-Modifying Protein 2 Transgenic Mice [Original Articles]

Wed, 18 Nov 2009 13:33:26 PST

The vasodilator and vascular regulatory peptide adrenomedullin (AM), a member of the calcitonin gene-related peptide family of peptides, is predicted to play a pivotal protective role in cardiovascular dysfunction. The principle AM (AM1) receptor is composed of a G protein–linked calcitonin receptor-like receptor and a receptor activity-modifying protein (receptor activity-modifying protein 2). There is little knowledge of the receptors via which AM acts in diseases. Using smooth muscle-targeted receptor activity–modifying protein 2 transgenic mice with increased vascular density of functional AM1 receptors, we demonstrate that receptor activity-modifying protein 2 transgenic mice are not protected against angiotensin II–induced hypertension or cardiac hypertrophy. However, vascular hypertrophy, together with vascular cell adhesion molecule 1 and monocyte chemotactic protein 1 expression, is significantly reduced in the aortic walls of transgenic mice, as determined by histological techniques. This indicates that the AM1 vascular smooth muscle receptor can mediate local protection in vivo. This is supported by proliferation studies in cultured smooth muscle cells. By comparison, levels of hypotension and inflammation in a shock model were similar to those in wild-type mice. Thus, a role of the AM1 receptor in the vasoactive component could not be detected, and evidence is provided to show that the hypotensive response to AM is subject to desensitization in vivo. The finding that the vascular smooth muscle AM1 receptor acts at a local level to protect against hypertension-induced vascular hypertrophy and inflammation provides evidence that targeting this receptor may be a beneficial therapeutic approach.

Role of Angiotensin II Type 1A Receptors in Cardiovascular Reactivity and Neuronal Activation After Aversive Stress in Mice [Original Articles]

Davern, P. J., Chen, D., Head, G. A., Chavez, C. A., Walther, T., Mayorov, D. N. — Wed, 18 Nov 2009 13:33:26 PST

We determined whether genetic deficiency of angiotensin II Type 1A (AT_1A) receptors in mice results in altered neuronal responsiveness and reduced cardiovascular reactivity to stress. Telemetry devices were used to measure mean arterial pressure, heart rate, and activity. Before stress, lower resting mean arterial pressure was recorded in AT_1A^–/– (85±2 mm Hg) than in AT_1A^+/+ (112±2 mm Hg) mice; heart rate was not different between groups. Cage-switch stress for 90 minutes elevated blood pressure by +24±2 mm Hg in AT_1A^+/+ and +17±2 mm Hg in AT_1A^–/– mice (P<0.01), and heart rate increased by +203±9 bpm in AT_1A^+/+ and +121±9 bpm in AT_1A^–/– mice (P<0.001). Locomotor activation was less in AT_1A^–/– (3.0±0.4 U) than in AT_1A^+/+ animals (6.0±0.4 U), but differences in blood pressure and heart rate persisted during nonactive periods. In contrast to wild-type mice, spontaneous baroreflex sensitivity was not inhibited by stress in AT_1A^–/– mice. After cage-switch stress, c-Fos immunoreactivity was less in the paraventricular (P<0.001) and dorsomedial (P=0.001) nuclei of the hypothalamus and rostral ventrolateral medulla (P<0.001) in AT_1A^–/– compared with AT_1A^+/+ mice. Conversely, greater c-Fos immunoreactivity was observed in the medial nucleus of the amygdala, caudal ventrolateral medulla, and nucleus of the solitary tract (P<0.001) of AT_1A^–/– compared with AT_1A^+/+ mice. Greater activation of the amygdala suggests that AT_1A receptors normally inhibit the degree of stress-induced anxiety, whereas the lesser activation of the hypothalamus and rostral ventrolateral medulla suggests that AT_1A receptors play a key role in autonomic cardiovascular reactions to acute aversive stress, as well as for stress-induced inhibition of the baroreflex.

Pressure-Induced Renal Injury in Angiotensin II Versus Norepinephrine-Induced Hypertensive Rats [Original Articles]

Polichnowski, A. J., Cowley, A. W. — Wed, 18 Nov 2009 13:33:26 PST

The susceptibility to renal perfusion pressure (RPP)–induced renal injury was investigated in angiotensin II (Ang II)– versus norepinephrine (NE)-infused hypertensive rats. To determine the magnitude of RPP-induced injury, Sprague-Dawley rats fed a 4% salt diet were instrumented with a servocontrolled aortic balloon occluder positioned between the renal arteries to maintain RPP to the left kidney at baseline levels whereas the right kidney was exposed to elevated RPP during a 2-week infusion of Ang II IV (25 ng/kg per minute), NE IV (0.5, 1.0, and 2.0 µg/kg per minute on days 1, 2, and 3 to 14, respectively), or saline IV (sham rats). Over the 14 days of Ang II infusion, RPP averaged 161.5±8.0 mm Hg to uncontrolled kidneys and 121.9±2.0 mm Hg to servocontrolled kidneys. In NE-infused rats, RPP averaged 156.3±3.0 mm Hg to uncontrolled kidneys and 116.9±2.0 mm Hg to servocontrolled kidneys. RPP averaged 111.1±1.0 mm Hg to kidneys of sham rats. Interlobular arterial injury and juxtamedullary glomerulosclerosis were largely RPP dependent in both models of hypertension. Superficial cortical glomerulosclerosis was greater and RPP dependent in NE- versus Ang II-infused rats, which was primarily independent of RPP. Outer medullary tubular necrosis and interstitial fibrosis were also primarily RPP dependent in both models of hypertension; however, the magnitude of injury was exacerbated in Ang II-infused rats. We conclude that elevated RPP is the dominant cause of renal injury in both NE- and Ang II-induced hypertensive rats and that underlying neurohumoral factors in these models of hypertension alter the pattern and magnitude of RPP-induced renal injury.

Reinforcing Feedback Loop of Renal Cyclic Guanosine 3' 5' -Monophosphate and Interstitial Hydrostatic Pressure in Pressure-Natriuresis [Original Articles]

Lieb, D. C., Kemp, B. A., Howell, N. L., Gildea, J. J., Carey, R. M. — Wed, 18 Nov 2009 13:33:26 PST

This study addresses the hypothesis that renal interstitial (RI) cGMP, a modulator of pressure-natriuresis, exerts its effect through a relationship with renal interstitial hydrostatic pressure (RIHP). Increasing renal perfusion pressure in Sprague-Dawley rats led to increases in RIHP (5.2±0.6 to 10.9±1.6 mm Hg; P<0.01), urine sodium excretion (0.062±0.009 to 0.420±0.068 µmol/min per gram; P<0.01), and RI cGMP (3.5±0.8 to 9.5±1.7 fmol/min; P<0.01), and these effects were blocked by partial renal decapsulation. Infusion of cGMP into the RI compartment of decapsulated animals restored natriuresis (0.067±0.010 to 0.310±0.061 µmol/min per gram; P<0.01). These changes were independent of changes in glomerular filtration rate . Artificially increasing RIHP in normotensive animals increased RI cGMP (4.1±0.6 to 6.9±0.7 fmol/min; P<0.01) and urine sodium excretion (0.071±0.013 to 0.179±0.039 µmol/min per gram; P<0.05). Coinfusion of organic anion transport-inhibitor probenecid, or soluble guanylyl cyclase inhibitor 1-H(1,2,4) oxadiazolo-(4,2)quinoxalin-1-one, abolished these effects. Infusion of cGMP into the RI compartment of normotensive animals increased RIHP (6.7±0.4 to 10.3±0.9 mm Hg; P<0.001). Exogenous RI cGMP delivery did not affect total, cortical, or medullary renal blood flow. These studies suggest that extracellular RI cGMP is required for the natriuresis observed after increases in renal perfusion pressure and RIHP and that cGMP acts via a tubule mechanism. The results support an intrarenal positive-feedback loop wherein RI cGMP increases RIHP, which, in turn, increases RI cGMP, contributing to the reinforcement of pressure-natriuresis.

Inhibition of the Adenosine2A Receptor-Epoxyeicosatrienoic Acid Pathway Renders Dahl Salt-Resistant Rats Hypertensive [Original Articles]

Wed, 18 Nov 2009 13:33:26 PST

Adenosine-induced renovasodilation in Dahl rats is mediated via activation of adenosine_2A receptors (A_2ARs) and stimulation of epoxyeicosatrienoic acid (EET) synthesis. Unlike Dahl salt-resistant rats, salt-sensitive rats exhibit an inability to upregulate the A_2AR-EET pathway with salt loading; therefore, we examined the effect of in vivo inhibition of the A_2AR-EET pathway on blood pressure and the natriuretic response to salt-loading in Dahl salt-resistant rats. N-Methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 20 mg/kg per day), an epoxygenase inhibitor, or ZM241385 (ZM; 5 mg/kg per day), an A_2AR antagonist, was given daily as an IV bolus dose for 3 days before and after placing rats on high salt intake (2% saline). After 3 days of high salt, systolic blood pressure per 24 hours increased from 108±2 mm Hg to 136±5 mm Hg and 140±4 mm Hg when treated with MS-PPOH or ZM, respectively (P<0.001). Plasma levels of EETs and dihydroxyeicosatrienoic acids during salt loading and MS-PPOH (29.3±1.8 ng/mL) or ZM treatment (9.8±0.5 ng/mL) did not increase to the same extent as in vehicle-treated rats (59.4±1.7 ng/mL; P<0.001), and renal levels of EETs+dihydroxyeicosatrienoic acids were 2-fold lower with MS-PPOH or ZM treatment. On day 3 of the high salt intake, MS-PPOH– and ZM-treated rats exhibited a positive Na⁺ balance, and plasma Na⁺ levels were significantly increased (163.3±1.2 and 158.1±4.5 mEq/L, respectively) compared with vehicle-treated rats (142.1±1 mEq/L), reflecting a diminished natriuretic capacity. These data support a role for the A_2AR-EET pathway in the adaptive natriuretic response to modulate blood pressure during salt loading.

Renal Proximal Tubular Reabsorption Is Reduced In Adult Spontaneously Hypertensive Rats: Roles of Superoxide and Na+/H+ Exchanger 3 [Original Articles]

Panico, C., Luo, Z., Damiano, S., Artigiano, F., Gill, P., Welch, W. J. — Wed, 18 Nov 2009 13:33:26 PST

Proximal tubule reabsorption is regulated by systemic and intrinsic mechanisms, including locally produced autocoids. Superoxide, produced by NADPH oxidase enhances NaCl transport in the loop of Henle and the collecting duct, but its role in the proximal tubule is unclear. We measured proximal tubule fluid reabsorption (Jv) in WKY rats and compared that with Jv in the spontaneously hypertensive rat (SHR), a model of enhanced renal superoxide generation. Rats were treated with the NADPH oxidase inhibitor apocynin (Apo) or with small interfering RNA for p22^phox, which is the critical subunit of NADPH oxidase. Jv was lower in SHR compared with Wistar-Kyoto rats (WKY; WKY: 2.3±0.3 vs SHR: 1.1±0.2 nL/min per millimeter; n=9 to 11; P<0.001). Apo and small interfering RNA to p22^phox normalized Jv in SHRs but had no effect in WKY rats. Jv was reduced in proximal tubules perfused with S-1611, a highly selective inhibitor of the Na⁺/H⁺ exchanger 3, the major Na⁺ uptake pathway in the proximal tubule, in WKY rats but not in SHRs. Pretreatment with Apo restored an effect of S-1611 to reduce Jv in the SHRs (SHR+Apo: 2.9±0.4 vs SHR+Apo+S-1611: 1.0±0.3 nL/min per millimeter; P<0.001). However, because expression of the Na⁺/H⁺ exchanger 3 was similar between SHR and WKY rats, this suggests that superoxide affects Na⁺/H⁺ exchanger 3 activity. Direct microperfusion of Tempol or Apo into the proximal tubule also restored Jv in SHRs. In conclusion, superoxide generated by NADPH oxidase inhibits proximal tubule fluid reabsorption in SHRs. This finding implies that proximal tubule fluid reabsorption is regulated by redox balance, which may have profound effects on ion and fluid homeostasis in the hypertensive kidney.

Ablation of Transient Receptor Potential Vanilloid 1 Abolishes Endothelin-Induced Increases in Afferent Renal Nerve Activity: Mechanisms and Functional Significance [Original Articles]

Xie, C., Wang, D. H. — Wed, 18 Nov 2009 13:33:26 PST

Endothelin 1 (ET-1) and its receptors, ETA and ETB, play important roles in regulating renal function and blood pressure, and these components are expressed in sensory nerves. Activation of transient receptor potential vanilloid (TRPV) 1 channels expressed in sensory nerves innervating the renal pelvis enhances afferent renal nerve activity (ARNA), diuresis, and natriuresis. We tested the hypothesis that ET-1 increases ARNA via activation of ETB, whereas ETA counterbalances ETB in wild-type (WT) but not TRPV1-null mutant mice. ET-1 alone or with BQ123, an ETA antagonist, perfused into the left renal pelvis increased ipsilateral ARNA in WT but not in TRPV1-null mutant mice, and ARNA increases were greater in the latter. [Ala1, 3,11,15]-endothelin 1, an ETB agonist, increased ARNA that was greater than that induced by ET-1 in WT mice only. [Ala1, 3,11,15]-endothelin 1-induced increases in ARNA were abolished by chelerythrine, a protein kinase C inhibitor, but not by H89, a protein kinase A inhibitor. Chelerythrine, H89, and BQ788, an ETB antagonist, did not affect ARNA triggered by capsaicin in WT mice. Substance P release from the renal pelvis was increased by [Ala1, 3,11,15]-endothelin 1 in WT mice only, and the increase was abolished by chelerythrine but not by H89. Chelerythrine, H89, and BQ788 did not affect capsaicin-induced substance P release. Our data show that ET1 increases ARNA via activation of ETB, whereas ETA counterbalances ETB in WT but not in TRPV1-null mutant mice, suggesting that TRPV1 mediates ETB-dependent increases in ARNA, diuresis, and natriuresis possibly via the protein kinase C pathway.

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction [Original Articles]

Mihailidou, A. S., Loan Le, T. Y., Mardini, M., Funder, J. W. — Wed, 18 Nov 2009 13:33:26 PST

Myocardial ischemia-reperfusion leads to significant changes in redox state, decreased postischemic functional recovery, and cardiomyocyte apoptosis, with development and progression of heart failure. Ischemia-reperfusion in the isolated perfused rat heart has been used as a model of heart failure. Clinically, mineralocorticoid receptor blockade in heart failure decreases morbidity and mortality versus standard care alone. The effects of corticosteroids on infarct area and apoptosis were determined in rat hearts subjected to 30 minutes of ischemia and 2.5 hours of reperfusion. Both aldosterone and cortisol increased infarct area and apoptotic index, an effect half-maximal between 1 and 10 nM and reversed by spironolactone. Dexamethasone and mifepristone aggravated infarct area and apoptotic index, similarly reversed by spironolactone. Spironolactone alone reduced infarct area and apoptotic index below ischemia-reperfusion alone, in hearts from both intact and adrenalectomized rats. The present study shows that cardiac damage is aggravated by activation of mineralocorticoid receptors by aldosterone or cortisol or of glucocorticoid receptors by dexamethasone. Mifepristone unexpectedly acted as a glucocorticoid receptor agonist, for which there are several precedents. Spironolactone protected cardiomyocytes via inverse agonist activity at mineralocorticoid receptors, an effect near maximal at a relatively low dose (10 nM). Spironolactone acts not merely by excluding corticosteroids from mineralocorticoid receptors but as a protective inverse agonist at low concentration. Mineralocorticoid receptor antagonists may, thus, provide an additional therapeutic advantage in unstable angina and acute myocardial infarction.

Spironolactone Attenuates Experimental Uremic Cardiomyopathy by Antagonizing Marinobufagenin [Original Articles]

Wed, 18 Nov 2009 13:33:26 PST

Spironolactone has been noted to attenuate cardiac fibrosis. We have observed that the cardiotonic steroid marinobufagenin plays an important role in the diastolic dysfunction and cardiac fibrosis seen with experimental renal failure. We performed the following studies to determine whether and how spironolactone might ameliorate these changes. First, we studied rats subjected to partial nephrectomy or administration of exogenous marinobufagenin. We found that spironolactone (20 mg/kg per day) attenuated the diastolic dysfunction as assessed by ventricular pressure-volume loops and essentially eliminated cardiac fibrosis as assessed by trichrome staining and Western blot. Next, we examined the effects of spironolactone and its major metabolite, canrenone (both 100 nM), on marinobufagenin stimulation of rat cardiac fibroblasts. Both spironolactone and canrenone prevented the stimulation of collagen production by 1 nM marinobufagenin but not 100 nM marinobufagenin, as assessed by proline incorporation and procollagen 1 expression, as well as signaling through the sodium-potassium-ATPase, as evidenced by protein kinase C isoform translocation and extracellular signal regulated kinase 1/2 activation. Both spironolactone and canrenone also altered ouabain binding to cultured porcine cells in a manner consistent with competitive inhibition. Our data suggest that some of the antifibrotic effects of spironolactone may be attributed to antagonism of marinobufagenin signaling through the sodium-potassium-ATPase.

Mammalian Target of Rapamycin Is a Critical Regulator of Cardiac Hypertrophy in Spontaneously Hypertensive Rats [Original Articles]

Wed, 18 Nov 2009 13:33:26 PST

Evidence exists that protein kinase C and the mammalian target of rapamycin are important regulators of cardiac hypertrophy. We examined the contribution of these signaling kinases to cardiac growth in spontaneously hypertensive rats (SHRs). Systolic blood pressure was increased (P<0.001) at 10 weeks in SHRs versus Wistar-Kyoto controls (162±3 versus 128±1 mm Hg) and was further elevated (P<0.001) at 17 weeks in SHRs (184±7 mm Hg). Heart:body weight ratio was not different between groups at 10 weeks but was 22% greater (P<0.01) in SHRs versus Wistar-Kyoto controls at 17 weeks. At 10 weeks, activation of Akt and S6 ribosomal protein was greater (P<0.01) in SHRs but returned to normal by 17 weeks. In contrast, SHRs had protein kinase C activation only at 17 weeks. To determine whether mammalian target of rapamycin regulates the initial development of hypertrophy, rats were treated with rapamycin (2 mg/kg per day IP) or saline vehicle from 13 to 16 weeks of age. Rapamycin inhibited cardiac mammalian target of rapamycin in SHRs, as evidenced by reductions (P<0.001) in phosphorylation of S6 ribosomal protein and eukaryotic translation initiation factor-4E binding protein 1. Rapamycin treatment also reduced (P<0.001) heart weight and hypertrophy by 47% and 53%, respectively, in SHRs in spite of increased (P<0.001) systolic blood pressure versus untreated SHRs (213±8 versus 189±6 mm Hg). Atrial natriuretic peptide, brain natriuretic peptide, and cardiac function were unchanged between SHRs treated with rapamycin or vehicle. These data show that mammalian target of rapamycin is required for the development of cardiac hypertrophy evoked by rising blood pressure in SHRs.

Dissociation of Aortic Pulse Wave Velocity With Risk Factors for Cardiovascular Disease Other Than Hypertension: A Systematic Review [Original Articles]

Cecelja, M., Chowienczyk, P. — Wed, 18 Nov 2009 13:33:26 PST

Carotid-femoral pulse wave velocity (cfPWV), a measure of large artery stiffness, is an important predictor of cardiovascular events. This has been attributed to it being an integrative measure of the impact of cardiovascular risk factors on the arterial wall. Pulse wave velocity is strongly associated with age and blood pressure. However, findings with regard to its relation with other risk factors have been inconsistent. We performed a systematic review of cross-sectional published literature reporting independent associations of cfPWV in multivariable regression models. Articles were selected from a PubMed search using a prespecified search strategy. Studies were included if they did the following: (1) measured cfPWV; (2) reported on associations with cfPWV from regression models; and (3) considered age and blood pressure in the model. From 637 retrieved articles, 65 met our inclusion criteria, and 12 studies were included from reference searches. Age and blood pressure were consistently independently associated with cfPWV (91% and 90% of studies, respectively). Diabetes mellitus was associated with cfPWV in 52% studies, but the strength of the association was low. The majority of studies found no independent association between cfPWV and sex, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, smoking, or body mass index. The contribution of risk factors other than age and blood pressure to cfPWV is, thus, small or insignificant. The prognostic value of cfPWV may relate to a process of arterial ageing unrelated to classic risk factors other than hypertension.

Elastase-Induced Intracranial Aneurysms in Hypertensive Mice [Original Articles]

Nuki, Y., Tsou, T.-L., Kurihara, C., Kanematsu, M., Kanematsu, Y., Hashimoto, T. — Wed, 18 Nov 2009 13:33:26 PST

Mechanisms of formation and growth of intracranial aneurysms are poorly understood. To investigate the pathophysiology of intracranial aneurysms, an animal model of intracranial aneurysm yielding a high incidence of large aneurysm formation within a short incubation period is needed. We combined two well-known clinical factors associated with human intracranial aneurysms, hypertension and the degeneration of elastic lamina, to induce intracranial aneurysm formation in mice. Roles of matrix metalloproteinases (MMPs) in this model were investigated using doxycycline, a broad-spectrum MMP inhibitor, and MMP knockout mice. Hypertension was induced by continuous infusion of angiotensin II for 2 weeks. The disruption of elastic lamina was achieved by a single stereotaxic injection of elastase into the cerebrospinal fluid at the right basal cistern. A total of 77% of the mice that received 35 milliunits of elastase and 1000 ng/kg per minute of angiotensin II developed intracranial aneurysms in 2 weeks. There were dose-dependent effects of elastase and angiotensin II on the incidence of aneurysms. Histologically, intracranial aneurysms observed in this model closely resembled human intracranial aneurysms. Doxycycline, a broad-spectrum MMP inhibitor, reduced the incidence of aneurysm to 10%. MMP-9 knockout mice, but not MMP-2 knockout mice, had reduced the incidence of intracranial aneurysms. In summary, a stereotaxic injection of elastase into the basal cistern in hypertensive mice resulted in intracranial aneurysms that closely resembled human intracranial aneurysms. The intracranial aneurysm formation in this model appeared to depend on MMP activation.

Angiotensin Receptor Blocker Prevented {beta}-Amyloid-Induced Cognitive Impairment Associated With Recovery of Neurovascular Coupling [Original Articles]

Wed, 18 Nov 2009 13:33:26 PST

Recent studies suggest that vascular risk factors play a considerable role in the development of Alzheimer disease. Furthermore, the use of antihypertensive drugs has been suggested to reduce the incidence of dementia, including Alzheimer disease. In this study, we examined the effects of an angiotensin receptor blocker, olmesartan, on β-amyloid-induced cerebrovascular dysfunction and cognitive impairment. Oral administration of a low dose of olmesartan attenuated cerebrovascular dysfunction in young Alzheimer disease-model transgenic mice (APP23 mouse), without a reduction in the brain β-amyloid level. Moreover, treatment of APP23 mice with olmesartan decreased oxidative stress in brain microvessels. Using an acute mouse model induced by ICV administration of β-amyloid 1-40, we assessed the effect of oral administration of olmesartan on spatial learning evaluated with the Morris water maze. Olmesartan significantly improved cognitive function independent of its blood pressure-lowering effect, whereas there was no improvement by other types of antihypertensive drugs (hydralazine and nifedipine). We found that pretreatment with a low dose of olmesartan completely prevented β-amyloid-induced vascular dysregulation and partially attenuated the impairment of hippocampal synaptic plasticity. These findings suggest the possibility that amelioration of cerebrovascular dysfunction with an angiotensin receptor blocker could be a novel therapeutic strategy for the early stage of Alzheimer disease.

Telmisartan-Induced Inhibition of Vascular Cell Proliferation Beyond Angiotensin Receptor Blockade and Peroxisome Proliferator-Activated Receptor-{gamma} Activation [Original Articles]

Yamamoto, K., Ohishi, M., Ho, C., Kurtz, T. W., Rakugi, H. — Wed, 18 Nov 2009 13:33:27 PST

We investigated the ability of angiotensin II type 1 (AT1) receptor blockers with peroxisome proliferator-activated receptor (PPAR)- agonist activity (telmisartan and irbesartan) and AT1 receptor blockers devoid of PPAR agonist activity (eprosartan and valsartan) to inhibit vascular cell proliferation studied in the absence of angiotensin II stimulation. Telmisartan and, to a lesser extent, irbesartan inhibited proliferation of human aortic vascular smooth muscle cells in a dose-dependent fashion, whereas eprosartan and valsartan did not. To investigate the role of PPAR in the antiproliferative effects of telmisartan, we studied genetically engineered NIH3T3 cells that express PPAR. Pioglitazone inhibited proliferation of NIH3T3 cells expressing PPAR but had little effect on control NIH3T3 cells that lack PPAR. In contrast, telmisartan inhibited proliferation equally in NIH3T3 with and without PPAR. Valsartan failed to inhibit proliferation of either cell line. In addition, telmisartan inhibited proliferation equally in aortic smooth muscle cells derived from mice with targeted knockout of PPAR in the smooth muscle and from control mice, whereas valsartan had no effect on cell proliferation. Telmisartan, but not valsartan, reduced phosphorylation of AKT but not extracellular signal–regulated kinase otherwise induced by exposure to serum of quiescent human smooth muscle cells, quiescent mice smooth muscle cells lacking PPAR, or quiescent Chinese hamster ovary-K1 cells lacking the AT1 receptor. In summary, the antiproliferative effects of telmisartan in the absence of exogenously supplemented angiotensin II involve more than just AT1 receptor blockade and do not require activation of PPAR. It might be postulated that inhibition of AKT activation is a mechanism mediating the antiproliferative effects of telmisartan, including in cells lacking AT1 receptors or PPAR.

Glutathione S-Transferase-{micro}1 Regulates Vascular Smooth Muscle Cell Proliferation, Migration, and Oxidative Stress [Original Articles]

Yang, Y., Parsons, K. K., Chi, L., Malakauskas, S. M., Le, T. H. — Wed, 18 Nov 2009 13:33:27 PST

Glutathione S-transferase-µ1, GSTM1, belongs to a superfamily of glutathione S-transferases that metabolizes a broad range of reactive oxygen species and xenobiotics. Across species, genetic variants that result in decreased expression of the Gstm1 gene are associated with increased susceptibility for vascular diseases, including atherosclerosis in humans. We previously identified Gstm1 as a positional candidate in our gene mapping study for susceptibility to renal vascular injury characterized by medial hypertrophy and hyperplasia of the renal vessels. To determine the role of Gstm1 in vascular smooth muscle cells (VSMCs), we isolated VSMCs from mouse aortas. We demonstrate that VSMCs from the susceptible C57BL/6 mice have reduced expression of Gstm1 mRNA and its protein product compared with that of the resistant 129 mice. After serum stimulation, C57BL/6 VSMCs proliferate and migrate at a much faster rate than 129 VSMCs. Furthermore, C57BL/6 VSMCs have higher levels of reactive oxygen species and exhibit exaggerated p38 mitogen-activated protein kinase phosphorylation after exposure to H₂O₂. To establish causality, we show that knockdown of Gstm1 by small interfering RNA results in increased proliferation of VSMCs in a dose-dependent manner, as well as in increased reactive oxygen species levels and VSMC migration. Moreover, Gstm1 small interfering RNA causes increased p38 mitogen-activated protein kinase phosphorylation and attenuates the antiproliferative effect of Tempol. Our data suggest that Gstm1 is a novel regulator of VSMC proliferation and migration through its role in handling reactive oxygen species. Genetic variants that cause a decremental change in expression of Gstm1 may permit an environment of exaggerated oxidative stress, leading to susceptibility to vascular remodeling and atherosclerosis.

Cardiovascular Responses to Hypothalamic Arcuate Nucleus Stimulation in the Rat: Role of Sympathetic and Vagal Efferents [Original Articles]

Nakamura, T., Bhatt, S., Sapru, H. N. — Wed, 18 Nov 2009 13:33:27 PST

Experiments were carried out in urethane-anesthetized, artificially ventilated, adult male Wistar rats. Microinjections (50 nL) of N-methyl-d-aspartic acid (1, 5, and 10 mmol/L), but not artificial cerebrospinal fluid, into the hypothalamic arcuate nucleus (ARCN) elicited increases in mean arterial pressure (5.7±0.5, 13.2±1.4, and 17.3±1.1 mm Hg, respectively) and heart rate (24.3±4.3, 49.3±5.2, and 75.2±8.0 bpm, respectively). ARCN stimulation was accomplished by microinjections of a maximally effective concentration of N-methyl-d-aspartic acid (10 mmol/L). The tachycardic responses to the ARCN stimulation were significantly attenuated after bilateral vagotomy. Intrathecal injections of ionotropic glutamate receptor (iGLUR) antagonists completely blocked pressor responses to the ARCN stimulation, whereas the tachycardic responses were significantly attenuated but not abolished. Intrathecal injections of iGLUR antagonists at T9 to T10, combined with bilateral vagotomy, completely blocked the tachycardic responses to ARCN stimulation. ARCN stimulation with N-methyl-d-aspartic acid elicited increased activities of the greater splanchnic nerve (91.7±14.8%) and the renal nerve (109.3±13%). Intrathecal injections of iGLURs at T9 to T10 blocked the increase in the greater splanchnic nerve activity in response to ARCN stimulation. These results indicate the following: (1) the chemical stimulation of the ARCN elicits increases in mean arterial pressure, greater splanchnic nerve and renal nerve activity, and heart rate; (2) the increases in mean arterial pressure and sympathetic nerve activity are mediated via the activation of spinal cord iGLURs; and (3) the increases in heart rate are mediated via the activation of spinal cord iGLURs and decreases in vagal input to the heart.

Dietary-Induced Obesity Hastens the Progression From Concentric Cardiac Hypertrophy to Pump Dysfunction in Spontaneously Hypertensive Rats [Original Articles]

Wed, 18 Nov 2009 13:33:27 PST

We explored whether dietary-induced obesity hastens the transition from concentric left ventricular (LV) hypertrophy to pump dysfunction in spontaneously hypertensive rats (SHRs) and the mechanisms thereof. After feeding rats a diet for 4 to 5 months, obesity was induced in SHRs and Wistar-Kyoto (WKY) control rats. Obesity was not associated with abnormal blood glucose control (glycosylated hemoglobin) or with increases in systolic blood pressure. However, in SHRs, but not in WKY rats, obesity was associated with a reduced LV chamber systolic function, as determined by echocardiography, and in isolated perfused heart studies. A marked increase in LV end diastolic diameter and a right shift in the LV diastolic pressure-volume relation were noted in obese SHRs but not in obese WKY rats. Moreover, LV intrinsic myocardial systolic function, as determined from the slope of the linearized LV systolic stress-strain relationship (LV myocardial end systolic elastance), was markedly reduced in obese as compared with lean SHRs, whereas LV myocardial end systolic elastance was maintained in obese WKY rats. Obesity increased LV weight, cardiomyocyte width, cardiomyocyte apoptosis (TUNEL), the activity of myocardial matrix metalloproteinases (zymography), and serum leptin concentrations in SHRs but not in WKY rats. In conclusion, SHRs are susceptible to the adverse effects of dietary-induced obesity on the heart, an effect that hastens the progression from concentric LV hypertrophy to pump dysfunction independent of blood pressure changes or alterations in glycosylated hemoglobin. This effect may be mediated through a proclivity of SHRs to developing both obesity-induced effects on cardiomyocyte apoptosis and activation of myocardial collagenases through leptin resistance and obesity-induced hypertrophy.

Endothelial Nitric Oxide Synthase Uncoupling and Perivascular Adipose Oxidative Stress and Inflammation Contribute to Vascular Dysfunction in a Rodent Model of Metabolic Syndrome [Original Articles]

Marchesi, C., Ebrahimian, T., Angulo, O., Paradis, P., Schiffrin, E. L. — Wed, 18 Nov 2009 13:33:27 PST

The metabolic syndrome represents a constellation of cardiovascular risk factors that promote the development of cardiovascular disease. Oxidative stress is a mediator of endothelial dysfunction and vascular remodeling. We investigated vascular dysfunction in the metabolic syndrome and the oxidant mechanisms involved. New Zealand obese (NZO) mice with metabolic syndrome and New Zealand black control mice were studied. NZO mice showed insulin resistance and increased visceral fat and blood pressure compared with New Zealand black mice. Mesenteric resistance arteries from NZO mice exhibited increased media:lumen ratio and media cross-sectional area, demonstrating hypertrophic vascular remodeling. Endothelium-dependent relaxation to acetylcholine, assessed by pressurized myography, was impaired in NZO mice, not affected by N^G-nitro-l-arginine methyl ester, inhibitor of endothelial NO synthase, and improved by the antioxidant Tempol, suggesting reduced NO bioavailability and increased oxidative stress. Dimer:monomer ratio of endothelial NO synthase was decreased in NZO mice compared with New Zealand black mice, suggesting endothelial NO synthase uncoupling. Furthermore, vascular superoxide and peroxynitrite production was increased, as well as adhesion molecule expression. Perivascular adipose tissue of NZO mice showed increased superoxide production and NADPH oxidase activity, as well as adipocyte hypertrophy, associated with inflammatory Mac-3–positive cell infiltration. Vasoconstriction to norepinephrine decreased in the presence of perivascular adipose tissue in New Zealand black mice but was unaffected by perivascular adipose tissue in NZO mice, suggesting loss of perivascular adipose tissue anticontractile properties. Our data suggest that this rodent model of metabolic syndrome is associated with perivascular adipose inflammation and oxidative stress, hypertrophic resistance artery remodeling, and endothelial dysfunction, the latter a result of decreased NO and enhanced superoxide generated by uncoupled endothelial NO synthase.

Role of Proinflammatory Cytokines and Redox Homeostasis in Exercise-Induced Delayed Progression of Hypertension in Spontaneously Hypertensive Rats [Original Articles]

Agarwal, D., Haque, M., Sriramula, S., Mariappan, N., Pariaut, R., Francis, J. — Wed, 18 Nov 2009 13:33:27 PST

Hypertension is a well-known risk factor for various cardiovascular diseases. Recently, exercise has been recommended as a part of lifestyle modification for all hypertensive patients. However, the precise mechanisms of exercise training (ExT)–induced effects on the development of hypertension are poorly understood. Therefore, we hypothesized that chronic ExT would delay the progression of hypertension in young spontaneously hypertensive rats (SHRs). In addition, we explored whether the beneficial effects of chronic ExT were mediated by reduced proinflammatory cytokines and improved redox status. We also investigated the involvement of nuclear factor-B in exercise-induced effects. To test our hypotheses, young normotensive (Wistar-Kyoto) and SHRs were given moderate-intensity ExT for 16 weeks. Blood pressure was determined by the tail-cuff method, and cardiac function was assessed by echocardiography. Myocardial total reactive oxygen species and superoxide production were measured by electron paramagnetic resonance spectroscopy; tumor necrosis factor-, interleukin-1β, gp91^phox, and inducible NO synthase by real-time PCR; and nuclear factor B activity by electrophoretic mobility shift assay. Chronic ExT in hypertensive rats resulted in significantly reduced blood pressure, reduced concentric hypertrophy, and improved diastolic function. ExT significantly reduced proinflammatory cytokines and inducible NO synthase, attenuated total reactive oxygen species and superoxide production, and increased antioxidants in SHRs. ExT also resulted in increased NO production and decreased nuclear factor B activity in SHRs. In summary, chronic ExT delays the progression of hypertension and improves cardiac function in young SHRs; these ExT-induced beneficial effects are mediated by reduced proinflammatory cytokines and improved redox homeostasis via downregulation of nuclear factor-B.

Mice Overexpressing Both Human Angiotensinogen and Human Renin as a Model of Superimposed Preeclampsia on Chronic Hypertension [Original Articles]

Wed, 18 Nov 2009 13:33:27 PST

Preeclampsia is the major cause of maternal and fetal mortality/morbidity. Because hypertension is an important risk factor for preeclampsia, we investigated whether hypertensive mice that overexpress human renin and angiotensinogen develop superimposed preeclampsia. Given that the mechanisms underlying this disease are still poorly understood, animal models are of great use for elucidatation. Blood pressure and proteinuria were measured by telemetry and ELISA, respectively. Heart function was evaluated by echocardiography, whereas pathological cardiac hypertrophy–related genes were assessed by real-time PCR. Soluble fms-like tyrosine kinase 1 plasma concentrations were quantitated by ELISA and placental expression by real-time PCR. Transgenic mice develop de novo proteinuria during gestation and marked blood pressure elevation, which are hallmarks of superimposed preeclampsia on chronic hypertension. Abnormal placentation present in these mothers produced a significant decrease in pup and placental weight and was associated with an increased placental expression of soluble fms-like tyrosine kinase 1. We also found heightened circulating levels of this receptor, when adjusted for placental mass, as has been observed in women who suffer from preeclampsia. Cardiac hypertrophy could be observed in the transgenic mice and was exacerbated by gestation. As a result, heart function was significantly decreased, and markers of pathological hypertrophy were increased. Our data, thus, confirm the characterization of a new model of superimposed preeclampsia on chronic hypertension. Because chronically hypertensive women are at risk of developing the pathology, our model reflects a clinical reality and is, thus, an excellent tool to elucidate the molecular mechanisms triggering this disease.

Relationship of Carotid Distensibility and Thoracic Aorta Calcification: Multi-Ethnic Study of Atherosclerosis [Original Articles]

Wed, 18 Nov 2009 13:33:27 PST

Stiffening of the central elastic arteries is one of the earliest detectable manifestations of adverse change within the vessel wall. Although an association between carotid artery stiffness and adverse events has been demonstrated, little is known about the relationship between stiffness and atherosclerosis. Even less is known about the impact of age, sex, and race on this association. To elucidate this question, we used baseline data from the Multi-Ethnic Study of Atherosclerosis (2000–2002). Carotid artery distensibility coefficient was calculated after visualization of the instantaneous waveform of the common carotid diameter using a high-resolution B-mode ultrasound. Thoracic aorta calcification was identified using noncontrast cardiac computed tomography. We found a strong association between decreasing distensibility coefficient (increasing carotid stiffness) and increasing thoracic aorta calcification, as well as a graded increase in the thoracic aorta calcification score (P<0.001). After controlling for age, sex, race, and traditional and emerging cardiovascular risk factors, individuals in the stiffest quartile had a prevalence ratio of 1.52 (95% CI: 1.15 to 2.00) for thoracic aorta calcification compared with the least stiff quartile. In exploratory analysis, carotid stiffness was more highly correlated with calcification of the aorta than calcification of the coronary arteries (=0.32 versus 0.22; P<0.001 for comparison). In conclusion, there is a strong independent association between carotid stiffness and thoracic aorta calcification. Carotid stiffness is more highly correlated with calcification of the aorta, a central elastic artery, than calcification of the coronary arteries. The prognostic significance of these findings requires longitudinal follow-up of the Multi-Ethnic Study of Atherosclerosis cohort.

Relation of Serum Leptin to Blood Pressure of Japanese in Japan and Japanese-Americans in Hawaii [Original Articles]

Wed, 18 Nov 2009 13:33:27 PST

Data from animal studies clearly indicate an association between leptin and hypertension; results of human studies are less concordant. We investigated the role of leptin in obesity-related higher blood pressure (BP) in Japanese Americans living in Hawaii and Japanese in Japan. Serum leptin and BP were examined by standardized methods in men and women ages 40 to 59 years from 2 population samples, one Japanese American in Hawaii (88 men and 94 women) and the other Japanese in central Japan (123 men and 111 women). Multiple linear regression models were used to assess role of leptin in obesity-related higher BP. Across quartiles of leptin, there were significantly higher mean body mass index levels, systolic BP, and diastolic BP for both sexes and sites (P<0.01 to 0.02). In multivariate regression analyses using all of the data combined, relations of body mass index and leptin to systolic BP and diastolic BP remained significant with the interaction term (body mass indexxlog-leptin) in the models (P<0.01 to <0.05). These findings are consistent with the inference that leptin may be an independent mediator for obesity-related elevations in BP.

Validation of a Case Definition to Define Hypertension Using Administrative Data [Original Articles]

Wed, 18 Nov 2009 13:33:27 PST

We validated the accuracy of case definitions for hypertension derived from administrative data across time periods (year 2001 versus 2004) and geographic regions using physician charts. Physician charts were randomly selected in rural and urban areas from Alberta and British Columbia, Canada, during years 2001 and 2004. Physician charts were linked with administrative data through unique personal health number. We reviewed charts of 50 randomly selected patients >35 years of age from each clinic within 48 urban and 16 rural family physician clinics to identify physician diagnoses of hypertension during the years 2001 and 2004. The validity indices were estimated for diagnosed hypertension using 3 years of administrative data for the 8 case-definition combinations. Of the 3362 patient charts reviewed, the prevalence of hypertension ranged from 18.8% to 33.3%, depending on the year and region studied. The administrative data hypertension definition of "2 claims within 2 years or 1 hospitalization" had the highest validity relative to the other definitions evaluated (sensitivity 75%, specificity 94%, positive predictive value 81%, negative predictive value 92%, and 0.71). After adjustment for age, sex, and comorbid conditions, the sensitivities between regions, years, and provinces were not significantly different, but the positive predictive value varied slightly across geographic regions. These results provide evidence that administrative data can be used as a relatively valid source of data to define cases of hypertension for surveillance and research purposes.

Home Blood Pressure Measurements Will or Will Not Replace 24-Hour Ambulatory Blood Pressure Measurement [Letters to the Editor]

O'Brien, E. — Wed, 21 Oct 2009 13:34:01 PDT

Response to Home Blood Pressure Measurements Will or Will Not Replace 24-Hour Ambulatory Blood Pressure Measurement [Letters to the Editor]

Parati, G., Bilo, G. — Wed, 21 Oct 2009 13:34:01 PDT

Response to Home Blood Pressure Measurements Will or Will Not Replace 24-Hour Ambulatory Blood Pressure Measurement [Letters to the Editor]

Verdecchia, P., Angeli, F., Mazzotta, G., Gentile, G., Reboldi, G. — Wed, 21 Oct 2009 13:34:01 PDT

Flawed Measurement of Brachial Tonometry for Calculating Aortic Pressure? [Letters to the Editor]

O'Rourke, M. F., Takazawa, K. — Wed, 21 Oct 2009 13:34:01 PDT

Response to Flawed Measurement of Brachial Tonometry for Calculating Aortic Pressure? [Letters to the Editor]

Segers, P., Mahieu, D., Kips, J., Rietzschel, E., De Buyzere, M., Van Bortel, L. — Wed, 21 Oct 2009 13:34:01 PDT

Long-Term Risk in Subjects With White-Coat Hypertension [Letters to the Editor]

Obara, T., Ohkubo, T., Imai, Y. — Wed, 21 Oct 2009 13:34:01 PDT

Response to Long-Term Risk in Subjects With White-Coat Hypertension [Letters to the Editor]

Wed, 21 Oct 2009 13:34:01 PDT

A Novel Measurement Index for Antihypertensive Medication Burden and Its Use [Letters to the Editor]

Wan, S.-H., Hart, M., Hajjar, I. — Wed, 21 Oct 2009 13:34:01 PDT

Determination of Travel Distance for Noninvasive Measurement of Pulse Wave Velocity: Case Closed? [Letters to the Editor]

Weber, T., Rammer, M., Eber, B., O'Rourke, M. F. — Wed, 21 Oct 2009 13:34:01 PDT

Correction [Corrections]

Wed, 21 Oct 2009 13:34:01 PDT

Thomas G. Pickering: 1940-2009 [In Memoriam]

White, W. B. — Wed, 21 Oct 2009 13:33:58 PDT

Noninvasive Assessment of Subclinical Atherosclerosis in Children and Adolescents: Recommendations for Standard Assessment for Clinical Research: A Scientific Statement From the American Heart Association [AHA Scientific Statement]

Wed, 21 Oct 2009 13:33:58 PDT

Deterioration in endothelial function and arterial stiffness are early events in the development of cardiovascular diseases. In adults, noninvasive measures of atherosclerosis have become established as valid and reliable tools for refining cardiovascular risk to target individuals who need early intervention. With limited pediatric data, the use of these techniques in children and adolescents largely has been reserved for research purposes. Therefore, this scientific statement was written to (1) review the current literature on the noninvasive assessment of atherosclerosis in children and adolescents, (2) make recommendations for the standardization of these tools for research, and (3) stimulate further research with a goal of developing valid and reliable techniques with normative data for noninvasive clinical evaluation of atherosclerosis in pediatric patients. Precise and reliable noninvasive tests for atherosclerosis in youth will improve our ability to estimate future risk for heart attack and stroke. Currently, large longitudinal studies of cardiovascular risk factors in youth, such as the Bogalusa and Muscatine studies, lack sufficient adult subjects experiencing hard outcomes, such as heart attack and stroke, to produce meaningful risk scores like those developed from Framingham data.

The Choice of Thiazide Diuretics: Why Chlorthalidone May Replace Hydrochlorothiazide [Editorials]

Kaplan, N. M. — Wed, 21 Oct 2009 13:33:58 PDT

Does Prehypertension Represent an Increased Risk for Incident Hypertension and Adverse Cardiovascular Outcome? [Editorial Commentaries]

Glasser, S. P., Basile, J. N., Lackland, D. T. — Wed, 21 Oct 2009 13:33:58 PDT

Newly Reported Hypertension After Military Combat Deployment: Research Implications From a Biopsychosocial Perspective [Editorial Commentaries]

Jorgensen, R. S. — Wed, 21 Oct 2009 13:33:58 PDT

Wave Intensity Analysis and Central Blood Pressure [Editorial Commentaries]

Cameron, J. D. — Wed, 21 Oct 2009 13:33:59 PDT

Exogenous Ghrelin on Nitric Oxide-Endothelin 1 Imbalance in Metabolic Syndrome: Can We Kill 2 Birds With 1 Stone? [Editorial Commentaries]

Taddei, S., Virdis, A. — Wed, 21 Oct 2009 13:33:59 PDT

Yes, No, Maybe So: ENaC Proteins as Mediators of Renal Myogenic Constriction [Editorial Commentaries]

Drummond, H. A. — Wed, 21 Oct 2009 13:33:59 PDT

A New PIXel in the Puzzle: How Increased Vascular Pressure Induces Oxidative Stress [Editorial Commentaries]

Brandes, R. P. — Wed, 21 Oct 2009 13:33:59 PDT

Newly Reported Hypertension After Military Combat Deployment in a Large Population-Based Study [Original Articles]

Wed, 21 Oct 2009 13:33:59 PDT

High-stress situations, such as combat deployments, are a potential risk factor for hypertension. Although stress is postulated to increase blood pressure, the underlying role of stress on hypertension is not well established. We sought to determine the relations between combat deployment–induced stress and hypertension. The Millennium Cohort baseline questionnaire (2001–2003) was completed by 77 047 US active-duty and Reserve/National Guard members. Follow-up was completed by 55 021 responders 3 years later (2004–2006). Multivariable logistic regression was used to estimate the 3-year risk of newly reported hypertension, adjusting for general and mental health, demographics, and occupational and behavioral characteristics. After applying exclusion criteria, our analyses included 36 061 service members. Subanalyses of deployers included 8829 participants. Newly reported hypertension was identified in 6.9% of the cohort between baseline and follow-up, many of whom had deployed on military operations in support of the conflicts in Iraq and Afghanistan. After adjusting, deployers who experienced no combat exposures were less likely to report hypertension than nondeployers (odds ratio: 0.77; 95% CI: 0.67 to 0.89). Among deployers, those reporting multiple combat exposures were 1.33 times more likely to report hypertension compared with noncombat deployers (95% CI: 1.07 to 1.65). Although military deployers, in general, had a lower incidence of hypertension than nondeployers, deployment with multiple stressful combat exposures appeared to be a unique risk factor for newly reported hypertension.

Cardiovascular and Metabolic Predictors of Progression of Prehypertension Into Hypertension: The Strong Heart Study [Original Articles]

Wed, 21 Oct 2009 13:33:59 PDT

Prehypertension (defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) frequently evolves to hypertension (HTN) and increases cardiovascular risk. It is unclear whether metabolic and/or cardiac characteristics favor development of HTN in prehypertensive subjects. We evaluated baseline anthropometric, laboratory, and echocardiographic characteristics of 625 untreated prehypertensive participants in the Strong Heart Study, without prevalent cardiovascular disease (63% women; 22% with diabetes mellitus; mean age: 59±7 years) to identify predictors of the 4-year incidence of HTN. Diabetes mellitus was assessed by American Diabetic Association criteria, and a diabetes-specific definition of HTN was used. Four-year incidence of HTN was 38%. Incident HTN was independently predicted by baseline systolic blood pressure (odds ratio [OR]: 1.60 per 10 mm Hg; 95% CI: 1.30 to 2.00; P<0.0001), waist circumference (OR: 1.10 per 10 cm; 95% CI: 1.01 to 1.30; P=0.04), and diabetes mellitus (OR: 2.73; 95% CI=1.77 to 4.21; P<0.0001), with no significant effect for age, sex, hemoglobin A1c, homeostatic model assessment index, C-reactive protein, fibrinogen, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides, plasma creatinine, or urine albumin:creatinine ratio. Higher left ventricular mass index (OR: 1.15 per 5 g/m^2.7; 95% CI: 1.01 to 1.25; P=0.03) or stroke volume index (OR: 1.25 per 5 mL/m^2.04; 95% CI: 1.10 to 1.50; P=0.03) was also identified, together with baseline systolic blood pressure and the presence of diabetes mellitus, as an independent predictor of incident HTN, without an additional predictive contribution from other anthropometric, metabolic, or echocardiographic parameters (all P>0.10). Thus, progression to HTN in 38% of Strong Heart Study prehypertensive participants could be predicted by higher left ventricular mass and stroke volume in addition to baseline systolic blood pressure and prevalent diabetes mellitus.

Environmental Mercury Exposure and Blood Pressure Among Nunavik Inuit Adults [Original Articles]

Valera, B., Dewailly, E., Poirier, P. — Wed, 21 Oct 2009 13:33:59 PDT

Epidemiological evidence suggests a negative impact of methylmercury on the cardiovascular system, but findings regarding the effect on blood pressure (BP) are not consistent. We aimed to study the impact of mercury levels on BP among Nunavik Inuit adults. The health survey Qanuippitaa? was conducted in Nunavik (northern Quebec, Canada), and data were obtained from 732 Inuit ≥18 years of age. Anthropometric blood samples, as well as systolic BP and diastolic BP, were assessed. Pulse pressure (systolic BP–diastolic BP) was calculated. Mercury blood concentration was used as a biomarker of recent exposure. Simple relations between mercury and BP parameters were studied by using the Pearson correlation, whereas multiple regressions were performed to control for confounders. Mean age of the participants was 34.3 years (95% CI: 33.6 to 34.9 years). Systolic BP, diastolic BP, and pulse pressure means were 117 mm Hg (95% CI: 116 to 118 mm Hg), 73 mm Hg (95% CI: 72 to 74 mm Hg), and 43 mm Hg (95% CI: 42 to 44 mm Hg), respectively. Mercury mean was 50.2 nmol/L. In multivariable analyses, mercury was associated with systolic BP (β=2.14; P=0.0004), whereas the association with diastolic BP was near the significance level (β=0.96; P=0.069). In conclusion, mercury is associated with increasing BP and pulse pressure among Nunavik Inuit adults after considering the effect of fish nutrients (n-3 fatty acids and selenium) and other confounders.

Early Progression of the Autonomic Dysfunction Observed in Pediatric Type 1 Diabetes Mellitus [Original Articles]

Wed, 21 Oct 2009 13:33:59 PDT

To focus on early cardiac and vascular autonomic dysfunction that might complicate type 1 diabetes mellitus in children, we planned an observational, cross-sectional study in a population of 93 young patients, under insulin treatment, subdivided in 2 age subgroups (children: 11.5±0.4 years; adolescents: 19.3±0.2 years). Time and frequency domain analysis of RR interval and systolic arterial pressure variability provided quantitative indices of the sympatho-vagal balance regulating the heart period, of the gain of cardiac baroreflex, and of the sympathetic vasomotor control. Sixty-eight children of comparable age served as a reference group. At rest, systolic arterial pressure and the power of its low-frequency component were greater in patients than in controls, particularly in children (14.0±2.3 versus 3.1±0.3 mm Hg²). Moreover, baroreflex gain was significantly reduced in both subgroups of patients. Standing induced similar changes in the autonomic profiles of controls and patients. A repeat study after 1 year showed a progression in low-frequency oscillations of arterial pressure and a shift toward low frequency in RR variability. Data in young patients with type 1 diabetes mellitus show a significant increase in arterial pressure, a reduced gain of the baroreflex regulation of the heart period, and an increase of the low-frequency component of systolic arterial pressure variability, suggestive of simultaneous impairment of vagal cardiac control and increases of sympathetic vasomotor regulation. A repeat study after 1 year shows a further increase of sympathetic cardiac and vascular modulation, suggesting early progression of the autonomic dysfunction.

Ghrelin Restores the Endothelin 1/Nitric Oxide Balance in Patients With Obesity-Related Metabolic Syndrome [Original Articles]

Wed, 21 Oct 2009 13:33:59 PDT

Obesity is associated with endothelial dysfunction related to decreased NO bioavailability, increased endothelin 1 vasoconstrictor activity, and decreased circulating ghrelin. Therefore, we tested whether exogenous ghrelin may have benefits to improve the balance between endothelin 1 and NO in patients with obesity-related metabolic syndrome. Vasoactive actions of endothelin 1 and NO were assessed in 8 patients with metabolic syndrome and 8 matched controls by evaluating forearm blood flow responses (strain-gauge plethysmography) to intra-arterial infusion of BQ-123 (endothelin A receptor antagonist; 10 nmol/min), followed by N^G-monomethyl-l-arginine (NO synthase inhibitor; 4 µmol/min), before and after infusion of ghrelin (200 ng/min). In the absence of ghrelin, the vasodilator response to BQ-123 was greater in patients than in controls (P<0.001), whereas infusion of N^G-monomethyl-l-arginine induced smaller vasoconstriction in patients than in controls (P=0.006). Importantly, exogenous ghrelin decreased the vasodilator response to BQ-123 (P=0.007 versus saline) and enhanced the magnitude of changes in forearm blood flow induced by N^G-monomethyl-l-arginine (P=0.003) in patients but not in controls (both P>0.05). The favorable effect of ghrelin on endothelin A–dependent vasoconstriction was likely related to the stimulation of NO production, because no change in the vascular effect of BQ-123 was observed after ghrelin (P=0.44) in 5 patients with metabolic syndrome during continuous infusion of the NO donor sodium nitroprusside (0.2 µg/min). In patients with metabolic syndrome, ghrelin has benefits to normalize the balance between vasoconstrictor (endothelin 1) and vasodilating (NO) mediators, thus suggesting that this peptide has important peripheral actions to preserve vascular homeostasis in humans.

Leptin Impairs Cardiovagal Baroreflex Function at the Level of the Solitary Tract Nucleus [Original Articles]

Arnold, A. C., Shaltout, H. A., Gallagher, P. E., Diz, D. I. — Wed, 21 Oct 2009 13:33:59 PDT

Circulating leptin is elevated in some forms of obesity-related hypertension, associated with impaired baroreflex function. Leptin receptors are present on vagal afferent fibers and neurons within the solitary tract nucleus, providing an anatomic distribution consistent with baroreflex modulation. Although solitary tract nucleus microinjection of 144 fmol/60 nL of leptin had no significant effect on baroreflex sensitivity for control of the heart rate in urethane/chloralose-anesthetized Sprague-Dawley rats, 500 fmol of leptin impaired baroreflex sensitivity for bradycardia in response to increases in pressure (1.15±0.04 versus 0.52±0.12 ms/mm Hg; P<0.01). Transgenic ASrAOGEN rats with low brain angiotensinogen have an upregulation of the leptin receptor and p85 mRNA in the dorsal medulla relative to Sprague-Dawley rats. Consistent with these observations, the response to leptin was enhanced in ASrAOGEN rats, because both the 144-fmol (1.46±0.08 versus 0.75±0.10 ms/mm Hg; P<0.001) and 500-fmol (1.36±0.32 versus 0.44±0.06 ms/mm Hg; P<0.05) leptin microinjections impaired baroreflex sensitivity. At these doses, leptin microinjection had no effect on resting pressure, heart rate, or the tachycardic response to decreases in pressure in Sprague-Dawley or ASrAOGEN rats. Thus, exogenous leptin at sites within the solitary tract nucleus impairs the baroreflex sensitivity for bradycardia induced by increases in arterial pressure, consistent with a permissive role in mediating increases in arterial pressure. Baroreflex inhibition was enhanced in animals with evidence of increased leptin receptor and relevant signaling pathway mRNA.

Atorvastatin Treatment Is Associated With Less Augmentation of the Carotid Pressure Waveform in Hypertension: A Substudy of the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) [Original Articles]

Wed, 21 Oct 2009 13:33:59 PDT

Hydroxymethylglutaryl-CoA reductase inhibitors (statins) reduce cardiovascular events in hypertensive subjects, but their effect on carotid BP, pressure augmentation, and wave reflection is unknown. We compared the effect of atorvastatin with placebo in a substudy of the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA). Hypertensive patients (n=142; age=43 to 79 years; 127 male) with total cholesterol ≤6.5 mmol/L were randomized to atorvastatin 10 mg or placebo. Carotid BP and flow velocity were measured by tonometry and Doppler ultrasound. Augmentation index (carotid AI_x) was calculated, and waveforms were separated into backward and forward components by wave intensity analysis. Brachial BP was similar in atorvastatin and placebo groups. Carotid AI_x and augmentation pressure were significantly less in patients randomized to atorvastatin (mean [SD]: 21.7 [12.1] versus 25.9 [10.3] %; P=0.027 and 10.2 [6.5] versus 13.1 [6.6] mm Hg; P=0.016, respectively), and atorvastatin treatment was associated with significantly less wave reflection from the body. Carotid systolic BP was slightly lower in the atorvastatin group, but there was a statistically significant interaction between lipid-lowering and antihypertensive regimen with lower carotid systolic BP in patients randomized to amlodipine-based therapy and atorvastatin. Carotid wave velocity, timings of waves, and wave intensities did not differ significantly between atorvastatin and placebo groups. Atorvastatin treatment is associated with less augmentation of the carotid BP waveform and less wave reflection from the body. This could contribute to the reduction in risk of cardiovascular events by statins.

Effect of Cardiorespiratory Fitness on Vascular Regulation and Oxidative Stress in Postmenopausal Women [Original Articles]

Pialoux, V., Brown, A. D., Leigh, R., Friedenreich, C. M., Poulin, M. J. — Wed, 21 Oct 2009 13:33:59 PDT

Increasing evidence exists suggesting an important role for oxidative stress in the pathogenesis and progression of hypertension in women via a decrease of NO production after menopause. Regular physical training has been shown to upregulate antioxidant enzymatic systems, which may slow down the usual increase of oxidative stress in postmenopausal women. The aims of this study were to determine the impact of fitness status on enzymatic antioxidant efficiency, oxidative stress, and NO production and to determine the associations among oxidative stress, enzymatic antioxidant and NO production, mean arterial blood pressure (MABP), and cerebrovascular conductance (CVC) in postmenopausal women (n=40; 50 to 90 years old). Physical fitness, physical activity, resting MABP, and CVC were measured. End product of NO, lipid peroxidation (malondialdehyde and 8-iso-prostaglandin F2), DNA oxidation (8-hydroxy-2'-deoxyguanosine), protein nitration (nitrotyrosine), antioxidant glutathione peroxidase, and catalase activities were measured in plasma. We identified significant negative associations between oxidative stress and indices of physical fitness (malondialdehyde: r=–0.33, P<0.05; 8-iso-prostaglandin F2: r=–0.39, P<0.05; 8-hydroxy-2'-deoxyguanosine: r=–0.35, P<0.05) and physical activity (malondialdehyde: r=–0.30, P<0.05; 8-iso-prostaglandin F2: r=–0.41, P<0.01; 8-hydroxy-2'-deoxyguanosine: r=–0.39, P<0.05). Conversely, glutathione peroxidase was positively correlated with fitness level (r=0.55; P<0.01). Finally, MABP and CVC were significantly associated with 8-hydroxy-2'-deoxyguanosine (MABP: r=0.36, P<0.05; CVC: r=–0.36, P<0.05), nitrotyrosine (MABP: r=0.39, P<0.05; CVC: r=–0.32, P<0.05), and the end product of NO (MABP: r=–0.57, P<0.01; CVC: r=0.44, P<0.01). These findings demonstrate that, after menopause, fitness level and regular physical activity mediate against oxidative stress by maintaining antioxidant enzyme efficiency. Furthermore, these results suggest that oxidative stress and NO production modulate MABP and CVC.

Arterial Wave Reflections During the Menstrual Cycle of Healthy Women: A Reproducibility Study [Original Articles]

Wed, 21 Oct 2009 13:33:59 PDT

Increased wave reflection is an independent factor associated with cardiovascular diseases, risk, and mortality. The influence of the menstrual cycle on wave reflections and particularly on the reproducibility of their measurement has never been examined. The aim of the present study was to examine the reproducibility and variability of wave reflection indices in premenopausal healthy women during their menstrual cycle. Thirty-two women were examined at 3 phases of their menstrual cycle: days 1 to 2 (menstrual phase), days 6 to 14 (late follicular), and days 4 to 7 after ovulation (early luteal phase). Applanation tonometry of the radial artery and aortic pulse wave analysis were performed for the calculation of augmentation pressure, augmentation index, and timing of reflected waves. Reproducibility of these measures was evaluated by intraclass correlation coefficient and Bland-Altman analysis, whereas ANOVA was performed to assess their variability during the menstrual cycle. The SD of augmentation index differences between repeated measurements within the menstrual cycle ranged from 7.6% to 9.9%. Bland-Altman analysis indicated no evidence of systemic bias and no trend for the reproducibility of measurements to vary with their underlying mean value. Intraclass correlation coefficient indicated a moderate reproducibility of augmentation index and augmentation pressure (>0.80) and a rather low reproducibility for timing of reflected waves (0.43). Mean augmentation pressure, augmentation index, and timing of reflected waves did not vary significantly during the menstrual cycle (ANOVA). Measurement of wave reflections at the same phase of the menstrual cycle or statistical adjustment could be suggested for optimal study design and data interpretation.

Pressure-Induced Vascular Oxidative Stress Is Mediated Through Activation of Integrin-Linked Kinase 1/{beta}PIX/Rac-1 Pathway [Original Articles]

Wed, 21 Oct 2009 13:33:59 PDT

High blood pressure induces a mechanical stress on vascular walls and evokes oxidative stress and vascular dysfunction. The aim of this study was to characterize the intracellular signaling causing vascular oxidative stress in response to pressure. In carotid arteries subjected to high pressure levels, we observed not only an impaired vasorelaxation, increased superoxide production, and NADPH oxidase activity, but also a concomitant activation of Rac-1, a small G protein. Selective inhibition of Rac-1, with an adenovirus carrying a dominant-negative Rac-1 mutant, significantly reduced NADPH oxidase activity and oxidative stress and, more importantly, rescued vascular function in carotid arteries at high pressure. The analysis of molecular events associated with mechanotransduction demonstrated at high pressure levels an overexpression of integrin-linked kinase 1 and its recruitment to plasma membrane interacting with paxillin. The inhibition of integrin-linked kinase 1 by small interfering RNA impaired Rac-1 activation and rescued oxidative stress–induced vascular dysfunction in response to high pressure. Finally, we showed that βPIX, a guanine-nucleotide exchange factor, is the intermediate molecule recruited by integrin-linked kinase 1, converging the intracellular signaling toward Rac-1–mediated oxidative vascular dysfunction during pressure overload. Our data demonstrate that biomechanical stress evoked by high blood pressure triggers an integrin-linked kinase 1/βPIX/Rac-1 signaling, thus generating oxidative vascular dysfunction.

Hepatocyte gp130 Deficiency Reduces Vascular Remodeling After Carotid Artery Ligation [Original Articles]

Wed, 21 Oct 2009 13:34:00 PDT

Inflammation and vascular remodeling are hallmarks of atherosclerosis, hypertension, and restenosis after angioplasty. Here we investigated the role of the hepatocyte gp130-dependent systemic acute phase response on vascular remodeling after carotid artery ligation. Mice with a hepatocyte-specific gp130 knockout on an apolipoprotein E^–/– background (gp130^–) were compared with control mice (gp130^flox). Vascular remodeling was induced by permanent ligation of the left common carotid artery. This, in turn, activated the systemic acute phase reaction in gp130^flox mice, as measured by serum amyloid A plasma levels, which was completely abrogated in gp130^– mice (P<0.05). Morphometric analysis of the carotid artery revealed severe neointima formation and media thickening 28 days after ligation in gp130^flox mice, which was suppressed in gp130^– mice (P<0.01). Serial sections from gp130^– carotid segments showed significantly less smooth muscle cell (SMC) proliferation and monocyte recruitment (P<0.01). To evaluate the impact of the gp130-dependent systemic acute phase response on SMCs, hepatocytes from gp130^flox and gp130^– mice were stimulated with interleukin 6. Interleukin 6–induced secretion of serum amyloid A was completely abolished in gp130^– hepatocytes (P<0.01). Moreover, when stimulated with supernatants from gp130^– hepatocytes, SMCs showed significantly less migration and proliferation compared with supernatants from gp130^flox hepatocytes (P<0.01). Recombinant serum amyloid A induced SMC migration and proliferation (P<0.05) and serum amyloid A injection after carotid artery ligation restored vascular remodeling in gp130^– mice (P<0.01). These results imply a critical role for the gp130-dependent systemic acute phase response for vascular inflammation and SMC migration, as well as proliferation, and, subsequently, for vascular remodeling.

Sildenafil Increases Endothelial Progenitor Cell Function and Improves Ischemia-Induced Neovascularization in Hypercholesterolemic Apolipoprotein E-Deficient Mice [Original Articles]

Wed, 21 Oct 2009 13:34:00 PDT

Hypercholesterolemia is associated with impaired neovascularization in response to ischemia. Potential mechanisms include defective NO bioactivity and a reduction in the number/function of endothelial progenitor cells (EPCs). Here we tested the hypothesis that sildenafil, a phosphodiesterase 5 inhibitor that increases NO-driven cGMP levels, could stimulate EPC function and improve ischemia-induced neovascularization in hypercholesterolemic conditions. Apolipoprotein E–deficient (ApoE^–/–) mice were treated (or not treated) with sildenafil (40 mg/kg per day in water), and hindlimb ischemia was surgically induced by femoral artery removal. Sildenafil treatment led to an improved blood flow recovery, an increased capillary density, and a reduction of oxidative stress levels in ischemic muscles at day 7 after surgery. Sildenafil therapy is associated with an increased activation of angiogenic transduction pathways, including Akt, p44/42 mitogen-activated protein kinase, and p38. In vitro, sildenafil increases cellular migration and tubule formation of mature endothelial cells (human umbilical vascular endothelial cells) in a cGMP-dependent manner. In vivo, ApoE^–/– mice treated with sildenafil exhibit a significant increase in the number of bone marrow–derived EPCs. Moreover, the angiogenic activities of EPCs (migration and adhesion) are significantly improved in ApoE^–/– mice treated with sildenafil. In summary, this study demonstrates that sildenafil treatment is associated with improved ischemia-induced neovascularization in hypercholesterolemic ApoE^–/– mice. The mechanisms involve beneficial effects on angiogenic transduction pathways together with an increase in the number and the functional activity of EPCs. Sildenafil could constitute a novel therapeutic strategy to reduce tissue ischemia in atherosclerotic diseases.

Hypertension Correlates With Lenticulostriate Arteries Visualized by 7T Magnetic Resonance Angiography [Original Articles]

Wed, 21 Oct 2009 13:34:00 PDT

Hypertension, a major risk factor for stroke, is associated with altered arterial anatomy and function; however, the limited resolution of current imaging techniques has restricted the in vivo study of microvascular changes in the brain. In this report, we quantitatively examined the lenticulostriate arteries in hypertensive patients using ultrahigh-field 7T MRI. We compared the number of stems and branches, curvature, and tortuosity of the lenticulostriate arteries by 3D time-of-flight magnetic resonance angiography among 20 hypertensive patients (mean age: 46.6±9.1 years) and 20 age-matched healthy subjects (mean age: 47.7±8.1 years). The average numbers of stems and branches in hypertensive patients were significantly less than those of healthy subjects (P<0.002). However, this difference was abolished in older volunteers (>45 years old), whereas the difference between young hypertensive patients (≤45 years old) and age-matched healthy controls was augmented by 55% for stems and 91% for branches (P=0.001). In comparison, there were no differences in the average curvature and tortuosity of the lenticulostriate arteries and no significant difference when corrected for smoking (P=0.064). In conclusion, our results showed that there was a substantial difference in the lenticulostriate arteries of hypertensive patients compared with healthy individuals when observed in vivo by ultrahigh-resolution 7T magnetic resonance angiography, and the difference was considerable in young subjects.

Renal Impairment of Pure Autonomic Failure [Original Articles]

Wed, 21 Oct 2009 13:34:00 PDT

Supine hypertension is difficult to manage in patients with pure autonomic failure (PAF), because treatment can worsen orthostatic hypotension. Supine hypertension in PAF has been associated with left ventricular hypertrophy, but end organ damage in the kidney has not been assessed. We reviewed hemodynamic and laboratory data of 64 male patients with PAF who were 69±11 (mean±SD) years old. Systolic blood pressure fell by 67±40 mm Hg within 10 minutes of standing, with an inappropriately low 13±11-bpm increase in heart rate. Plasma norepinephrine levels were below normal (0.62±0.32 nmol/L supine and 1.28±1.25 nmol/L standing). A control data set of 75 men (67±12 years) was obtained from a deidentified version of the Vanderbilt University Medical Center electronic medical chart database. Compared with controls, PAF patients had lower hemoglobin (8.3±0.9 versus 9.3±0.8 mmol/L; P<0.001), packed cell volume (0.40±0.04 versus 0.45±0.04; P<0.001), and red blood cell count (4.4±0.5x10¹² versus 5.0±0.5x10¹² cells/L; P<0.001). Serum creatinine and blood urea nitrogen levels were elevated in patients. Forty-eight percent of patients with PAF had supine hypertension (supine systolic blood pressure: ≥150 mm Hg). Serum creatinine was higher in patients with supine hypertension (133±44 versus 106±27 µmol/L; P=0.021) and estimated glomerular filtration rate was lower (57±22 versus 70±20 mL/min per 1.73 m²; P=0.022) compared with patients who did not have supine hypertension. These findings may indicate that renal function is diminished in PAF in association with supine hypertension.

Effect of Epithelial Sodium Channel Blockade on the Myogenic Response of Rat Juxtamedullary Afferent Arterioles [Original Articles]

Guan, Z., Pollock, J. S., Cook, A. K., Hobbs, J. L., Inscho, E. W. — Wed, 21 Oct 2009 13:34:00 PDT

The mechanotransduction mechanism underlying the myogenic response is poorly understood, but evidence implicates participation of epithelial sodium channel (ENaC)-like proteins. Therefore, the role of ENaC on the afferent arteriolar myogenic response was investigated in vitro using the blood-perfused juxtamedullary nephron technique. Papillectomy was used to isolate myogenic influences by eliminating tubuloglomerular feedback signals. Autoregulatory responses were assessed by manipulating perfusion pressure in 30-mm Hg steps. Under control conditions, arteriolar diameter increased by 15% from 13.0±1.3 to 14.7±1.2 µm (P<0.05) after reducing perfusion pressure from 100 to 70 mm Hg. Diameter decreased to 11.3±1.1 and 10.6±1.0 µm after increasing pressure to 130 and 160 mm Hg (88±1 and 81±2% of control diameter, P<0.05), respectively. Pressure-mediated autoregulatory responses were significantly inhibited by superfusion of 10 µmol/L amiloride (102±2, 97±4, and 94±3% of control diameter), or 10 µmol/L benzamil (106±5, 100±3, and 103±3% of control diameter), and when perfusing with blood containing 5 µmol/L amiloride (106±2, 97±4, and 97±4% of control diameter). Vasoconstrictor responses to 55 mmol/L KCl were preserved as diameters decreased by 67±4, 55±8, and 60±4% in afferent arterioles superfused with amiloride or benzamil, and perfused with amiloride, respectively. These responses were similar to responses obtained from control afferent arterioles (64±6%, P>0.05). Immunofluorescence revealed expression of the , β, and subunits of ENaC in freshly isolated preglomerular microvascular smooth muscle cells. These results demonstrate that selective ENaC inhibitors attenuate afferent arteriolar myogenic responses and suggest that ENaC may function as mechanosensitive ion channels initiating pressure-dependent myogenic responses in rat juxtamedullary afferent arterioles.

Caveolin-1 and Dopamine-Mediated Internalization of NaKATPase in Human Renal Proximal Tubule Cells [Original Articles]

Wed, 21 Oct 2009 13:34:00 PDT

In moderate sodium-replete states, dopamine 1–like receptors (D₁R/D₅R) are responsible for regulating >50% of renal sodium excretion. This is partly mediated by internalization and inactivation of NaKATPase, when associated with adapter protein 2. We used dopaminergic stimulation via fenoldopam (D₁-like receptor agonist) to study the interaction among D₁-like receptors, caveolin-1 (CAV1), and the G protein–coupled receptor kinase type 4 in cultured human renal proximal tubule cells (RPTCs). We compared 2 groups of RPTCs, 1 of cell lines that were isolated from normal subjects (nRPTCs) and a second group of cell lines that have D₁-like receptors that are uncoupled (uncoupled RPTCs) from adenylyl cyclase second messengers. In nRPTCs, fenoldopam increased the plasma membrane expression of D₁R (10.0-fold) and CAV1 (1.3-fold) and markedly decreased G protein–coupled receptor kinase type 4 by 94±8%; no effects were seen in uncoupled RPTCs. Fenoldopam also increased the association of adapter protein 2 and NaKATPase by 53±9% in nRPTCs but not in uncoupled RPTCs. When CAV1 expression was reduced by 86.0±8.5% using small interfering RNA, restimulation of the D₁-like receptors with fenoldopam in nRPTCs resulted in only a 7±9% increase in association between adapter protein 2 and NaKATPase. Basal CAV1 expression and association with G protein–coupled receptor kinase type 4 was decreased in uncoupled RPTCs (58±5% decrease in association) relative to nRPTCs. We conclude that the scaffolding protein CAV1 is necessary for the association of D₁-like receptors with G protein–coupled receptor kinase type 4 and the adapter protein 2–associated reduction in plasma membrane NaKATPase.

Intrarenal Dopamine Attenuates Deoxycorticosterone Acetate/High Salt-Induced Blood Pressure Elevation in Part Through Activation of a Medullary Cyclooxygenase 2 Pathway [Original Articles]

Yao, B., Harris, R. C., Zhang, M.-Z. — Wed, 21 Oct 2009 13:34:00 PDT

Locally produced dopamine in the renal proximal tubule inhibits salt and fluid reabsorption, and a dysfunctional intrarenal dopaminergic system has been reported in essential hypertension and experimental hypertension models. Using catechol-O-methyl-transferase knockout (COMT^–/–) mice, which have increased renal dopamine because of deletion of the major renal dopamine-metabolizing enzyme, we investigated the effect of intrarenal dopamine on the development of hypertension in the deoxycorticosterone acetate/high-salt (DOCA/HS) model. DOCA/HS led to significant increases in systolic blood pressure in wild-type mice (from 115±2 to 153±4 mm Hg), which was significantly attenuated in COMT^–/– mice (from 114±2 to 135±3 mm Hg). In DOCA/HS COMT^–/– mice, the D1-like receptor antagonist SCH-23390 increased systolic blood pressure (156±2 mm Hg). DOCA/HS COMT^–/– mice also exhibited more urinary sodium excretion (COMT^–/– versus wild-type: 3038±430 versus 659±102 µmol/L per 24 hours; P<0.01). Furthermore, DOCA/HS-induced renal oxidative stress was significantly attenuated in COMT^–/– mice. COX-2–derived prostaglandins in the renal medulla promote sodium excretion, and dopamine stimulates medullary prostaglandin production. Renal medullary COX-2 expression and urinary prostaglandin E₂ excretion were significantly higher in COMT^–/– than in wild-type mice after DOCA/HS treatment. In DOCA/HS-treated COMT^–/– mice, the COX-2 inhibitor SC-58236 reduced urinary sodium and prostaglandin E₂ excretion and increased systolic blood pressure (153±2 mm Hg). These studies indicate that an activated renal dopaminergic system attenuates the development of hypertension, at least in large part through activating medullary COX-2 expression/activity, and also decreases oxidative stress resulting from DOCA/HS.

Regression of Left Ventricular Mass by Antihypertensive Treatment: A Meta-Analysis of Randomized Comparative Studies [Original Articles]

Fagard, R. H., Celis, H., Thijs, L., Wouters, S. — Wed, 21 Oct 2009 13:34:00 PDT

Blood pressure–lowering therapy reduces left ventricular mass, but the question of whether differences exist among drug classes has not been fully resolved. Our aim was to compare the effects of diuretics, β-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers on left ventricular mass regression in patients with hypertension on the basis of prospective, randomized comparative studies. We performed meta-analyses, involving pooled pairwise comparisons of the drug classes and of each class versus other classes statistically combined, and meta-regression analyses to identify the determinants of the regression. The 75 relevant publications involved 84 pairwise comparisons and 6001 patients. Regression of left ventricular mass was significantly less (P=0.01) with β-blockers (9.8%) than with angiotensin receptor blockers (12.5%), but none of the other analyzable pairwise comparisons between drug classes revealed significant differences (P>0.10). In addition, β-blockers showed less regression than the other 4 classes statistically combined (P<0.01), and regression was more pronounced with angiotensin receptor blockers versus the others (P<0.01). In multivariable meta-regression analysis on all of the treatment arms, β-blocker treatment was a significant and negative predictor of the regression (–3.6%; P<0.01), but this was not the case for the other drug classes, including angiotensin receptor blockers. In conclusion, β-blockers show less regression of left ventricular mass, whereas angiotensin receptor blockers may induce larger regression. The inferiority of β-blockers appears to be more convincing than the superiority of angiotensin receptor blockers.

Influence of Altered Blood Rheology on Ventricular-Vascular Response to Exercise [Original Articles]

Wed, 21 Oct 2009 13:34:00 PDT

Blood (or plasma) rheology is related to cardiovascular risk. Mechanisms of this association are unclear but may be partially related to impaired left ventricular (LV) function and increased central blood pressure (BP) during light activity. This study aimed to test these hypotheses. Twenty patients (14 men; aged 61±12 years) with polycythemia rubra vera (n=16) or hemochromatosis (n=4) were studied at rest and during exercise at 50% of maximal heart rate before and after venesection (500 mL; volume replaced with saline) to elicit an acute decrease in plasma viscosity at stable BP. Controls (n=20) underwent the same protocol with 25-mL venesection. Central BP and augmentation index were determined by tonometry. Resting LV systolic (peak longitudinal systolic strain rate and strain) and diastolic functions were determined by tissue-Doppler echocardiography. Venesection with blood volume replacement decreased viscosity (1.46±0.10 to 1.41±0.11 centipoise), protein, and hemoglobin (P<0.05 for all) and increased strain rate and strain (P<0.001 for both) in patients but not in controls (P>0.10 for all). There was no change in LV diastolic function (P>0.12 for all). Exercise augmentation index in patients was reduced after venesection (24±12% to 17±9%; P=0.001) despite no significant change in other BP variables. Hemodynamics (resting or exercise) were not significantly changed in controls. Exercise central systolic BP correlated with triglycerides (r=0.59; P<0.001). However, neither exercise hemodynamic changes nor LV functional changes correlated with any biochemical changes after venesection (P>0.05). We conclude that an acute change in blood rheology improves ventricular-vascular interaction by enhanced LV systolic function and reduced light-exercise central BP.

Augmentation Index, Left Ventricular Contractility, and Wave Reflection [Original Articles]

Sharman, J. E., Davies, J. E., Jenkins, C., Marwick, T. H. — Wed, 21 Oct 2009 13:34:00 PDT

Augmentation index (AIx), a correlate of mortality, is thought to be influenced by left ventricular contractility and wave reflections. However, the relationship of AIx with left ventricular contractility changes has never been assessed, and the wave reflection theory has recently been questioned. This study sought to examine arterial waveform changes in response to reduced "wave reflection" and increased left ventricular contractility induced by dobutamine. Simultaneous radial tonometry (for AIx) and tissue Doppler echocardiography (for peak longitudinal systolic strain rate [SR] as an analogue of left ventricular contractility) were recorded at rest and peak dobutamine-induced stress in 50 patients (41 men; aged 62±10 years). From baseline to peak stress there was an increase in heart rate (70±11 to 127±17 bpm; P<0.001) and SR (–0.88±0.23 to –1.81±0.43 1/s; P<0.001), whereas AIx decreased (27±9% to –7±15%; P<0.001). There was also a greater increase in the systolic (compared with diastolic) pressure-time integral relative to cardiac cycle length (3.2±1.9 versus 1.8±1.1 mm Hg; P<0.001), indicating that wave reflection was not shifted into diastole as per the current belief. AIx was significantly associated with ejection duration (r=0.88), heart rate (r=–0.81), and SR (r=0.72; P<0.001 for all). However, when SR was heart rate corrected, there was no significant association with AIx (r=0.18; P=0.11). The strongest independent correlate of AIx was ejection duration, accounting for 78% variance (β=0.88; model R²=0.77; P<0.001). Neither SR (β=0.12; P=0.18) nor heart rate–corrected SR (β=0.02; P=0.72) was associated with AIx. We conclude that AIx is determined by chronotropic rather than inotropic effects, as well as factors other than wave reflection.

Genetic Silencing of Nox2 and Nox4 Reveals Differential Roles of These NADPH Oxidase Homologues in the Vasopressor and Dipsogenic Effects of Brain Angiotensin II [Original Articles]

Wed, 21 Oct 2009 13:34:00 PDT

The renin-angiotensin system exerts a tremendous influence over fluid balance and arterial pressure. Angiotensin II (Ang-II), the effector peptide of the renin-angiotensin system, acts in the central nervous system to regulate neurohumoral outflow and thirst. Dysregulation of Ang-II signaling in the central nervous system is implicated in cardiovascular diseases; however, the mechanisms remain poorly understood. Recently we established that NADPH oxidase (Nox)–derived superoxide acting in the forebrain subfornical organ is critical in the physiological responses to central Ang-II. In addition, we have found that Nox2 and Nox4 are the most abundantly expressed Nox homologues within Ang-II–sensitive sites in the forebrain. To dissect out the functional importance and unique roles of these Nox enzymes in the pressor and dipsogenic effects of central Ang-II, we developed adenoviral vectors expressing small interfering RNA to selectively silence Nox2 or Nox4 expression in the subfornical organ. Our results demonstrate that both Nox2 and Nox4 are required for the full vasopressor effects of brain Ang-II but that only Nox2 is coupled to the Ang-II–induced water intake response. These studies establish the importance of both Nox2- and Nox4-containing NADPH oxidases in the actions of Ang-II in the central nervous system and are the first to reveal differential involvement of these Nox enzymes in the various physiological effects of central Ang-II.

Prenatal Dexamethasone Exposure Does Not Alter Blood Pressure and Nephron Number in the Young Adult Marmoset Monkey [Original Articles]

Wed, 21 Oct 2009 13:34:00 PDT

The influence of prenatal factors on the development of arterial hypertension has gained considerable interest in recent years. Prenatal dexamethasone exposure was found to induce hypertension and to alter nephron number and size in rodents and sheep. However, it is not clear whether these findings are applicable to nonhuman primates. Thus, we examined the effects of prenatal dexamethasone treatment on blood pressure (BP) and nephron number in marmoset monkeys. Fifty-two marmosets were allotted to 3 groups according to the gestational stage during which their mothers were exposed to oral 5-mg/kg dexamethasone for 7 days (gestation period: 20 weeks): (1) the early dexamethasone group at week 7; (2) the late dexamethasone group at week 13; and (3) the control group. BP was determined by telemetric (n=12) or cuff measurements (n=30), along with cystatin C, proteinuria, and body weight. All of the animals were euthanized at the age of 24 months, and glomerular number and volume were determined. Prenatal exposure to dexamethasone did not lead to a significant difference between the groups with regard to BP, kidney morphology and function, or body weight. BP correlated significantly with body weight, relative kidney weight, and mean glomerular volume and the body weight with the glomerular volume regardless of dexamethasone treatment. In conclusion, prenatal exposure to dexamethasone in marmosets does not, in contrast to other mammals studied, result in hypertension or changes in kidney morphology. Our data support the role of body weight as a predictor of elevated glomerular volume and BP development rather than prenatal dexamethasone exposure.

Prenatal Cocaine Exposure Causes Sex-Dependent Impairment in the Myogenic Reactivity of Coronary Arteries in Adult Offspring [Original Articles]

Xiao, D., Yang, S., Zhang, L. — Wed, 21 Oct 2009 13:34:00 PDT

Cocaine abuse is a significant problem among pregnant women. The present study tested the hypothesis that prenatal cocaine exposure impairs myogenic reactivity of coronary arteries in adult offspring. Pregnant rats received cocaine (30 mg kg^–1 day^–1) or saline from days 15 to 21 of gestational age, and experiments were conducted in 3-month-old offspring. In pressurized coronary septal arteries, the diameter and vessel wall intracellular Ca²⁺ concentrations were measured simultaneously in the same tissue as a function of intraluminal pressure. Cocaine did not affect KCl-induced contractions of coronary arteries in either males or females but decreased the distensibility in male vessels. In male offspring, cocaine treatment resulted in a significant decease in pressure-dependent myogenic contractions. Inhibition of eNOS with N^G-nitro-l-arginine did not alter the myogenic response in either saline control or cocaine-treated animals. In females, cocaine caused a significant increase in pressure-dependent myogenic contractions. N^G-nitro-l-arginine did not affect the myogenic response in the control animals but blocked the cocaine-mediated effect. In both males and females, the pressure-induced increases in vessel wall Ca²⁺ concentrations were not significantly different between cocaine and saline groups. The ratio of changes in the diameter to Ca²⁺ concentrations in the pressurized arteries was significantly less in male but greater in female offspring after cocaine treatment. The results suggest that prenatal cocaine exposure causes reprogramming of coronary myogenic tone via changes in the Ca²⁺ sensitivity in a sex-dependent manner, leading to an increased risk of dysfunction of coronary autoregulation in adult offspring.

Effect of Recombinant Placental Growth Factor 2 on Hypertension Induced by Full-Length Mouse Soluble fms-Like Tyrosine Kinase 1 Adenoviral Vector in Pregnant Mice [Original Articles]

Wed, 21 Oct 2009 13:34:00 PDT

The first aim of our study was to develop a pregnant mouse model for preeclampsia using adenoviral vector containing mouse full-length soluble fms-like tyrosine kinase 1 (sFlt-1) but not truncated sFlt-1. The second aim was to evaluate effects of recombinant mouse (rm) vascular endothelial growth factor (VEGF) and rm placental growth factor (PlGF) on a preeclampsia model induced by adenoviral vector containing mouse full-length sFlt-1. We injected adenoviral vector containing mouse full-length sFlt-1 on day 8.5 or 9.5 of gestation into pregnant Institute of Cancer Research mice, resulting in hypertension, proteinuria, and similar glomerular histological changes as those seen in human preeclamptic women with glomerular endotheliosis on day 16.5 or 17.5 of gestation. The preeclampsia models were treated with 100 µg/kg of rmVEGF164 (n=5), 100 µg/kg of rmPlGF-2 (n=5), or vehicle (n=7) twice a day for 2 days IP. The rmVEGF164 treatment significantly decreased the mean blood pressure on day 16.5 or 17.5 of gestation compared with the vehicle treatment (85±4 versus 97±2 mm Hg; P=0.018). The rmPlGF-2 treatment also significantly decreased the mean blood pressure on day 16.5 or 17.5 of gestation compared with the vehicle treatment (86±3 versus 97±2 mm Hg; P=0.018). However, proteinuria was not affected by either rmVEGF164 or rmPlGF-2. In conclusion, we, for the first time, created a mouse preeclampsia model using mouse full-length sFlt-1. VEGF and PlGF may be promising for ameliorating hypertension in women with preeclampsia. Additional study of PlGF as a potential drug for preeclampsia is warranted.

Time-Dependent Effects of Low-Dose Aspirin on Plasma Renin Activity, Aldosterone, Cortisol, and Catecholamines [Original Articles]

Wed, 21 Oct 2009 13:34:00 PDT

Studies have shown that aspirin may decrease blood pressure when given at bedtime but not when administered on awakening. However, until now, a biologically plausible mechanism of this striking phenomenon was not revealed. We investigated the effect of 100 mg of aspirin administered at bedtime compared with administration on awakening on plasma renin activity and aldosterone levels over 24 hours and excretion of cortisol and catecholamines in 24-hour urine samples. A randomized, placebo-controlled, double-blind, crossover trial was performed in 16 grade 1 hypertensive subjects. During 2 periods of 2 weeks separated by a 4-week washout period, participants used aspirin both at morning and at night, which was blinded with placebo. After both periods, subjects were admitted for 24 hours to measure the aforementioned parameters. Aspirin intake at bedtime compared with on awakening reduced average (24-hour) plasma renin activity by 0.08 µg/L per hour (95% CI: 0.03 to 0.13 µg/L per hour; P=0.003) without affecting aldosterone levels (95% CI: –0.01 to 0.01 nmol/L; P=0.93). Cortisol excretion in 24-hour urine was 52 nmol/24 hours (95% CI: 5 to 99 nmol/24 hours; P=0.05) lower, and dopamine and norepinephrine excretions were 0.25 µmol/24 hours (95% CI: 0.01 to 0.48 µmol/24 hours; P=0.04) and 0.22 µmol/24 hours (95% CI: –0.03 to 0.46 µmol/24 hours; P=0.02) lower in patients treated with bedtime aspirin. In conclusion, aspirin taken at bedtime compared with on awakening significantly diminished 24-hour plasma renin activity and excretion of cortisol, dopamine, and norepinephrine in 24-hour urine. Decreased activity of these pressor systems forms a biologically plausible explanation for the finding that aspirin at night may reduce blood pressure, whereas aspirin at morning does not.

Mediterranean-Style Diet Effect on the Structural Properties of the Erythrocyte Cell Membrane of Hypertensive Patients: The Prevencion con Dieta Mediterranea Study [Original Articles]

Wed, 21 Oct 2009 13:34:01 PDT

A currently ongoing randomized trial has revealed that the Mediterranean diet, rich in virgin olive oil or nuts, reduces systolic blood pressure in high-risk cardiovascular patients. Here, we present a structural substudy to assess the effect of a Mediterranean-style diet supplemented with nuts or virgin olive oil on erythrocyte membrane properties in 36 hypertensive participants after 1 year of intervention. Erythrocyte membrane lipid composition, structural properties of reconstituted erythrocyte membranes, and serum concentrations of inflammatory markers are reported. After the intervention, the membrane cholesterol content decreased, whereas that of phospholipids increased in all of the dietary groups; the diminishing cholesterol:phospholipid ratio could be associated with an increase in the membrane fluidity. Moreover, reconstituted membranes from the nuts and virgin olive oil groups showed a higher propensity to form a nonlamellar inverted hexagonal phase structure that was related to an increase in phosphatidylethanolamine lipid class. These data suggest that the Mediterranean-style diet affects the lipid metabolism that is altered in hypertensive patients, influencing the structural membrane properties. The erythrocyte membrane modulation described provides insight in the structural bases underlying the beneficial effect of a Mediterranean-style diet in hypertensive subjects.

Inhibition of 20-Hydroxyeicosatetraenoic Acid Synthesis Using Specific Plant Lignans: In Vitro and Human Studies [Original Articles]

Wed, 21 Oct 2009 13:34:01 PDT

Sesamin, the major lignan found in sesame, has been shown to increase vitamin E levels by inhibiting its metabolism via the cytochrome P₄₅₀ isozyme CYP4F2. CYP4F2 and CYP4A11 are the predominant human isoforms that synthesize 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. Considerable evidence suggests that 20-HETE may play a role in the pathogenesis of hypertension. We hypothesized that sesamin could be an inhibitor of 20-HETE synthesis. This study investigated the effects of sesamin on 20-HETE synthesis in vitro and the effect of sesame supplementation on plasma and urinary 20-HETE concentrations in humans. Human microsomes were used to investigate the potency and selectivity of sesamin inhibition of 20-HETE synthesis. Sesamin inhibited human renal and liver microsome 20-HETE synthesis with IC₅₀ <20 µmol/L. It was selective toward CYP4F2 (IC₅₀: 1.9 µmol/L) and had reduced activity toward CYP4A11 (IC₅₀: >150 µmol/L), as well as cytochrome P epoxygenation of arachidonic acid (IC₅₀: >50 µmol/L). In a randomized, controlled crossover trial, overweight men and women (n=33) consumed 25 g/d of sesame (50 mg/d of sesame lignan) or an isocaloric matched control for 5 weeks each. Relative to control, sesame supplementation resulted in a 28% decrease in plasma and a 32% decrease in urinary 20-HETE (P<0.001). Urinary sodium, potassium, and blood pressure were not affected. This study demonstrates for the first time that sesame supplementation in humans reduces the plasma and urinary levels of 20-HETE, likely via inhibition of CYP4F2 by sesame lignans. These results suggest that sesame lignans could be used for the investigation of potential roles of 20-HETE in humans.

Potassium Inhibits Dietary Salt-Induced Transforming Growth Factor-{beta} Production [Original Articles]

Ying, W.-Z., Aaron, K., Wang, P.-X., Sanders, P. W. — Wed, 21 Oct 2009 13:34:01 PDT

Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-β, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-β. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-β demonstrated increased (35.2%) amounts of active TGF-β in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-β but did not affect production of TGF-β by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K⁺] inhibited production of dietary salt-induced vascular production levels of total and active TGF-β but did not alter TGF-β production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-β in animals receiving the high-salt diet but did not change urinary active TGF-β in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated potassium channel in the vascular response to excess salt intake.

Abstracts From the 14th Annual Meeting of the ECCR [Abstracts From the 14th Annual Meeting of the European Council for Cardiovascular Research (ECCR)]

Wed, 21 Oct 2009 13:34:01 PDT

63rd Annual High Blood Pressure Research Conference 2009 [63rd Annual High Blood Pressure Research Conference 2009]

Wed, 16 Sep 2009 13:41:28 PDT

Thirtieth Anniversary of Hypertension: Evolution of a Journal and a Progress Report [Editorials]

Hall, J. E. — Wed, 16 Sep 2009 13:41:26 PDT

Jacques de Champlain, MD, PhD, FAHA: 1938-2009 [In Memoriam]

Schiffrin, E. L. — Wed, 16 Sep 2009 13:41:26 PDT

Assessment of Sympathetic Cardiovascular Drive in Human Hypertension: Achievements and Perspectives [Brief Reviews]

Grassi, G. — Wed, 16 Sep 2009 13:41:26 PDT

Methodological refinements in the assessment of human sympathetic cardiovascular drive have allowed throughout the years to better define the role of the sympathetic nervous system in the pathophysiology of hypertension. Earlier studies have provided evidence that indirect markers of adrenergic drive, such as plasma or urinary norepinephrine as well as heart rate, often display an increase in the hypertensive state. Direct recording of efferent postganglionic muscle sympathetic nerve traffic via microneurography and regional norepinephrine spillover technique have conclusively documented the occurrence of an adrenergic overdrive in hypertension, showing that the sympathetic activation is directly related to the severity of the hypertensive state and is widespread to different cardiovascular districts. The present review will focus on some major features of the "neuroadrenergic hypothesis of hypertension." In particular it will examine the mechanisms responsible for the adrenergic overdrive, the relationships between the sympathetic activation and the metabolic disarray of frequent detection in the hypertensive state, and the participation of neuroadrenergic factors at the development of the hypertension-related target organ damage. Further issues addressed will be the contribution of the hyperadrenergic state to the different patterns of the 24-hour blood pressure profile as well as to the day/night blood pressure variability described in the hypertensive state and the behavior of the sympathetic function in the hypertensive states complicated by the presence of other cardiovascular or metabolic disease. Finally, the clinical and therapeutic implications of the neuroadrenergic abnormalities occurring in hypertension, as well as the areas worthy of future research, will be highlighted.

Optimal Dietary Strategies for Reducing Incident Hypertension [Editorial Commentaries]

Weir, M. R., Anderson, C. A.M. — Wed, 16 Sep 2009 13:41:26 PDT

Weight Loss and Reduction of Blood Pressure and Hypertension [Editorial Commentaries]

Kuller, L. H. — Wed, 16 Sep 2009 13:41:26 PDT

Treating Hypertension in Acute Ischemic Stroke [Editorial Commentaries]

Spence, J. D. — Wed, 16 Sep 2009 13:41:26 PDT

Central Blood Pressure Under Angiotensin and Calcium Channel Blockade [Editorial Commentaries]

Safar, M. E., Protogerou, A., Blacher, J. — Wed, 16 Sep 2009 13:41:26 PDT

Protein Kinase C-Inhibiting Properties of the Losartan Metabolite EXP3179 Make the Difference [Editorial Commentaries]

Wenzel, P., Schulz, E., Munzel, T. — Wed, 16 Sep 2009 13:41:26 PDT

Losartan Metabolite EXP3179: An AT1-Receptor-Independent Treatment Strategy for Patients With the Metabolic Syndrome? [Editorial Commentaries]

Rossi, G. P. — Wed, 16 Sep 2009 13:41:26 PDT

Nectin-2: An Intercalated Disc Protein That Maintains Cardiac Function in a Setting of Pressure Overload [Editorial Commentaries]

McMullen, J. R. — Wed, 16 Sep 2009 13:41:26 PDT

Differential Effects Between a Calcium Channel Blocker and a Diuretic When Used in Combination With Angiotensin II Receptor Blocker on Central Aortic Pressure in Hypertensive Patients [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

The aim of this study was to compare the effects between calcium channel blockers and diuretics when used in combination with angiotensin II receptor blocker on aortic systolic blood pressure (BP) and brachial ambulatory systolic BP. We conducted a prospective, randomized, open-label, blinded end point study in 207 hypertensive patients (mean age: 68.4 years). Patients received olmesartan monotherapy for 12 weeks, followed by additional use of azelnidipine (n=103) or hydrochlorothiazide (n=104) for 24 weeks after randomization. The central BP by radial artery tonometry, aortic pulse wave velocity, and ambulatory BP were assessed at baseline and 24 weeks later. After adjustment for baseline covariates, the extent of the reduction in central systolic BP in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/hydrochlorothiazide group (the between-group difference was 5.2 mm Hg; 95% CI: 0.3 to 10.2 mm Hg; P=0.039), whereas the difference in the reduction in brachial systolic BP between the groups was not significant (2.6 mm Hg; 95% CI: –2.2 to 7.5 mm Hg; P=0.29). The aortic pulse wave velocity showed a significantly greater reduction for the olmesartan/azelnidipine combination than for the olmesartan/hydrochlorothiazide combination (0.8 m/s; 95% CI: 0.5 to 1.1 m/s; P<0.001) after adjustment for covariates. The extent of the reduction in brachial ambulatory systolic BP was similar between the groups. These data showed that the combination of olmesartan (20.0 mg) and azelnidipine (16.0 mg) had a more beneficial effect on central systolic BP and arterial stiffness than the combination of olmesartan (20.0 mg) and hydrochlorothiazide (12.5 mg), despite the lack of a significant difference in brachial systolic BP reduction between the 2 treatments.

Differences in the Magnitude of Wave Reflection Account for Differential Effects of Amlodipine- Versus Atenolol-Based Regimens on Central Blood Pressure: An Anglo-Scandinavian Cardiac Outcome Trial Substudy [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

Antihypertensive agents may differ in their effects on central systolic blood pressure, and this may contribute to treatment-related differences in cardiovascular outcomes. In a substudy of the Anglo-Scandinavian Cardiac Outcome Trial, we investigated whether directly measured carotid systolic blood pressure differed between people randomized to amlodipine- and atenolol-based therapies and whether this is accounted for by differences in wave reflection patterns. Additional analysis was undertaken to establish whether differences in carotid systolic blood pressure predicted left ventricular mass, accounting for between-treatment differences in left ventricular mass index. Blood pressure and flow velocity were measured in the right carotid artery of 259 patients. Wave intensity analysis was used to separate and quantify forward and backward waves. Brachial blood pressure did not differ significantly between groups, but carotid systolic blood pressure (127 [12] versus 133 [15] mm Hg; P<0.001), the ratio of backward:forward pressure (0.48 [0.17] versus 0.53 [0.19]; P=0.01), and wave reflection index (19.8% [10.9%] versus 23.3% [13.3%]; P=0.02) were significantly lower in patients randomized to amlodipine-based therapy. Left ventricular mass index was also lower in this group, and adjustment for carotid blood pressure attenuated treatment differences to a greater extent than brachial blood pressure. Carotid systolic blood pressure was also a significant independent predictor of left ventricular mass index in a multivariate model. Carotid systolic blood pressure is lower in people randomized to amlodipine-based compared with atenolol-based treatment despite there being no significant difference in brachial blood pressure. This difference is attributable to a lesser magnitude of wave reflection in patients randomized to the amlodipine-based regimen.

Magnetic Resonance Imaging Left Ventricular Mass Reduction With Fixed-Dose Angiotensin-Converting Enzyme Inhibitor-Based Regimens in Patients With High-Risk Hypertension [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

Left ventricular hypertrophy, a major cardiovascular risk factor for morbidity and mortality, is commonly caused by arterial hypertension. The renin-angiotensin-aldosterone system may contribute to the pathogenesis of left ventricular hypertrophy. The Assessment of Lotrel in Left Ventricular Hypertrophy and Hypertension Study compared a single-pill combination of amlodipine/benazepril at doses 5.0/20.0 mg, 5.0/40.0 mg, and 10.0/40.0 mg with hydrochlorothiazide/benazepril at doses 12.5/20.0 mg, 12.5/40.0 mg, and 25.0/40.0 mg on the reduction of left ventricular mass index measured by cardiac MRI in stage 2 hypertensive patients over 52 weeks of treatment in a randomized clinical trial. A total of 125 male and female patients, ≥55 years of age, with echocardiographic left ventricular hypertrophy and high-risk hypertension defined as blood pressure ≥160/100 mm Hg or current antihypertensive treatment were enrolled. After 52 weeks of treatment, left ventricular mass index was significantly reduced from baseline with amlodipine/benazepril (mean: 10.16 g/m²) or hydrochlorothiazide/benazepril (mean: 6.74 g/m²; both P<0.0001), with a mean difference between treatment groups of 3.36 g/m² (P=0.16). No significant treatment differences were observed in subgroups defined by age, male gender, race, diabetes status, or dose level. However, in female patients, left ventricular mass index reduction was greater with amlodipine/benazepril (P=0.02). Both treatments were well tolerated.

Chronic Treatment With Losartan Results in Sufficient Serum Levels of the Metabolite EXP3179 for PPAR{gamma} Activation [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

The losartan metabolite EXP3174 exhibits angiotensin II receptor 1 (AT1R)-blocking properties, whereas the metabolite EXP3179 potently induces the activity of the insulin-sensitizing peroxisome proliferator-activated receptor (PPAR) as a partial agonist in vitro. We investigated whether chronic treatment with losartan leads to sufficient serum levels of EXP3179 to activate PPAR in monocytes derived from losartan-treated patients. Hypertensive patients (n=15) treated with losartan (100 mg/daily for at least the past 2 months) and untreated control patients (n=7) were included. Monocytes were extracted by negative isolation using a Dynal Monocyte Kit, followed by analysis of PPAR target gene expression (CD36, ABC transporter G1 [ABCG1]) by quantitative real-time RT-PCR. Serum was prepared before, 2, 4, and 6 hours after losartan (100 mg) ingestion for HPLC-based determination of losartan, EXP3174, and EXP3179. Chronic treatment with losartan resulted in basal levels of losartan, EXP3174, and EXP3179 of 348.3±101.8 ng/mL, 115.3±56.1 ng/mL, and 176.2±143.4 ng/mL, respectively. Levels of both EXP3174 and EXP3179 were time-dependently increased in serum with a maximum 2 hours after drug intake (1706.0±760.1 ng/mL, 808.9±618.2 ng/mL, respectively). In consonance with detectable PPAR-activating EXP3179 serum levels, monocytic PPAR target gene expression was significantly upregulated in patients treated with losartan by 3.75±0.95- and 252.02±46.86-fold for CD36 and ABCG1 (P=0.043, P=0.0045 versus control patients, respectively). This is the first clinical description of monocytic PPAR-target gene regulation by chronic treatment with losartan, which likely is mediated by its metabolite EXP3179. Our data show that sufficient serum levels of EXP3179 are present under losartan treatment. PPAR activation by AT1R-blockers may translate into synergistic beneficial actions in monocytes.

Losartan Metabolite EXP3179 Blocks NADPH Oxidase-Mediated Superoxide Production by Inhibiting Protein Kinase C: Potential Clinical Implications in Hypertension [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

Oxidative stress plays a critical role in the pathogenesis of hypertension. The NADPH oxidase constitutes a major source of superoxide anion in phagocytic cells, and its activation is associated with matrix metalloproteinase (MMP)-9 secretion by these cells. We investigated the effects of the angiotensin II type 1 receptor antagonist losartan and its metabolites (EXP3174 and EXP3179) on NADPH oxidase activity and MMP-9 secretion in human phagocytic cells. EXP3179, but not losartan and EXP3174, dose-dependently inhibited (P<0.05) phorbol myristate acetate and insulin-stimulated NADPH oxidase activity. EXP3179 also inhibited phorbol myristate acetate–induced NADPH oxidase in endothelial cells. In addition, EXP3179 inhibited (P<0.05) both phorbol myristate acetate–stimulated p47phox translocation from cytosol to membranes and protein kinase C activity. Affinity experiments and enzymatic assays confirmed that EXP3179 inhibited several protein kinase C isoforms. EXP3179 also inhibited (P<0.05) phorbol myristate acetate–stimulated MMP-9 secretion. In a study performed in 153 hypertensive patients, phagocytic NADPH oxidase activity was lower (P<0.05) in losartan-treated compared with untreated patients and in patients treated with other angiotensin II type 1 receptor antagonists or with angiotensin-converting enzyme inhibitors. Plasma levels of MMP-9 were lower (P<0.05) in losartan-treated hypertensives compared with the other group of patients. Thus, EXP3179 acts as a blocker of the NADPH oxidase in phagocytic cells by a potential mechanism that targets the protein kinase C signaling pathway. This effect can be involved in reduced MMP-9 secretion by these cells. It is proposed that the EXP3179 metabolite may confer to losartan the specific capacity to reduce oxidative stress mediated by phagocytic cells in hypertensive patients.

Diet-Dependent Net Acid Load and Risk of Incident Hypertension in United States Women [Original Articles]

Zhang, L., Curhan, G. C., Forman, J. P. — Wed, 16 Sep 2009 13:41:27 PDT

Animal and human studies suggest a potential link between acid-base status and blood pressure. Contemporary Western diets yield a daily systemic acid load of varying amounts, yet the association with hypertension has never been explored. We prospectively examined the association between the diet-dependent net acid load (also known as the estimated net endogenous acid production) and the risk of incident hypertension among 87 293 women without a history of hypertension in the Nurses’ Health Study II. We also used the ratio of animal protein intake to potassium intake as an alternative evaluation of diet-dependent net acid load. We identified 15 385 incident cases of hypertension during 995 239 person-years of follow-up. After adjusting for potential confounders, women in the top decile of estimated diet-dependent net acid load had an increased risk of hypertension (relative risk: 1.14; 95% CI: 1.05 to 1.24; P for trend=0.01) compared with women in the bottom decile. To test whether the association between estimated diet-dependent net acid load and hypertension is independent of its individual components, an additional adjustment for intakes of protein and potassium was made and resulted in a relative risk of 1.23 (95% CI: 1.08 to 1.41; P for trend=0.003) for the top decile of estimated diet-dependent net acid load. Results of the ratio of animal protein intake to potassium intake were similar with those of estimated diet-depend net acid load. In conclusion, a high diet-dependent net acid load is independently associated with a higher risk of incident hypertension.

Long-Term Weight Loss From Lifestyle Intervention Benefits Blood Pressure?: A Systematic Review [Original Articles]

Aucott, L., Rothnie, H., McIntyre, L., Thapa, M., Waweru, C., Gray, D. — Wed, 16 Sep 2009 13:41:27 PDT

Weight gain may increase blood pressure. Weight loss may reduce this. Reviews have considered the long-term effects of weight loss but are related mainly to more obese participants often on obesity medication and/or undergoing obesity surgery. This systematic review, based on lifestyle interventions for adults (18 to 65 years) with mean baseline BMI of <35 kg/m², links weight change to blood pressure difference. A systematic review of studies reporting weight differences and blood pressure outcomes, published between 1990 and 2008 with follow-up of ≥2 years identified 8 clinical trials or controlled before and after studies (represented by 9 articles) and 8 cohort studies. Differences ranged from –11 to +4kg for weight, –7 to +2.2 mm Hg for diastolic blood pressure and –13 to +6.1 mm Hg for systolic blood pressure. For this population group, no quantifiable relationship between weight and diastolic blood pressure difference was found, possibly because of small weight losses, differing weight status responses, or because pharmacologically controlled hypertension masked weight loss influences. Systolic differences were in line with previous reviews of 1 kg:1 mm Hg relationship, but only for follow-up periods of 2 to 3 years, possibly reflecting the fact that regardless of maintained weight loss, blood pressure often reverts back to higher levels. Lifestyle interventions for weight and blood pressure are limited in this target group, and there has been no exploration of successful intervention components. An individual patient data analysis may uncover baseline and medication effects, explore differences between weight groups, and may identify successful components. Such an analysis would enable effective development of preventative interventions for both hypertension and obesity.

Arterial Destiffening With Atorvastatin in Overweight and Obese Middle-Aged and Older Adults [Original Articles]

Orr, J. S., Dengo, A. L., Rivero, J. M., Davy, K. P. — Wed, 16 Sep 2009 13:41:27 PDT

We hypothesized that atorvastatin (ATOR) treatment would reduce arterial stiffness in overweight and obese middle-aged and older adults. Twenty-six (11 men and 15 women) overweight or obese (body mass index: 31.6±0.7 kg/m²) middle-aged and older adults (age: 54±2 years) were randomly assigned to receive either ATOR (80 mg/d) or placebo for 12 weeks. Arterial stiffness (β-stiffness and pulse wave velocity) was measured before and after the intervention. At baseline, the ATOR (n=16) and placebo (n=10) groups did not differ with respect to age, body mass index, blood pressure, serum lipid and lipoprotein concentrations, high-sensitivity C-reactive protein, indices of arterial stiffness, or compliance (all P>0.05). After the 12-week treatment period, the ATOR group experienced a 47% reduction in low-density lipoprotein cholesterol (149±6 to 80±8 mg/dL) and a 42% reduction in high-sensitivity C-reactive protein (3.6±0.8 to 2.1±0.5 mg/L; both P<0.05). In addition, β-stiffness (9.4±0.6 to 7.6±0.5 U) and aortic pulse wave velocity (1096±36 to 932±32 cm/s), but not brachial pulse wave velocity, decreased (both P<0.05) with ATOR. In contrast, there were no significant changes in β-stiffness (9.1±0.8 to 9.1±0.7 U) or aortic pulse wave velocity (1238±89 to 1191±90 cm/s; both P>0.05) in the placebo group. There were no relations between the reductions in arterial stiffness indices and any of the baseline cardiometabolic risk factors (all P>0.05). However, the reductions in arterial stiffness were correlated with the reduction in low-density lipoprotein cholesterol but not high-sensitivity C-reactive protein or any other cardiometabolic variables (all P<0.05). Taken together, these findings suggest that ATOR reduces arterial stiffness in overweight and obese middle-aged and older adults, and these favorable changes occur irrespective of baseline cardiometabolic risk factors.

Age Determines the Effects of Blood Pressure Lowering During the Acute Phase of Ischemic Stroke: The TICA Study [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

To increase understanding of the influence of blood pressure (BP) changes on functional outcome, we designed a multicenter, prospective, observational study involving patients with ischemic stroke. We included 1092 patients with ischemic stroke. BP was measured on admission and after 8, 16, 24, 32, 40, and 48 hours, and the averages of the readings were taken every 8 hours on days 3 to 7, at the day of discharge, and at 3 months. The main study variable was modified Rankin scale at 3 months. Systolic BPs >181 mm Hg at the emergency department and after 24 hours were associated with poor prognosis (odds ratio [OR]: 2.2, 95% CI: 1.2 to 4.2 and OR: 1.3, 95% CI: 1.1 to 2.3, respectively); systolic BP <136 mm Hg at the emergency department also determined worse prognosis at 3 months (OR: 1.3; 95% CI: 1.1 to 2.9). The influence of systolic BP changes in the first hours depended on patient age. In elder patients (>70 years), reductions in systolic BP determined a significant increase in the proportion of patients with worse prognosis. In patients >80 years of age, decreases in systolic BP >27.2 mm Hg determined a worse prognosis in patients with antihypertensive treatment at the emergency department (n=91) compared with those who did not receive treatment (n=106; OR: 21.7, 95% CI: 13.6 to 33.5 versus OR: 8.5, 95% CI: 3.2 to 19.6). In summary, the effect of BP modification during the acute phase of ischemic stroke on functional outcome is strongly dependent on age.

Relationship Between Therapeutic Changes in Blood Pressure and Outcomes in Acute Stroke: A Metaregression [Original Articles]

Geeganage, C. M., Bath, P. M.W. — Wed, 16 Sep 2009 13:41:27 PDT

Both low and high blood pressures (BPs) during the acute phase of stroke are associated independently with a poor outcome. Several small clinical trials have involved the alteration of BP, and this study assessed the relationship between change in BP and functional outcome. Randomized, controlled trials of interventions that would be expected, on pharmacological grounds, to alter BP in patients within 1 week of the onset of acute ischemic or hemorrhagic stroke were sought using electronic searches. Data were collected on BP and clinical outcome. The relationship between the differences in on-treatment BP and odds ratios for outcomes was assessed using meta-regression. Thirty-seven trials involving 9008 patients were included. A U- or J-shaped relationship was found among on-treatment BP difference and early death, death at the end of 90-day follow-up, and combined death or dependency at the end of follow-up. Although outcomes were not significantly reduced at any level of change in BP, the lowest odds occurred at the following times: early death (odds ratio: 0.87; 95% CI: 0.54 to 1.23), 8.1 mm Hg; death at the end of follow-up (odds-ratio: 0.96; 95% CI: 0.31 to 1.65), 14.4 mm Hg; and combined death or dependency at the end of follow-up (odds ratio: 0.95; 95% CI: 0.11 to 1.72), 14.6 mm Hg. Although large falls or increases in BP are associated with a worse outcome, modest reductions may reduce death and combine death or dependency, although the CIs are wide and compatible with an overall benefit or hazard.

Cognitive Deficit in Amyloid-{beta}-Injected Mice Was Improved by Pretreatment With a Low Dose of Telmisartan Partly Because of Peroxisome Proliferator-Activated Receptor-{gamma} Activation [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

The pathological hallmark of Alzheimer disease is deposition of amyloid-β protein (Aβ) in the brain. Telmisartan is a unique angiotensin II receptor blocker with peroxisome proliferator-activated receptor- (PPAR-)–stimulating activity. Activation of PPAR- is expected to prevent inflammation and Aβ accumulation in the brain. We investigated the possible preventive effect of telmisartan on cognitive decline in an Alzheimer disease mouse model via PPAR- activation. Here, male ddY mice underwent ICV injection of Aβ 1-40. Cognitive function was evaluated by the Morris water maze test. A low dose of telmisartan (0.35 mg/kg per day) was administered in drinking water with or without GW9662, a PPAR- antagonist. Cerebral blood flow was evaluated by laser speckle flowmetry. Inflammatory cytokine levels were measured by quantitative RT-PCR. Aβ 1-40 ICV injection significantly impaired cognitive function. Pretreatment with telmisartan improved this cognitive decline to a similar level to that in control mice. Cotreatment with GW9662, a PPAR- antagonist, attenuated this telmisartan-mediated improvement of cognition. Treatment with telmisartan enhanced cerebral blood flow and attenuated the Aβ-induced increase in expression of cytokines, such as tumor necrosis factor- and inducible NO synthase in the brain. Interestingly, coadministration of GW9662 cancelled these beneficial effects of telmisartan. Aβ 1-40 concentration in the brain was significantly decreased by treatment with telmisartan, whereas administration of GW9662 attenuated the decrease in telmisartan-mediated Aβ 1-40 concentration. Taken together, our findings suggest that even a low dose of telmisartan had a preventive effect on cognitive decline in an Alzheimer disease mouse model, partly because of PPAR- activation.

Quantitative Genetic Analysis of the Retinal Vascular Caliber: The Australian Twins Eye Study [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

Research into the genetic effects and specific genes associated with retinal vascular caliber, a risk marker of cardiovascular diseases, may provide new insights into the genetic contribution of early microvascular disease. A combined 374 monozygotic and 536 dizygotic twin pairs and 322 siblings from the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study underwent complete ophthalmic examinations, including retinal photography, and bilateral retinal vascular caliber was measured. Structural equation modeling was used to estimate the heritability. Genome-wide linkage analysis was conducted on 836 individuals from 381 Brisbane Adolescent Twin Study families, with adjustments for age, sex, and other covariates. The heritabilities for the retinal arteriolar caliber were 59.4% (95% CI: 53.2% to 64.7%) and 56.5% (95% CI: 50.1% to 61.9%) in the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study, respectively, and for venular caliber they were 61.7% (95% CI: 55.6% to 67.0%) and 64.2% (95% CI: 58.7% to 68.8%), respectively, after adjusting for age, sex, and body mass index. Two multipoint peaks detected on chromosomes 3p12.3 and 8p23.1 for retinal arteriolar caliber had suggestive linkage, with the highest multipoint peak logarithm of odds score of 2.24 on chromosome 8p23.1 (genome-wide P=7.0x10^–4). Two suggestive logarithm of odds scores for venular caliber were identified on chromosomes 2p14 and 9q21.13. The largest multipoint logarithm of odds score was 2.69 on chromosome 2p14 (genome-wide P=2.0x10^–4). In this large twin population, genetic factors appear to play a significant role in the variation of retinal vascular caliber. Several putative loci were identified for the retinal vascular caliber.

A Functional Variant of NEDD4L Is Associated With Hypertension, Antihypertensive Response, and Orthostatic Hypotension [Original Articles]

Luo, F., Wang, Y., Wang, X., Sun, K., Zhou, X., Hui, R. — Wed, 16 Sep 2009 13:41:27 PDT

NEDD4L is involved in the regulation of plasma volume and blood pressure by controlling cell surface expression of the kidney epithelial Na⁺ channel. Previously, the cryptic splice variant rs4149601(G/A) A allele of NEDD4L, generating isoform I, was estimated to decrease blood pressure by downregulating Na⁺ reabsorption. However, a recent functional study showed that isoform I should lead to abnormal Na⁺ reabsorption increases by antagonistically downregulating epithelial Na⁺ channel activities. To determine whether the variant rs4149601 A allele is a risk factor for hypertension, has an impact on the antihypertensive response to hydrochlorothiazide, and is associated with orthostatic hypotension, we performed a case-control study of hypertension (n=1686), a 4-week clinical trial (n=542), and a case-control study of orthostatic hypotension (n=793) in Chinese subjects. We found that the A allele was significantly associated with hypertension after appropriate adjustment (odds ratio: 1.39; 95% CI: 1.13 to 1.72; P=0.002). The blood pressure reduction in A carriers after hydrochlorothiazide treatment was greater than that in GG carriers, with differences of 6.1 mm Hg (P=0.009) in systolic blood pressure and 2.7 mm Hg (P=0.027) in diastolic blood pressure. The A allele was significantly associated with orthostatic hypotension after adjustment for cardiovascular risk factors (odds ratio: 0.68; 95% CI: 0.48 to 0.98; P=0.039). In conclusion, rs4149601 is a genetic risk factor for hypertension and a protective factor against orthostatic hypotension in hypertensive subjects, and the antihypertensive response to hydrochlorothiazide is more sensitive in A allele carriers than in GG carriers. Consequently, the A allele may be a useful marker for predicting hypertension, orthostatic hypotension, and antihypertensive response to hydrochlorothiazide.

Genetic Analysis of Blood Pressure in 8 Mouse Intercross Populations [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

The genetic basis of hypertension is well established, yet very few genes that cause common forms of hypertension are known. Quantitative trait locus (QTL) analyses in rodent models can guide the search for human hypertension genes, but the excellent genetic resources for mice have been underused in this regard. To address this issue, we surveyed blood pressure variation in mice from 37 inbred strains and generated 2577 mice in 8 intercross populations to perform QTL analyses of blood pressure. We identified 14 blood pressure QTL in these populations, including ≥7 regions of the mouse genome not linked previously to blood pressure. Many QTL were detected in multiple crosses, either within our study or in studies published previously, which facilitates the use of bioinformatics methods to narrow the QTL and focus the search for candidate genes. The regions of the human genome that correspond to all but 1 of the 14 blood pressure QTL in mice are linked to blood pressure in humans, suggesting that these regions contain causal genes with a conserved role in blood pressure control. These results greatly expand our knowledge of the genomic regions underlying blood pressure regulation in mice and support future studies to identify the causal genes within these QTL intervals.

Klotho Gene Delivery Prevents the Progression of Spontaneous Hypertension and Renal Damage [Original Articles]

Wang, Y., Sun, Z. — Wed, 16 Sep 2009 13:41:27 PDT

Klotho is a recently discovered antiaging gene. The objective of this study was to test the hypothesis that klotho gene delivery attenuates the progression of spontaneous hypertension and renal damage in spontaneous hypertensive rats (SHRs). An adeno-associated virus (AAV) carrying mouse klotho full-length cDNA (AAV.mKL) was constructed for in vivo expression of klotho. Four groups of male SHRs and 1 group of sex- and age-matched Wistar-Kyoto rats (5 rats per group) were used. Blood pressure was measured twice in all of the animals before gene delivery. Four groups of SHRs received an IV injection of AAV.mKL, AAV.LacZ, AAV.GFP, and PBS, respectively. The Wistar-Kyoto group received PBS and served as a control. AAV.mKL stopped the further increase in blood pressure in SHRs, whereas blood pressures continued to increase in other SHR groups. One single dose of AAV.mKL prevented the progression of spontaneous hypertension for at least 12 weeks (length of the study). Klotho expression and production were suppressed in SHRs, which were reverted by AAV.mKL. AAV.mKL increased plasma interleukin 10 levels but decreased Nox2 expression, NADPH oxidase activity, and superoxide production in kidneys and aortas in SHRs. AAV.mKL abolished renal tubular atrophy and dilation, tubular deposition of proteinaceous material, glomerular collapse, and collagen deposition seen in SHRs, indicating that klotho gene delivery attenuated renal damage. Therefore, the suppressed klotho expression may play a role in the progression of spontaneous hypertension and renal damage in SHRs. AAV delivery of klotho may offer a new approach for the long-term control of hypertension and for renoprotection.

Biomarkers of Left Atrial Volume: A Longitudinal Study in Patients With End Stage Renal Disease [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

Left atrial volume (LAV) has recently emerged as a useful biomarker for risk stratification and risk monitoring in patients with end stage renal disease. We investigated the relationship between cardiac natriuretic peptides (atrial natriuretic peptide [ANP] and brain natriuretic peptide [BNP]) and norepinephrine (NE) with LAV and LAV changes over time in 199 end stage renal disease patients. At baseline, LAV was directly related to BNP (r=0.60), ANP (r=0.59), and NE (r=0.28; P<0.001), and these relationships held true in multiple-regression models adjusting for potential confounders (P≤0.003). In the longitudinal study (17±2 months), LAV increased from 9.8±4.6 to 10.9±5.4 mL/m^2.7 (+11%). In a multiple linear regression model, BNP (β=0.28; P=0.003), ANP (β=0.22; P=0.03), and NE (β=0.27; P=0.003) predicted LAV changes. The area under the receiver operating characteristic curve for predicting LAV changes (>3 mL/m^2.7 per year) of a risk score on the basis of standard risk factors was 0.72. Plasma BNP (+12%; P=0.004), ANP (+8%; P=0.03), NE (+8%; P=0.05) and midwall fraction shortening (+8%; P=0.05) increased the area under the receiver operating characteristic curve to a significant extent, whereas LV mass did not (+5%; P=0.18). Predictive models, including BNP, ANP, and NE, maintained a satisfactory discriminatory power for LAV and LAV changes also when tested by a bootstrap resampling technique. BNP and ANP are strongly related to LAV in the end stage renal disease patients and predict LAV changes over time in these patients. Because an increased LAV underlies diastolic dysfunction and/or volume overload (ie, potentially modifiable risk factors), the measurement of the plasma concentration of these compounds might be useful for risk stratification and for guiding treatment in dialysis patients.

Deficiency of Nectin-2 Leads to Cardiac Fibrosis and Dysfunction Under Chronic Pressure Overload [Original Articles]

Wed, 16 Sep 2009 13:41:27 PDT

The intercalated disc, a cell-cell contact site between neighboring cardiac myocytes, plays an important role in maintaining the homeostasis of the heart by transmitting electric and mechanical signals. Changes in the architecture of the intercalated disc have been observed in dilated cardiomyopathy. Among cell-cell junctions in the intercalated disc, adherens junctions are involved in anchoring myofibrils and transmitting force. Nectins are Ca²⁺-independent, immunoglobulin-like cell-cell adhesion molecules that exist in adherens junctions. However, the role of nectins in cardiac homeostasis and integrity of the intercalated disc are unknown. Among the isoforms of nectins, nectin-2 and -4 were expressed at the intercalated disc in the heart. Nectin-2–knockout mice showed normal cardiac structure and function under physiological conditions. Four weeks after banding of the ascending aorta, cardiac function was significantly impaired in nectin-2–knockout mice compared with wild-type mice, although both nectin-2–knockout and wild-type mice developed similar degrees of cardiac hypertrophy. Banded nectin-2–knockout mice displayed cardiac fibrosis more evidently than banded wild-type mice. The disruption of the intercalated discs and disorganized myofibrils were observed in banded nectin-2–knockout mice. Furthermore, the number of apoptotic cardiac myocytes was increased in banded nectin-2–knockout mice. In the hearts of banded nectin-2–knockout mice, Akt remained at lower phosphorylation levels until 2 weeks after banding, whereas c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were highly phosphorylated compared with those of wild-type mice. These results indicate that nectin-2 is required to maintain structure and function of the intercalated disc and protects the heart from pressure-overload–induced cardiac dysfunction.

Exaggerated Blood Pressure Variability Superimposed on Hypertension Aggravates Cardiac Remodeling in Rats via Angiotensin II System-Mediated Chronic Inflammation [Original Articles]

Wed, 16 Sep 2009 13:41:28 PDT

Hypertensive patients with large blood pressure variability (BPV) have aggravated end-organ damage. However, the pathogenesis remains unknown. We investigated whether exaggerated BPV aggravates hypertensive cardiac remodeling and function by activating inflammation and angiotensin II–mediated mechanisms. A model of exaggerated BPV superimposed on chronic hypertension was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). SAD increased BPV to a similar extent in Wistar Kyoto rats and SHRs without significant changes in mean blood pressure. SAD aggravated left ventricular and myocyte hypertrophy and myocardial fibrosis to a greater extent and impaired left ventricular systolic function in SHRs. SAD induced monocyte chemoattractant protein-1, transforming growth factor-β, and angiotensinogen mRNA upregulations and macrophage infiltration of the heart in SHRs. The effects of SAD on cardiac remodeling and inflammation were much smaller in Wistar Kyoto rats compared with SHRs. Circulating levels of norepinephrine, the active form of renin, and inflammatory cytokines were not affected by SAD in Wistar Kyoto rats and SHRs. A subdepressor dose of candesartan abolished the SAD-induced left ventricular/myocyte hypertrophy, myocardial fibrosis, macrophage infiltration, and inductions of monocyte chemoattractant protein-1, transforming growth factor-β, and angiotensinogen and subsequently prevented systolic dysfunction in SHRs with SAD. These findings suggest that exaggerated BPV induces chronic myocardial inflammation and thereby aggravates cardiac remodeling and systolic function in hypertensive hearts. The cardiac angiotensin II system may play a role in the pathogenesis of cardiac remodeling and dysfunction induced by a combination of hypertension and exaggerated BPV.

Involvement of Tissue Transglutaminase in Endothelin 1-Induced Hypertrophy in Cultured Neonatal Rat Cardiomyocytes [Original Articles]

Wed, 16 Sep 2009 13:41:28 PDT

A potential link between tissue-type transglutaminase (tTG) and cardiac hypertrophy was suggested recently. However, whether tTG is implicated in hypertrophic agonist-induced cardiac hypertrophy is not yet known. The purpose of this study was to investigate the effects of tTG on cardiomyocyte hypertrophy induced by endothelin (ET) 1. Real-time quantitative RT-PCR and Western blot analysis demonstrated that ET-1 increased the expression of tTG mRNA and protein in cardiomyocytes by activating ET_A receptors. ET-1 failed to cause increases in cell size and [³H]leucine uptake, sarcomere reorganization, and gene induction of the atrial natriuretic factor when cardiomyocytes were treated with monodansylcadaverine, a competitive inhibitor of tTG. Furthermore, the effects of ET-1 on multifunctional activities of tTG were determined by evaluating the incorporation of [³H]putrescine into N,N'-dimethylated casein and charcoal absorption, respectively. The results showed that ET-1 did not influence the basal transglutaminase activity of cardiomyocytes but significantly inhibited the 0.1-mmol/L Ca²⁺-stimulated transglutaminase activity. Otherwise, ET-1 elevated the activity of GTPase in a concentration- and time-dependent manner. In vivo, right ventricular hypertrophy induced by 2 weeks of chronic hypoxia was depressed by the tTG inhibitor cystamine (10 to 30 mg/kg, 2 times per day, IP) in a dose-dependent manner. Taken together, our data strongly supported the notion that tTG may act as a positive regulator of the hypertrophic program in response to ET-1. This is probably attributable to the signaling activity of tTG rather than transglutaminase activity.

Phosphate-Activated Glutaminase-Containing Neurons in the Rat Paraventricular Nucleus Express Angiotensin Type 1 Receptors [Original Articles]

Wed, 16 Sep 2009 13:41:28 PDT

The centrally mediated cardiovascular regulatory actions of angiotensin II in normal and hypertensive rats include angiotensin II type 1 receptor (AT1R)–mediated actions at the paraventricular nucleus (PVN) of the hypothalamus. Because the PVN consists of multiple neuronal populations, it is important to understand which neuronal types in the PVN are influenced by angiotensin II. Here we have developed a viral vector (Adeno-associated vector 2 [AAV2]-PAG-eGFP [PAG; phosphate-activated glutaminase promoter]) to drive expression of green fluorescent protein (GFP) primarily within glutamate neurons. At 10 to 14 days after bilateral microinjection (200 nL per side; 1.2x10¹² genome copies) of AAV2-PAG-eGFP into adult Sprague-Dawley rat PVN, animals were euthanized and brains removed and used for isolation and culture of PVN neurons. Fluorescence microscopy and immunostaining using neuron and PAG-specific antibodies revealed the presence of GFP-containing glutamatergic neurons in these PVN cultures. Whole-cell patch-clamp recordings demonstrated that angiotensin II (100 nmol/L) produced a 16% decrease in delayed rectifier potassium current in 50% of the GFP-containing neurons, an effect that was abolished by the AT1R antagonist losartan (1 µmol/L). Consistently, 9 of 28 GFP/PAG-expressing neurons contained AT1R mRNA, as indicated by single-cell RT-PCR. Furthermore, specific GFP/PAG-positive neurons in the PVN that project to the rostral ventrolateral medulla of the brain stem express immunoreactive AT1R. In conclusion, we have demonstrated the presence of functional AT1R on PAG-positive (largely glutamate) neurons within rat PVN, certain of which project to the rostral ventrolateral medulla.

Role of the Sympathetic Nervous System in Schlager Genetically Hypertensive Mice [Original Articles]

Davern, P. J., Nguyen-Huu, T.-P., La Greca, L., Abdelkader, A., Head, G. A. — Wed, 16 Sep 2009 13:41:28 PDT

Early studies indicate that the hypertension observed in the Schlager inbred mouse strain may be attributed to a neurogenic mechanism. In this study, we examined the contribution of the sympathetic nervous system in maintaining hypertension in the BPH/2J mouse and used c-Fos immunohistochemistry to elucidate whether neuronal activation in specific brain regions was associated with waking blood pressure. Male hypertensive (BPH/2J; n=14), normotensive (BPN/3J; n=18), and C57/Bl6 (n=5) mice were implanted with telemetry devices, and after 10 days of recovery, recordings of blood pressure, heart rate, and locomotor activity were measured to determine circadian variation. Mean arterial pressure was higher in BPH/2J than in BPN/3J or C57/Bl6 mice (P<0.001), and BPH/2J animals showed exaggerated day-night differences (17±2 versus 6±1 mm Hg in BPN/3J or +8±2 mm Hg in C57/Bl6 mice; P<0.001). Acute sympathetic blockade with pentolinium (7.5 mg/kg IP) during the active and inactive phases reduced blood pressure to comparable levels in BPH/2J and BPN/3J mice. The number of c-Fos–labeled cells was greater in the amygdala (+180%; P<0.01), paraventricular nucleus (+110%; P<0.001), and dorsomedial hypothalamus (+48%; P<0.001) in the active (hypertensive) phase in BPH/2J compared with BPN/3J mice. The level of neuronal activation was mostly similar in these regions in the inactive phase. Of all of the regions studied, neuronal activation in the medial amygdala, as detected by c-Fos, was highly correlated to mean arterial pressure (r=0.98). These findings indicate that the hypertension is largely attributable to sympathetic nervous system activity, possibly generated through greater levels of arousal regulated by neurons located in the medial amygdala.

Sodium Transport in the Choroid Plexus and Salt-Sensitive Hypertension [Original Articles]

Amin, M. S., Reza, E., Wang, H., Leenen, F. H.H. — Wed, 16 Sep 2009 13:41:28 PDT

To elucidate the role of epithelial sodium channels (ENaCs) and Na⁺-K⁺-ATPase in Na⁺ transport by the choroid plexus, we studied ENaC expression and Na⁺ transport in the choroid plexus. Lateral ventricle choroid plexuses were obtained from young male Wistar, Dahl salt–resistant (SS.BN13), and Dahl salt–sensitive (SS/MCW) rats on a regular (0.3%) or high- (8.0%) salt diet. The effects of ENaC blocker benzamil and Na⁺-K⁺-ATPase blocker ouabain on sodium transport were evaluated by measuring the amounts of retained ²²Na⁺ and by evaluating intracellular [Na⁺] with Sodium Green fluorescence. In Wistar rats, ENaC distribution was as follows: microvilli, 10% to 30%; cytoplasm, 60% to 80%; and basolateral membrane, 5% to 10%. Benzamil (10^–8 m) decreased ²²Na⁺ retention by 20% and ouabain (10^–3 m) increased retention by 40%, whereas ouabain and benzamil combined caused no change. Similar changes were noted in intracellular [Na⁺]. In Dahl rats on a regular salt diet, intracellular [Na⁺] was similar, but the amount of retained ²²Na⁺ was less in sensitive versus resistant rats. High salt did not affect ENaC mRNA or protein, nor the benzamil induced decreases in retained ²²Na⁺ or intracellular [Na⁺] in either strain. However, high salt increased intracellular [Na⁺] and attenuated the increase in uptake of ²²Na⁺ by ouabain in resistant but not sensitive rats, suggesting a decrease in Na⁺-K⁺-ATPase activity only in resistant rats. These findings suggest that both ENaC and Na⁺-K⁺-ATPase regulate Na⁺ transport in the choroid plexus. Aberrant regulation of Na⁺ transport and of Na⁺-K⁺-ATPase activity, but not of ENaCs, might contribute to the increase in cerebrospinal fluid [Na⁺] in Dahl salt-sensitive rats on a high-salt diet.

Xanthine Oxidoreductase Depletion Induces Renal Interstitial Fibrosis Through Aberrant Lipid and Purine Accumulation in Renal Tubules [Original Articles]

Wed, 16 Sep 2009 13:41:28 PDT

Xanthine oxidoreductase (XOR) is an enzyme responsible for purine degradation, reactive oxygen species production, and adipogenesis. XOR gene-disrupted (XOR^–/–) mice demonstrate renal failure and early death within several months. The aim of this study was to elucidate the mechanism of renal damage in XOR^–/– mice and to determine the physiological role of XOR in the kidney. Histological analysis revealed that renal tubular damage in XOR^–/– mice was accompanied by deposition of crystals and lipid-rich substances. Triglyceride content in renal homogenates was significantly increased in XOR^–/– mice. The level of lipogenesis-related gene expression was comparable in XOR^+/+ and XOR^–/– mice, whereas the expression of adipogenesis-related gene expression was significantly elevated in XOR^–/– mice. Urinary excretions of xanthine and hypoxanthine were markedly elevated in XOR^–/– mice. Immunohistochemical analysis, Western blotting, and real time RT-PCR revealed that various markers of fibrosis, inflammation, ischemia, and oxidative stress were increased in XOR^–/– mice. Finally, we demonstrate that primary renal epithelial cells from XOR^–/– mice are more readily transformed to myofibroblasts, which is a marker of increased epithelial mesenchymal transition. These results suggest that XOR gene disruption induced the depletion of uric acid and the accumulation of triglyceride-rich substances, xanthine, and hypoxanthine in the renal tubules. We believe that these changes contribute to a complex cellular milieu characterized by inflammation, tissue hypoxia, and reactive oxygen species production, ultimately resulting in renal failure through increased renal interstitial fibrosis.

Angiotensin II Induces Connective Tissue Growth Factor and Collagen I Expression via Transforming Growth Factor-{beta}-Dependent and -Independent Smad Pathways: The Role of Smad3 [Original Articles]

Yang, F., Chung, A. C.K., Huang, X. R., Lan, H. Y. — Wed, 16 Sep 2009 13:41:28 PDT

Connective tissue growth factor (CTGF) plays a critical role in angiotensin II (Ang II)–mediated hypertensive nephropathy. The present study investigated the mechanisms and specific roles of individual Smads in Ang II–induced CTGF and collagen I expression in tubular epithelial cells with deletion of transforming growth factor (TGF)-β1, overexpression of Smad7, or knockdown of Smad2 or Smad3. We found that Ang II–induced tubular CTGF and collagen I mRNA and protein expressions were regulated positively by phosphorylated Smad2/3 but negatively by Smad7 because overexpression of Smad7-abolished Ang II–induced Smad2/3 phosphorylation and upregulation of CTGF and collagen I in vitro and in a rat model of remnant kidney disease. Additional studies revealed that, in addition to a late (24-hour) TGF-β–dependent Smad2/3 activation, Ang II also induced a rapid activation of Smad2/3 at 15 minutes and expression of CTGF and collagen I in tubular epithelial cells lacking the TGF-β gene, which was blocked by the addition of an Ang II type 1 receptor antagonist (losartan) and inhibitors to extracellular signal–regulated kinase 1/2 (PD98059) and p38 (SB203580) but not by inhibitors to Ang II type 2 receptor (PD123319) or c-Jun N-terminal kinase (SP600125), demonstrating a TGF-β–independent, Ang II type 1 receptor–mediated extracellular signal–regulated kinase/p38 mitogen-activated protein kinase cross-talk pathway in Ang II–mediated CTGF and collagen I expression. Importantly, the ability of knockdown of Smad3, but not Smad2, to inhibit Ang II–induced CTGF and collagen I expression further revealed an essential role for Smad3 in Ang II–mediated renal fibrosis. In conclusion, Ang II induces tubular CTGF expression and renal fibrosis via the TGF-β–dependent and –independent Smad3 signaling pathways, suggesting that targeting Smad3 may have therapeutic potential for hypertensive nephropathy.

Impact of Accessory Hepatic Veins on Adrenal Vein Sampling for Identification of Surgically Curable Primary Aldosteronism [Original Articles]

Wed, 16 Sep 2009 13:41:28 PDT

Adrenal vein sampling is the gold standard for identification of surgically curable primary aldosteronism, but its accuracy might be hindered by blood dilution from accessory vein blood. We prospectively investigated the presence of accessory veins draining into adrenal veins and their effect on the selectivity index (SI) in 74 consecutive patients undergoing adrenal vein sampling. On the right side, the venous anatomic pattern could be conclusively determined in 91.8% of the cases: we detected hepatic accessory veins in 12.1%, no accessory veins in 42.4%, and renal capsular veins in 45.5%. On the left side there was a phrenico-adrenal trunk in 89.4% and renal capsular accessory veins in 10.6% of the cases. On both sides, renal capsular and phrenic accessory veins did not affect the SI. At variance, on the right side, hepatic accessory veins were associated with SI values 3-fold lower than that found when such accessory veins were absent (median: 3.10 [range: 0.80 to 84.2] versus median: 1.10 [range: 0.70 to 2.20]; P=0.01). However, superselective adrenal catheterization resulted into higher SI values (median: 23.88; range: 4.80 to 84.20) in these cases. Thus, hepatic accessory veins sharing egress into the inferior vena cava with the right adrenal vein occurred in 12% of the patients and imply a low SI, likely because of adrenal blood dilution by hepatic blood carrying a low cortisol concentration. In the presence of this anatomic variation, superselective catheterization of the right adrenal vein should be undertaken to determine the lateralization of aldosterone secretion.

Mineralocorticoid and Glucocorticoid Receptors Stimulate Epithelial Sodium Channel Activity in a Mouse Model of Cushing Syndrome [Original Articles]

Bailey, M. A., Mullins, J. J., Kenyon, C. J. — Wed, 16 Sep 2009 13:41:28 PDT

Experiments in Cushing patients and healthy control subjects receiving adrenocorticotropic hormone (ACTH) indicate that transient renal sodium retention may contribute to the generation of hypertension. Here we have investigated the effect of chronic ACTH infusion on renal sodium handling in adult male C57BL/6J mice using selective antagonists to dissect mineralocorticoid and glucocorticoid receptor–mediated pathways. Mice were infused via osmotic minipump with ACTH (2.5 µg/d) or saline for 2 weeks before being anesthetized for renal function experiments. ACTH caused an increase in blood pressure and a reduction in fractional sodium excretion associated with enhanced activity of the epithelial sodium channel. Given separately, spironolactone and RU38486 blunted the pressor response to ACTH and the increased epithelial sodium channel activity; combined mineralocorticoid and glucocorticoid receptor blockade was required to resolve the response to ACTH excess. Dietary sodium depletion also prevented ACTH-induced hypertension. The effect of increased sodium reabsorption in the distal nephron is offset by downregulation of Na-K-Cl cotransport in the loop of Henle. Sodium excretion is normalized chronically, but blood pressure remains high; acute blockade of V1 receptors and 1 adrenoceptors in combination restored blood pressure to control values. In summary, ACTH excess promotes renal sodium reabsorption, contributing to the increased blood pressure; both glucocorticoid and mineralocorticoid receptor pathways are involved. These data are relevant to conditions associated with overactivity of the hypothalamic-pituitary-adrenal axis, such as obesity and chronic stress.

Evidence for Increased Methylglyoxal in the Vasculature of Women With Preeclampsia: Role in Upregulation of LOX-1 and Arginase [Original Articles]

Sankaralingam, S., Xu, H., Jiang, Y., Sawamura, T., Davidge, S. T. — Wed, 16 Sep 2009 13:41:28 PDT

Preeclampsia is characterized by vascular endothelial dysfunction partly attributed to oxidative stress. In the vasculature of preeclamptic women, we have shown increased lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) and arginase expression, which can contribute to vascular oxidative stress. However, the mechanisms of such upregulation are unknown. Methylglyoxal (MG) that plays a role in the vascular complications of diabetes mellitus and the development of hypertension can be one potential factor that can affect LOX-1 and arginase through its ability to induce oxidative stress in vascular cells. MG also reacts with lysine residues in proteins to generate advanced glycation end product, N-carboxy ethyl lysine, which also serves as a marker of MG. We hypothesized that markers of MG formation will be increased in the vasculature of preeclamptic women and that exogenous MG will induce oxidative stress by the upregulation of LOX-1 via arginase. We observed increased N-carboxy ethyl lysine expression in the vasculature of women with preeclampsia in comparison with normotensive pregnant women. Moreover, glyoxalase I and II, enzymes that detoxify MG, and glutathione reductase, which generates reduced glutathione, a cofactor for glyoxalase, are also reduced in preeclampsia. In cultured endothelial cells, MG increased arginase expression by 6 hours and LOX-1 expression by 24 hours. Inhibition of arginase or NO synthase significantly reduced MG-induced LOX-1 expression, superoxide levels, and nitrotyrosine staining. In conclusion, MG-induced LOX-1 expression is mediated via arginase upregulation likely because of uncoupling of NO synthase, which may have implications in preeclampsia.

Hypertension in Response to Autoantibodies to the Angiotensin II Type I Receptor (AT1-AA) in Pregnant Rats: Role of Endothelin-1 [Original Articles]

Wed, 16 Sep 2009 13:41:28 PDT

Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) and endothelin -1 (ET-1) are suggested to be important links between placental ischemia and hypertension during preeclampsia. Activation of the angiotensin II type 1 receptor (AT1R) increases endothelial cell production of ET-1; however, the importance of ET-1 in response to AT1-AA–mediated AT1 R activation during preeclampsia is unknown. Furthermore, the role of AT1-AA–mediated increases in blood pressure during pregnancy remains unclear. The objective of this study was to test the hypothesis that AT1-AA, increased to levels observed in preeclamptic women and placental ischemic rats, increases mean arterial pressure (MAP) by activation of the ET-1 system. Chronic infusion of purified rat AT1-AA into normal pregnant (NP) rats for 7 days increased AT1-AA from 0.68±0.5 to 10.88±1.1 chronotropic units (P<0.001). The increased AT1-AA increased MAP from 99±1 to 119±2 mm Hg (P<0.001). The hypertension was associated with significant increases in renal cortices (11-fold) and placental (4-fold) ET-1. To determine whether ET-1 mediates AT1-AA–induced hypertension, pregnant rats infused with AT1-AA and NP rats were treated with an ET_A receptor antagonist. MAP was 100±1 mm Hg in AT1-AA+ET_A antagonist-treated rats versus 98±2 mm Hg in ET_A antagonist-treated rats. Collectively, these data support the hypothesis that one potential pathway whereby AT1-AAs increase blood pressure during pregnancy is by an ET-1–dependent mechanism.

Contribution of Endothelin 1 to the Vascular Effects of Diesel Exhaust Inhalation in Humans [Original Articles]

Wed, 16 Sep 2009 13:41:28 PDT

Diesel exhaust inhalation impairs vascular function, and, although the underlying mechanism remains unclear, endothelin (ET) 1 and NO are potential mediators. The aim of this study was to identify whether diesel exhaust inhalation affects the vascular actions of ET-1 in humans. In a randomized, double-blind crossover study, 13 healthy male volunteers were exposed to either filtered air or dilute diesel exhaust (331±13 µg/m³). Plasma concentrations of ET-1 and big-ET-1 were determined at baseline and throughout the 24-hour study period. Bilateral forearm blood flow was measured 2 hours after the exposure during infusion of either ET-1 (5 pmol/min) or the ET_A receptor antagonist, BQ-123 (10 nmol/min) alone and in combination with the ET_B receptor antagonist, BQ-788 (1 nmol/min). Diesel exhaust exposure had no effect on plasma ET-1 and big-ET-1 concentrations (P>0.05 for both) or 24-hour mean blood pressure or heart rate (P>0.05 for all). ET-1 infusion increased plasma ET-1 concentrations by 58% (P<0.01) but caused vasoconstriction only after diesel exhaust exposure (–17% versus 2% after air; P<0.001). In contrast, diesel exhaust exposure reduced vasodilatation to isolated BQ-123 infusion (20% versus 59% after air; P<0.001) but had no effect on vasodilatation to combined BQ-123 and BQ-788 administration (P>0.05). Diesel exhaust inhalation increases vascular sensitivity to ET-1 and reduces vasodilatation to ET_A receptor antagonism despite unchanged plasma ET-1 concentrations. Given the tonic interaction between the ET and NO systems, we conclude that diesel exhaust inhalation alters vascular reactivity to ET-1 probably through its effects on NO bioavailability.

Severe Paradoxical Hypertension With Angiotensin-Converting Enzyme Inhibitors: An Unusual Feature of Renal Artery Stenosis [Letters to the Editor]

Cronin, E. M., Leavey, S. F., Walker, J. F. — Wed, 19 Aug 2009 13:32:52 PDT

Effects of Endothelin Receptor Antagonism Relate to the Degree of Renin-Angiotensin System Blockade in Chronic Proteinuric Kidney Disease [Letters to the Editor]

Wed, 19 Aug 2009 13:32:52 PDT

Normalization of Autonomic Function in Children With Coarctation of the Aorta After Surgical Correction in Infancy [Letters to the Editor]

Kenny, D., Polson, J. W., Martin, R. P., Paton, J. F.R., Wolf, A. R. — Wed, 19 Aug 2009 13:32:52 PDT

Adrenocorticotropic Hormone Stimulation During Adrenal Vein Sampling [Letters to the Editor]

Tanemoto, M., Mishima, E., Takeuchi, Y., Abe, T. — Wed, 19 Aug 2009 13:32:52 PDT

Response to Adrenocorticotropic Hormone Stimulation During Adrenal Vein Sampling [Letters to the Editor]

Seccia, T. M., Rossi, G. P. — Wed, 19 Aug 2009 13:32:52 PDT

Acknowledgment of Reviewers [Acknowledgment of Reviewers]

Wed, 19 Aug 2009 13:32:50 PDT

Immunology in Hypertension, Preeclampsia, and Target-Organ Damage [Hypertension Highlights]

Verlohren, S., Muller, D. N., Luft, F. C., Dechend, R. — Wed, 19 Aug 2009 13:32:50 PDT

Another Major Role for Dietary Sodium Reduction: Improving Blood Pressure Control in Patients With Resistant Hypertension [Editorial Commentaries]

Appel, L. J. — Wed, 19 Aug 2009 13:32:50 PDT

Pleiotropic Benefits of Moderate Salt Reduction [Editorial Commentaries]

Egan, B. M. — Wed, 19 Aug 2009 13:32:50 PDT

Sodium Chloride and Aldosterone: Harbingers of Hypertension-Related Cardiovascular Disease [Editorial Commentaries]

Kotchen, T. A. — Wed, 19 Aug 2009 13:32:50 PDT

Are Macrophages the Foot Soldiers in the War Waged by Aldosterone Against the Heart? [Editorial Commentaries]

Dorrance, A. M. — Wed, 19 Aug 2009 13:32:50 PDT

A Risk Score for Risk Factors: Rationale and Roadmap for Preventing Hypertension [Editorial Commentaries]

Vasan, R. S. — Wed, 19 Aug 2009 13:32:50 PDT

High Blood Pressure: A Lifetime Issue [Editorial Commentaries]

Lackland, D. T. — Wed, 19 Aug 2009 13:32:50 PDT

Role of Body Size on Cardiovascular Function: Can We See the Meat Through the Fat? [Editorial Commentaries]

Chantler, P. D., Lakatta, E. G. — Wed, 19 Aug 2009 13:32:50 PDT

Hypertension and Insulin Resistance [Editorial Commentaries]

Whaley-Connell, A., Sowers, J. R. — Wed, 19 Aug 2009 13:32:50 PDT

Vascular Endothelial Growth Factor Inhibitors and Hypertension: A Central Role for the Kidney and Endothelial Factors? [Editorial Commentaries]

Granger, J. P. — Wed, 19 Aug 2009 13:32:50 PDT

Angiotensin-Converting Enzyme and Dipeptidyl Peptidase IV Inhibitors: An Increased Risk of Angioedema [Editorial Commentaries]

Grouzmann, E., Livio, F., Buclin, T. — Wed, 19 Aug 2009 13:32:51 PDT

Tumor Necrosis Factor-{alpha}-Converting Enzyme Roles in Hypertension-Induced Hypertrophy: Look Both Ways When Crossing the Street [Editorial Commentaries]

Zamilpa, R., Chilton, R. J., Lindsey, M. L. — Wed, 19 Aug 2009 13:32:51 PDT

Is Resveratrol the Magic Bullet for Pulmonary Hypertension? [Editorial Commentaries]

Chicoine, L. G., Stewart, J. A., Lucchesi, P. A. — Wed, 19 Aug 2009 13:32:51 PDT

Effects of Dietary Sodium Reduction on Blood Pressure in Subjects With Resistant Hypertension: Results From a Randomized Trial [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Observational studies indicate a significant relation between dietary sodium and level of blood pressure. However, the role of salt sensitivity in the development of resistant hypertension is unknown. The present study examined the effects of dietary salt restriction on office and 24-hour ambulatory blood pressure in subjects with resistant hypertension. Twelve subjects with resistant hypertension entered into a randomized crossover evaluation of low (50 mmol/24 hoursx7 days) and high sodium diets (250 mmol/24 hoursx7 days) separated by a 2-week washout period. Brain natriuretic peptide; plasma renin activity; 24-hour urinary aldosterone, sodium, and potassium; 24-hour ambulatory blood pressure monitoring; aortic pulse wave velocity; and augmentation index were compared between dietary treatment periods. At baseline, subjects were on an average of 3.4±0.5 antihypertensive medications with a mean office BP of 145.8±10.8/83.9±11.2 mm Hg. Mean urinary sodium excretion was 46.1±26.8 versus 252.2±64.6 mmol/24 hours during low- versus high-salt intake. Low- compared to high-salt diet decreased office systolic and diastolic blood pressure by 22.7 and 9.1 mm Hg, respectively. Plasma renin activity increased whereas brain natriuretic peptide and creatinine clearance decreased during low-salt intake, indicative of intravascular volume reduction. These results indicate that excessive dietary sodium ingestion contributes importantly to resistance to antihypertensive treatment. Strategies to substantially reduce dietary salt intake should be part of the overall treatment of resistant hypertension.

Effect of Modest Salt Reduction on Blood Pressure, Urinary Albumin, and Pulse Wave Velocity in White, Black, and Asian Mild Hypertensives [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

A reduction in salt intake lowers blood pressure. However, most previous trials were in whites with few in blacks and Asians. Salt reduction may also reduce other cardiovascular risk factors (eg, urinary albumin excretion, arterial stiffness). However, few well-controlled trials have studied these effects. We carried out a randomized double-blind crossover trial of salt restriction with slow sodium or placebo, each for 6 weeks, in 71 whites, 69 blacks, and 29 Asians with untreated mildly raised blood pressure. From slow sodium to placebo, urinary sodium was reduced from 165±58 (±SD) to 110±49 mmol/24 hours (9.7 to 6.5 g/d salt). With this reduction in salt intake, there was a significant decrease in blood pressure from 146±13/91±8 to 141±12/88±9 mm Hg (P<0.001), urinary albumin from 10.2 (IQR: 6.8 to 18.9) to 9.1 (6.6 to 14.0) mg/24 hours (P<0.001), albumin/creatinine ratio from 0.81 (0.47 to 1.43) to 0.66 (0.44 to 1.22) mg/mmol (P<0.001), and carotid-femoral pulse wave velocity from 11.5±2.3 to 11.1±1.9 m/s (P<0.01). Subgroup analysis showed that the reductions in blood pressure and urinary albumin/creatinine ratio were significant in all groups, and the decrease in pulse wave velocity was significant in blacks only. These results demonstrate that a modest reduction in salt intake, approximately the amount of the current public health recommendations, causes significant falls in blood pressure in all 3 ethnic groups. Furthermore, it reduces urinary albumin and improves large artery compliance. Although both could be attributable to the falls in blood pressure, they may carry additional benefits on reducing cardiovascular disease above that obtained from the blood pressure falls alone.

Independent Relations of Left Ventricular Structure With the 24-Hour Urinary Excretion of Sodium and Aldosterone [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Previous studies reported on the association of left ventricular mass index (LVMI) with urinary sodium or with circulating or urinary aldosterone. We investigated the independent associations of LVMI with the urinary excretion of both sodium and aldosterone. We randomly recruited 317 untreated subjects from a white population (45.1% women; mean age 48.2 years). Measurements included echocardiographic left ventricular (LV) properties, the 24-hour urinary excretion of sodium and aldosterone, plasma renin activity (PRA), and proximal (RNa_prox) and distal (RNa_dist) renal sodium reabsorption, assessed from the endogenous lithium clearance. In multivariable-adjusted models, we expressed changes in LVMI per 1-SD increase in the explanatory variables, while accounting for sex, age, systolic blood pressure, and the waist-to-hip ratio. LVMI increased independently with the urinary excretion of both sodium (+2.48 g/m²; P=0.005) and aldosterone (+2.63 g/m²; P=0.004). Higher sodium excretion was associated with increased mean wall thickness (MWT: +0.126 mm, P=0.054), but with no change in LV end-diastolic diameter (LVID: +0.12 mm, P=0.64). In contrast, higher aldosterone excretion was associated with higher LVID (+0.54 mm; P=0.017), but with no change in MWT (+0.070 mm; P=0.28). Higher RNa_dist was associated with lower relative wall thickness (–0.81x10^–2, P=0.017), because of opposite trends in LVID (+0.33 mm; P=0.13) and MWT (–0.130 mm; P=0.040). LVMI was not associated with PRA or RNa_prox. In conclusion, LVMI independently increased with both urinary sodium and aldosterone excretion. Increased MWT explained the association of LVMI with urinary sodium and increased LVID the association of LVMI with urinary aldosterone.

Validating the Framingham Hypertension Risk Score: Results From the Whitehall II Study [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

A promising hypertension risk prediction score using data from the US Framingham Offspring Study has been developed, but this score has not been tested in other cohorts. We examined the predictive performance of the Framingham hypertension risk score in a European population, the Whitehall II Study. Participants were 6704 London-based civil servants aged 35 to 68 years, 31% women, free from prevalent hypertension, diabetes mellitus, and coronary heart disease. Standard clinical examinations of blood pressure, weight and height, current cigarette smoking, and parental history of hypertension were undertaken every 5 years for a total of 4 times. We recorded a total of 2043 incident (new-onset) cases of hypertension in three 5-year baseline follow-up data cycles. Both discrimination (C statistic: 0.80) and calibration (Hosmer-Lemeshow ²: 11.5) of the Framingham hypertension risk score were good. Agreement between the predicted and observed hypertension incidences was excellent across the risk score distribution. The overall predicted:observed ratio was 1.08, slightly better among individuals >50 years of age (0.99 in men and 1.02 in women) than in younger participants (1.16 in men and 1.18 in women). Reclassification with a modified score on the basis of our study population did not improve the prediction (net reclassification improvement: –0.5%; 95% CI: –2.5% to 1.5%). These data suggest that the Framingham hypertension risk score provides a valid tool with which to estimate near-term risk of developing hypertension.

Blood Pressure Differences by Ethnic Group Among United States Children and Adolescents [Original Articles]

Rosner, B., Cook, N., Portman, R., Daniels, S., Falkner, B. — Wed, 19 Aug 2009 13:32:51 PDT

Large differences in blood pressure (BP) by ethnic group are apparent among adults. There is uncertainty as to whether similar differences by ethnic group exist among children and, if so, the age of onset. BP measurements were obtained from 58 698 children at 78 556 visits using Pediatric Task Force data, a collection of 11 studies with BP data from children and adolescents age 1 to 17 years. Generalized estimating equation methods were used to identify sex-specific differences in body mass index (BMI)–adjusted rates of BP elevation and prehypertension by ethnic group. Significant BMI-adjusted differences in rates of BP elevation were found between Hispanic boys versus white boys (odds ratio: 1.21; 95% CI: 1.07 to 1.37; P=0.002). No overall significant differences were found between black boys versus white boys (odds ratio: 1.03; 95% CI: 0.95 to 1.12; P=0.49); however, there was significant effect modification (P=0.01) with significant differences found for normal-weight boys (BMI: <85th percentile; OR black versus white: 1.14; 95% CI: 1.03 to 1.27; P=0.01) but not for overweight boys (BMI: ≥85th percentile; OR black versus white: 0.90; 95% CI: 0.78 to 1.05; P=0.20). No overall ethnic group differences in BMI-adjusted rates of hypertension were found for girls. Ethnic differences in prevalence rates of pediatric BP elevation that are not explained by obesity are present, primarily in boys. Whether these differences are attributable to genetic or environmental factors is unknown.

Blood Pressure Is a Major Risk Factor for Renal Death: An Analysis of 560 352 Participants From the Asia-Pacific Region [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Chronic kidney disease is a major worldwide public health problem that causes substantial morbidity and mortality. Studies from the Asia-Pacific region have reported some of the highest chronic kidney disease prevalence rates in the world, but access to dialysis is limited in many countries, making it imperative to identify high-risk individuals. We performed a participant-level data overview of prospective studies conducted in the Asia-Pacific region to quantify the magnitude and direction of the associations between putative risk factors and renal death. Age- and sex-adjusted Cox proportional hazards models were applied to pooled data from 35 studies to calculate hazard ratios (95% CIs) for renal death associated with a standardized change in risk factors. Among 560 352 participants followed for a median of 6.8 years, a total of 420 renal deaths were observed. Continuous and positive associations among systolic blood pressure, diastolic blood pressure, fasting blood glucose, and total cholesterol levels with renal death were observed, as well as a continuous but inverse association with high-density lipoprotein cholesterol. Systolic blood pressure was the strongest risk factor for renal death with each SD increase in systolic blood pressure (19 mm Hg) associated with >80% higher risk (hazard ratio: 1.84; 95% CI: 1.60 to 2.12). Neither cigarette smoking nor excess weight was related to the risk of renal death (P>0.10). The results were similar for cohorts in Asia and Australia. These results suggest that primary prevention strategies for renal disease should focus on individuals with elevated blood pressure, diabetes mellitus, and dyslipidemia.

Dipeptidyl Peptidase-IV Inhibitor Use Associated With Increased Risk of ACE Inhibitor-Associated Angioedema [Original Articles]

Brown, N. J., Byiers, S., Carr, D., Maldonado, M., Warner, B. A. — Wed, 19 Aug 2009 13:32:51 PDT

Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical angioedema, by comparing the incidence of angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug–drug interaction.

Intensifying Therapy for Hypertension Despite Suboptimal Adherence [Original Articles]

Rose, A. J., Berlowitz, D. R., Manze, M., Orner, M. B., Kressin, N. R. — Wed, 19 Aug 2009 13:32:51 PDT

More intensive management can improve control blood pressure (BP) in hypertensive patients. However, many would posit that treatment intensification (TI) is not beneficial in the face of suboptimal adherence. We investigated whether the effect of TI on BP varies by adherence. We enrolled 819 patients with hypertension, managed in primary care at an academically-affiliated inner-city hospital. We used the following formula to characterize TI: (visits with a medication change–visits with elevated BP)/total visits. Adherence was characterized using electronic monitoring devices ("MEMS caps"). Patients who returned their MEMS caps (671) were divided into quartiles of adherence, whereas patients who did not return their MEMS caps (148) had "missing" adherence. We examined the relationship between TI and the final systolic blood pressure (SBP), controlling for patient-level covariates. In the entire sample, each additional therapy increase per 10 visits predicted a 2.0 mm Hg decrease in final SBP (P<0.001). After stratifying by adherence, in the "best" adherence quartile each therapy increase predicted a 2.1-mm Hg decrease in final SBP, followed by 1.8 for the "next-best" adherence quartile, 2.3 in the third quartile, and 2.4 in the "worst" adherence quartile. The effect size for patients with "missing" adherence was 1.6 mm Hg. The differences between the group with "best" adherence and the other 4 groups were not statistically significant. In this observational study, treatment intensification was associated with similar BP improvement regardless of the patient’s level of adherence. A randomized trial could further examine optimal management of patients with suboptimal adherence.

Effects of Chronic Baroreceptor Stimulation on the Autonomic Cardiovascular Regulation in Patients With Drug-Resistant Arterial Hypertension [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

In patients with drug-resistant hypertension, chronic electric stimulation of the carotid baroreflex is an investigational therapy for blood pressure reduction. We hypothesized that changes in cardiac autonomic regulation can be demonstrated in response to chronic baroreceptor stimulation, and we analyzed the correlation with blood pressure changes. Twenty-one patients with drug-resistant hypertension were prospectively included in a substudy of the Device Based Therapy in Hypertension Trial. Heart rate variability and heart rate turbulence were analyzed using 24-hour ECG. Recordings were obtained 1 month after device implantation with the stimulator off and after 3 months of chronic electric stimulation (stimulator on). Chronic baroreceptor stimulation decreased office blood pressure from 185±31/109±24 mm Hg to 154±23/95±16 mm Hg (P<0.0001/P=0.002). Mean heart rate decreased from 81±11 to 76±10 beats per minute^–1 (P=0.001). Heart rate variability frequency-domain parameters assessed using fast Fourier transformation (FFT; ratio of low frequency:high frequency: 2.78 versus 2.24 for off versus on; P<0.001) were significantly changed during stimulation of the carotid baroreceptor, and heart rate turbulence onset was significantly decreased (turbulence onset: –0.002 versus –0.015 for off versus on; P=0.004). In conclusion, chronic baroreceptor stimulation causes sustained changes in heart rate variability and heart rate turbulence that are consistent with inhibition of sympathetic activity and increase of parasympathetic activity in patients with drug-resistant systemic hypertension; these changes correlate with blood pressure reduction. Whether the autonomic modulation has favorable cardiovascular effects beyond blood pressure control should be investigated in further studies.

Deletion of Mineralocorticoid Receptors From Macrophages Protects Against Deoxycorticosterone/Salt-Induced Cardiac Fibrosis and Increased Blood Pressure [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Increased mineralocorticoid levels plus high salt promote vascular inflammation and cardiac tissue remodeling. Mineralocorticoid receptors are expressed in many cell types of the cardiovascular system, including monocytes/macrophages and other inflammatory cell types. Although mineralocorticoid receptors are expressed in monocytes/macrophages, their role in regulating macrophage function to date has not been investigated. We, thus, used the Cre/LoxP-recombination system to selectively delete mineralocorticoid receptors from monocytes/macrophages with the lysozyme M promoter used to drive Cre expression (MR^flox/flox/LysM^Cre/– mice). Male mice from each genotype (MR^flox/flox or wild-type and MR^flox/flox/LysM^Cre/– mice) were uninephrectomized, given 0.9% NaCl solution to drink, and treated for 8 days or 8 weeks with either vehicle (n=10) or deoxycorticosterone (n=10). Equivalent tissue macrophage numbers were seen for deoxycorticosterone treatment of each genotype at 8 days; in contrast, plasminogen activator inhibitor type 1 and NAD(P)H oxidase subunit 2 levels were increased in wild-type but not in MR^flox/flox/LysM^Cre/– mice given deoxycorticosterone. Baseline expression of other inflammatory genes was reduced in MR^flox/flox/LysM^Cre/– mice compared with wild-type mice. At 8 weeks, deoxycorticosterone-induced macrophage recruitment and connective tissue growth factor and plasminogen activator inhibitor type 1 mRNA levels were similar for each genotype; in contrast, MR^flox/flox/LysM^Cre/– mice showed no increase in cardiac fibrosis or blood pressure, as was seen in wild-type mice at 8 weeks. These data demonstrate the following points: (1) mineralocorticoid receptor signaling regulates basal monocyte/macrophage function; (2) macrophage recruitment is not altered by loss of mineralocorticoid receptor signaling in these cells; and (3) a novel and significant role is seen for macrophage signaling in the regulation of cardiac remodeling and systolic blood pressure in the deoxycorticosterone/salt model.

Critical Role of Apoptosis Signal-Regulating Kinase 1 in Aldosterone/Salt-Induced Cardiac Inflammation and Fibrosis [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

The molecular mechanism underlying aldosterone/salt-induced cardiovascular injury remains to be defined. This work was undertaken to determine the role of apoptosis signal-regulating kinase 1 (ASK1) in the mechanism underlying aldosterone-induced cardiac injury in vivo. We compared the in vivo effects of 4 weeks of aldosterone/salt treatment on wild-type and ASK1-deficient mice. Aldosterone infusion plus high salt intake in wild-type mice significantly increased blood pressure and urinary albumin excretion and decreased plasma potassium concentrations, and these effects of aldosterone/salt were not affected by ASK1 deficiency. Thus, ASK1 seems to play a minor role in aldosterone-induced hypertension and renal injury. ASK1 deficiency also failed to affect aldosterone-induced cardiac hypertrophy. However, ASK1 deficiency markedly ameliorated aldosterone-induced cardiac injury, eg, the enhancement of cardiac macrophage infiltration, monocyte chemotactic protein 1 expression, interstitial fibrosis, perivascular fibrosis, and transforming growth factor-β1 and collagen type I expressions. Thus, ASK1 participates in aldosterone-induced cardiac inflammation and fibrosis. Furthermore, the enhancement of NADPH oxidase–mediated cardiac oxidative stress caused by aldosterone infusion was markedly lessened by ASK1 deficiency, which was associated with the significant amelioration by ASK1 deficiency of aldosterone-induced cardiac Nox2 upregulation. Furthermore, aldosterone/salt treatment significantly enhanced cardiac expression of the angiotensin-converting enzyme and angiotensin II type 1 receptor in wild-type mice, whereas the enhancement of these proteins by aldosterone/salt was abolished by ASK1 deficiency. Our results demonstrate that ASK1 is implicated in aldosterone/salt-induced cardiac inflammation and fibrosis through the enhancement of NADPH oxidase-mediated oxidative stress and the upregulation of the cardiac renin-angiotensin system.

Role of Mineralocorticoid Receptor on Experimental Cerebral Aneurysms in Rats [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Activation of the renin-angiotensin (Ang)-aldosterone system is involved in the pathology of vascular diseases. Although the blockade of the mineralocorticoid receptor protects against vascular diseases, its role in cerebral aneurysms remains to be elucidated. We treated female rats subjected to renal hypertension, increased hemodynamic stress, and estrogen deficiency for 3 months with the mineralocorticoid receptor blocker eplerenone (30 or 100 mg/kg per day) or vehicle (vehicle control). Eplerenone reduced the incidence of cerebral aneurysms and saline intake without lowering of the blood pressure. In the aneurysmal wall, the production of Ang II and nitrotyrosine was increased. The mRNA levels of Ang-converting enzyme 1 and NADPH oxidase subunits NOX4, Rac1, monocyte chemoattractant protein 1, and matrix metalloproteinase 9 were increased. Eplerenone brought about a reduction in these molecules, suggesting that mineralocorticoid receptor blockade suppresses cerebral aneurysm formation by inhibiting oxidative stress, inflammatory factors, local renin-Ang system activation, and saline intake. Other female rats implanted with pellets of the mineralocorticoid receptor agonist deoxycorticosterone acetate manifested a high incidence of cerebral aneurysm formation and the upregulation of molecules related to oxidative stress, inflammatory factors, and the local renin-Ang system; their saline intake was increased. We demonstrate that mineralocorticoid receptor activation at least partly contributes to the pathogenesis of cerebral aneurysms.

Arterial Load and Ventricular-Arterial Coupling: Physiologic Relations With Body Size and Effect of Obesity [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Accurate quantification of arterial function is crucial to distinguishing disease states from normal variants. However, there are little data regarding methods to scale arterial load to body size in humans. We studied 2365 adults aged 35 to 55 years free of overt cardiovascular disease. We assessed arterial hemodynamics and ventricular-vascular coupling with carotid tonometry and Doppler echocardiography. To define normal (physiological) relationships between hemodynamic indices and body size, we used nonlinear regression to analyze a selected reference subsample (n=612) with normal weight (body mass index 18 to 25 kg/m²), waist circumference, and metabolic parameters. Most arterial hemodynamic indices demonstrated important relationships with body size, which were frequently allometric (nonlinear). Allometric indexation using appropriate powers (but not ratiometric indexation) effectively eliminated the relationships between indices of arterial load and body size in normal subjects. In the entire sample (n=2365), the adverse effects of obesity on arterial load and end-systolic ventricular stiffening were clearly demonstrated only after appropriate indexation to account for the expected normal relationship to body size. After adjustment for age and sex, a progressive increase in indexed systemic vascular resistance, effective arterial and ventricular end-systolic elastance, and a decrease in total arterial compliance were seen from normal weight to obesity (P<0.0001). Arterial load relates to body size in an allometric fashion, calling for scaling with the use of appropriate powers. Obesity exerts adverse effects on arterial load and ventricular stiffening that go beyond the normal relationship with body size. Allometric normalization should allow more accurate quantification of arterial load in future studies.

Ameliorating Hypertension and Insulin Resistance in Subjects at Increased Cardiovascular Risk: Effects of Acetyl-L-Carnitine Therapy [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Insulin resistance, a key component of the metabolic syndrome, is a risk factor for diabetes mellitus and cardiovascular disease. Acetyl-l-carnitine infusion acutely ameliorated insulin sensitivity in type 2 diabetics with insulin resistance. In this sequential off-on-off pilot study, we prospectively evaluated the effects of 24-week oral acetyl-l-carnitine (1 g twice daily) therapy on the glucose disposal rate (GDR), assessed by hyperinsulinemic euglycemic clamps, and components of the metabolic syndrome in nondiabetic subjects at increased cardiovascular risk a priori segregated into 2 groups with GDR ≤7.9 (n=16) or >7.9 (n=16) mg/kg per minute, respectively. Baseline GDR and systolic blood pressure were negatively correlated (n=32; P=0.001; r=–0.545), and patients with GDR ≤7.9 mg/kg per minute had higher systolic/diastolic blood pressure than those with higher GDR. Acetyl-l-carnitine increased GDR from 4.89±1.47 to 6.72±3.12 mg/kg per minute (P=0.003, Bonferroni-adjusted) and improved glucose tolerance in patients with GDR ≤7.9 mg/kg per minute, whereas it had no effects in those with higher GDRs. Changes in GDR were significantly different between groups (P=0.017, ANCOVA). Systolic blood pressure decreased from 144.0±13.6 to 135.1±8.4 mm Hg and from 130.8±12.4 to 123.8±10.8 mm Hg in the lower and higher GDR groups, respectively (P<0.05 for both; P<0.001 overall) and progressively recovered toward baseline over 8 weeks posttreatment. Total and high molecular weight adiponectin levels followed specular trends. Diastolic blood pressure significantly decreased only in those with higher GDRs. Treatment was well tolerated in all of the patients. Acetyl-l-carnitine safely ameliorated arterial hypertension, insulin resistance, impaired glucose tolerance, and hypoadiponectinemia in subjects at increased cardiovascular risk. Whether these effects may translate into long-term cardioprotection is worth investigating.

Tumor Necrosis Factor-{alpha}-Converting Enzyme Is a Key Regulator of Agonist-Induced Cardiac Hypertrophy and Fibrosis [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Cardiac remodeling is associated with hypertrophy and fibrosis processes, which may depend on the activity of matrix metalloproteinases (MMPs) and "a disintegrin and metalloproteinases" (ADAMs). We investigated whether ADAM-17 (tumor necrosis factor-–converting enzyme [TACE]) plays a role in agonist-induced cardiac remodeling and the relationships established among TACE, MMP-2, and ADAM-12. We targeted TACE in rodent models of spontaneous and agonist-induced hypertension using RNA interference combined with quantitative RT-PCR, activity determinations, and functional studies. Treatment of spontaneously hypertensive rats with previously validated TACE small-interfering RNA for 28 days resulted in systemic knockdown of TACE expression. TACE knockdown effectively stopped the development of cardiac hypertrophy. Mice receiving angiotensin II (1.4 mg/kg per day for 12 days) exhibited cardiac hypertrophy, as well as fibrosis, which was associated with elevated myocardial expression of molecular markers of hypertrophy (-skeletal actin, β-myosin heavy chain, and brain natriuretic peptide) and fibrosis (collagen types I and III and fibronectin), as well as MMP-2 and ADAM-12. Treatment with TACE small-interfering RNA (but not with PBS or luciferase small-interfering RNA) inhibited TACE expression, thus preventing angiotensin II–induced cardiac hypertrophy and fibrosis. Moreover, knockdown of TACE inhibited angiotensin II–induced overexpression of markers of myocardial hypertrophy and fibrosis, as well as ADAM-12 and MMP-2. These findings provide the first in vivo evidence that agonist-induced cardiac hypertrophy and fibrosis processes are signaled through TACE, which acts through novel pathways involving transcriptional regulation of ADAM-12 and MMP-2. Targeting TACE has potential therapeutic importance for modulating agonist-induced cardiac remodeling.

Effects of Fixed-Dose Isosorbide Dinitrate/Hydralazine on Diastolic Function and Exercise Capacity in Hypertension-Induced Diastolic Heart Failure [Original Articles]

Wilson, R. M., De Silva, D. S., Sato, K., Izumiya, Y., Sam, F. — Wed, 19 Aug 2009 13:32:51 PDT

Hypertension-induced diastolic heart failure accounts for a large proportion of all heart failure presentations. Hypertension also induces left ventricular (LV) hypertrophy. Fixed-dose isosorbide dinitrate/hydralazine (HISDN) decreased mortality in human systolic heart failure but it is unknown whether it improves maladaptive myocardial remodeling. We sought to test the hypothesis that chronic HISDN modulates LV hypertrophy and myocardial remodeling in hypertension-induced diastolic heart failure. FVB mice underwent either saline (n=18) or aldosterone (n=28) infusion. All underwent uninephrectomy and drank 1% salt water for 4 weeks. Mice were randomized after surgery to regular chow or chow containing HISDN (isosorbide dinitrate: 26 mg/kg per day; hydralazine: 50 mg/kg per day) for 4 weeks. Aldosterone infusion increased tail-cuff blood pressure (161±3 mm Hg) versus saline-infused mice (129±2 mm Hg). Aldosterone induced LV hypertrophy versus saline-infused mice (LV:body weight ratio: 4.2±0.1 versus 3.6±0.1 mg/g). HISDN attenuated the aldosterone-induced increased in systolic blood pressure (137±5 mm Hg) and also lowered blood pressure in saline-infused mice (114±2 mm Hg). However, HISDN did not cause LV hypertrophy regression in aldosterone-infused mice. Aldosterone increased LV end-diastolic dimensions that were not attenuated by HISDN. Similarly, neither aldosterone infusion nor HISDN affected LV end-systolic dimensions. LV ejection fraction and wet:dry lung ratio were not different between aldosterone-untreated and aldosterone-HISDN mice. However, mitral Doppler E/A ratio (a measure of diastolic function), exercise capacity, and plasma soluble vascular cell adhesion molecule 1 levels were improved in aldosterone-HISDN hearts. In conclusion, fixed-dose HISDN improved hypertension, diastolic function, and exercise capacity and reduced soluble vascular cell adhesion molecule 1 levels. There were no reductions in LV hypertrophy, cardiac fibrosis, or pulmonary congestion. These functional improvements are likely related to extracardiac effects, such as effects on the vasculature.

Effect of Rosuvastatin on Cardiac Remodeling, Function, and Progression to Heart Failure in Hypertensive Heart With Established Left Ventricular Hypertrophy [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Hypertensive patients with left ventricular hypertrophy (LVH) are the most common high-risk group to develop heart failure with preserved ejection fraction. Recent reports have noted the favorable effect of statins on LVH. We evaluated the effect of rosuvastatin on cardiac remodeling, function, and progression to heart failure in a hypertensive rat model with established LVH. Dahl salt-sensitive rats were fed a high-salt diet until 13 weeks of age. After LVH was confirmed by echocardiography, rats were randomly assigned to control and statin treatment (n=18 each group). The statin-treated group was treated with rosuvastatin until 21 weeks of ages. Serial echocardiography, blood pressure monitoring, and miniaturized conductance catheter hemodynamic monitoring were performed at 21 weeks. Echocardiographic parameters were not significantly different between the groups. On hemodynamic monitoring, systolic performance parameters were similar between the groups, whereas end diastolic pressure-volume relationships were lower in the statin-treated group (0.014±0.008 versus 0.008±0.004 mm Hg/µL, P<0.05), suggesting improvement in myocardial stiffness. Pathological analysis showed attenuation of perivascular and interstitial fibrosis in the statin-treated group (P<0.02). Rosuvastatin therapy did not alleviate LVH in hypertensive rats with established LVH, but it attenuated myocardial fibrosis and LV stiffness. It seems that rosuvastatin has limited therapeutic value when used to prevent progression from LVH to heart failure in hypertensive hearts.

[Pyr1]Apelin-13 Identified as the Predominant Apelin Isoform in the Human Heart: Vasoactive Mechanisms and Inotropic Action in Disease [Original Articles]

Maguire, J. J., Kleinz, M. J., Pitkin, S. L., Davenport, A. P. — Wed, 19 Aug 2009 13:32:51 PDT

Apelin receptors, present on vascular smooth muscle cells, endothelium, and cardiomyocytes, are activated by the family of apelin peptides to elicit cardiovascular effects in experimental animals, but functional activity in humans has not been studied in detail. We detected low levels of apelin immunoreactivity in plasma of volunteers consistent with an autocrine/paracrine action and detected apelin immunoreactivity in the supernatant from human cultured endothelial cells. We found that [Pyr¹]apelin-13 was the predominant isoform in cardiac tissue from patients with coronary artery disease. We tested the hypothesis that apelins have vascular and cardiac actions in human tissues in vitro and compared responses to [Pyr¹]apelin-13, apelin-13, and apelin-36. In endothelium-intact mammary artery, all 3 of the apelins induced concentration-dependent vasodilatation with comparable potency (EC₅₀: 0.6 to 1.6 nM; maximum response: 40% to 50%). Vasodilatation was abolished after endothelial removal or preincubation with indomethacin but was unaffected by preincubation with N^G-nitro-l-arginine methyl ester, indicating involvement of prostanoids but not NO in dilatation by apelins in this patient group. Apelins were potent constrictors of endothelium-denuded saphenous vein (EC₅₀: 0.6 to 1.6 nM; maximum response: 17% to 26%) and mammary artery ([Pyr¹]apelin-13; EC₅₀: 0.2 nM; maximum response: 29%). In paced atrial strips, all 3 of the peptides increased the force of contraction with subnanomolar potencies (EC₅₀: 40 to 125 pM). For the first time, we demonstrate that the 3 principal forms of apelin have comparable potency and efficacy in human cardiovascular tissues. Apelins are potent endothelium-dependent vasodilators acting via a prostanoid-dependent mechanism; however, removal of the endothelium revealed direct vasoconstrictor actions in both the artery and vein. Furthermore, in human cardiac tissue, the apelin peptides are among the most potent endogenous positive inotropic agents yet reported.

The Cardioprotective Effects of Fish Oil During Pressure Overload Are Blocked by High Fat Intake: Role Of Cardiac Phospholipid Remodeling [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil may prevent development of heart failure through alterations in cardiac phospholipids that favorably impact inflammation and energy metabolism. A high-fat diet may block these effects in chronically stressed myocardium. Pathological left ventricle (LV) hypertrophy was generated by subjecting rats to pressure overload by constriction of the abdominal aorta. Animals were fed: (1) standard diet (10% of energy from fat), (2) standard diet with EPA+DHA (2.3% of energy intake as EPA+DHA), (3) high fat (60% fat); or (4) high fat with EPA+DHA. Pressure overload increased LV mass by 40% in both standard and high-fat diets without fish oil. Supplementation with fish oil increased their incorporation into cardiac phospholipids, and decreased the proinflammatory fatty acid arachidonic acid and urine thromboxane B₂ with both the standard and high-fat diet. Linoleic acid and tetralinoloyl cardiolipin (an essential mitochondrial phospholipid) were decreased with pressure overload on standard diet, which was prevented by fish oil. Animals fed high-fat diet had decreased linoleic acid and tetralinoloyl cardiolipin regardless of fish oil supplemention. Fish oil limited LV hypertrophy on the standard diet, and prevented upregulation of fetal genes associated with heart failure (myosin heavy chain-β and atrial natriuetic factor). These beneficial effects of fish oil were absent in animals on the high-fat diet. In conclusion, whereas treatment with EPA+DHA prevented tetralinoloyl cardiolipin depletion, LV hypertrophy, and abnormal genes expression with pressure overload, these effects were absent with a high-fat diet.

Regional Release and Clearance of C-Type Natriuretic Peptides in the Human Circulation and Relation to Cardiac Function [Original Articles]

Palmer, S. C., Prickett, T. C.R., Espiner, E. A., Yandle, T. G., Richards, A. M. — Wed, 19 Aug 2009 13:32:51 PDT

Production and clearance of plasma C-type natriuretic peptide (CNP) and amino terminal (NT)-proCNP immunoreactivity in the human circulation remain poorly characterized. Accordingly, we have measured arterial and venous concentrations of CNP and NT-proCNP across multiple tissue beds during cardiac catheterization in 120 subjects (age: 64.2±9.0 years; 73% men) investigated for cardiovascular disorders. The heart, head and neck, and musculoskeletal tissues made the clearest contributions to both plasma CNP and NT-proCNP (P<0.05). Net release of NT-proCNP was also observed from hepatic tissue (P<0.001). Negative arteriovenous gradients for CNP were observed across renal, hepatic, and pulmonary tissue (P<0.05), indicating net clearance, whereas no tissue-specific site of NT-proCNP clearance was identified. Age, mean pulmonary artery pressure, left ventricular end diastolic pressure, Brandt score of myocardial jeopardy, and troponin I were independent predictors of circulating CNP levels in multivariable analysis. Sex and kidney function were independently predictive of arterial NT-proCNP. The proportional step-up of CNP (+60%) across the heart was less than for brain natriuretic peptide (+123%) but greater than for NT–pro-brain natriuretic peptide (NT-proBNP) (+36%) and NT-proCNP (+42%; P<0.001 for all). We conclude that cardiac and head and neck tissue are important sources of CNP. Circulating CNP but not NT-proCNP concentrations are related to cardiac hemodynamic load and ischemic burden. Although cardiac release is most evident, multiple additional tissues release NT-proCNP immunoreactivity without evidence for an organ-specific site for NT-proCNP degradation. Taken together, differences in magnitude and direction of transorgan gradients for CNP compared with NT-proCNP suggest net generalized cosecretion with differing mechanisms of clearance.

Endogenous Interleukin-10 Inhibits Angiotensin II-Induced Vascular Dysfunction [Original Articles]

Didion, S. P., Kinzenbaw, D. A., Schrader, L. I., Chu, Y., Faraci, F. M. — Wed, 19 Aug 2009 13:32:51 PDT

Angiotensin II (Ang II) produces inflammation and endothelial dysfunction in blood vessels. We tested the hypothesis that interleukin 10 (IL-10), an antiinflammatory cytokine, protects against Ang II–induced vascular dysfunction. Responses of carotid arteries from wild-type and IL-10–deficient mice (IL-10^–/–) were examined in vitro after overnight incubation with vehicle or Ang II (1 nmol/L). In arteries from wild-type mice, acetylcholine (an endothelium-dependent agonist) produced relaxation that was not affected by Ang II. In contrast, relaxation to acetylcholine in arteries from IL-10^–/– mice was reduced by >50% by Ang II (P<0.05) and this effect was prevented by a scavenger of superoxide. Vascular superoxide increased 2-fold (P<0.05) after treatment with Ang II in IL-10^–/– mice but not in wild-type. After systemic administration of Ang II (1.4 mg/kg per day for 10 days), Ang II produced modest impairment of endothelial function in wild-type mice but marked impairment in IL-10^–/– mice (P<0.05) that was reversed by a superoxide scavenger. Increases in arterial pressure in response to Ang II were similar in wild-type and IL-10^–/– mice. These findings provide the first evidence that endogenous IL-10 limits Ang II-mediated oxidative stress and vascular dysfunction both in vitro and in vivo suggesting that at least some of the protective effects of IL-10 may occur within the vessel wall.

Tyrosine Nitration of PA700 Activates the 26S Proteasome to Induce Endothelial Dysfunction in Mice With Angiotensin II-Induced Hypertension [Original Articles]

Xu, J., Wang, S., Wu, Y., Song, P., Zou, M.-H. — Wed, 19 Aug 2009 13:32:51 PDT

The ubiquitin-proteasome system has been implicated in oxidative stress–induced endothelial dysfunction in cardiovascular diseases. However, the mechanism by which oxidative stress alters the ubiquitin-proteasome system is poorly defined. The present study was conducted to determine whether oxidative modifications of PA700, a 26S proteasome regulatory subunit, contributes to angiotensin II (Ang II)–induced endothelial dysfunction. Exposure of human umbilical vein endothelial cells to low concentrations of Ang II, but not vehicle, for 6 hours significantly decreased the levels of tetrahydro-l-biopterin (BH4), an essential cofactor of endothelial NO synthase, which was accompanied by a decrease in GTP cyclohydrolase I, the rate-limiting enzyme for de novo BH4 synthesis. In addition, Ang II increased both tyrosine nitration of PA700 and the 26S proteasome activity, which were paralleled by increased coimmunoprecipitation of PA700 and the 20S proteasome. Genetic inhibition of NAD(P)H oxidase or administration of uric acid (a peroxynitrite scavenger) or N^G-nitro-l-arginine methyl ester (nonselective NO synthase inhibitor) significantly attenuated Ang II–induced PA700 nitration, 26S proteasome activation, and reduction of GTP cyclohydrolase I and BH4. Finally, Ang II infusion in mice decreased the levels of both BH4 and GTP cyclohydrolase I and impaired endothelial-dependent relaxation in isolated aortas, and all of these effects were prevented by the administration of MG132, a potent inhibitor for 26S proteasome. We conclude that Ang II increases tyrosine nitration of PA700 resulting in accelerated GTP cyclohydrolase I degradation, BH4 deficiency, and consequent endothelial dysfunction in hypertension.

Aliskiren Enhances the Protective Effects of Valsartan Against Cardiovascular and Renal Injury in Endothelial Nitric Oxide Synthase-Deficient Mice [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

The protective effect of aliskiren, a direct renin inhibitor, against hypertensive cardiovascular and renal injury remains to be defined. This study was undertaken to examine the protective effects of the combination of aliskiren and valsartan, an angiotensin receptor blocker, against cardiovascular and renal injury. Endothelial NO synthase–deficient mice, subjected to cuff injury of femoral artery, were divided into 5 groups and were treated with the following: (1) vehicle; (2) aliskiren (25 mg/kg per day); (3) valsartan (8 mg/kg per day); (4) combined aliskiren (12.5 mg/kg per day) and valsartan (4 mg/kg per day); and (5) hydralazine (10 mg/kg per day) for 4 weeks. Aliskiren and valsartan alone markedly and similarly suppressed cardiac hypertrophy, inflammation and fibrosis, and coronary remodeling; prevented cuff injury–induced arterial intimal thickening; and reduced urinary albumin excretion, glomerular inflammation, and glomerulosclerosis in endothelial NO synthase–deficient mice. These beneficial effects of aliskiren and valsartan were associated with the significant attenuation of oxidative stress in these tissues. Hence, aliskiren and valsartan markedly exert the protective effects against cardiovascular and renal injury through the reduction of oxidative stress. Furthermore, compared with monotherapy with aliskiren or valsartan, the combination of a half dose of these drugs more greatly improved the above-mentioned cardiovascular and renal injuries of endothelial NO synthase–deficient mice, which were associated with greater attenuation of tissue oxidative stress by the combination therapy. Thus, the combination of aliskiren and valsartan exerts the synergistic organ-protective effects through synergistic attenuation of oxidative stress. The combination of aliskiren and valsartan seems to be a promising therapeutic strategy for hypertensive organ injury caused by endothelial NO synthase dysfunction.

Dissection of Chromosome 18 Blood Pressure and Salt-Sensitivity Quantitative Trait Loci in the Spontaneously Hypertensive Rat [Original Articles]

Wed, 19 Aug 2009 13:32:51 PDT

Hypertension in humans and experimental models has a strong hereditary basis, but identification of causative genes remains challenging. Quantitative trait loci (QTLs) for hypertension and salt sensitivity have been reported on rat chromosome 18. We set out to genetically isolate and prioritize genes within the salt-sensitivity and hypertension QTLs on the spontaneously hypertensive rat (SHR) chromosome 18 by developing and characterizing a series of congenic strains derived from the SHR and normotensive Brown Norway rat strains. The SHR.BN-D18Rat113/D18Rat82 congenic strain exhibits significantly lower blood pressure and is salt resistant compared with the SHR. Transplantation of kidneys from SHR.BN-D18Rat113/D18Rat82 donors into SHR recipients is sufficient to attenuate increased blood pressure but not salt sensitivity. Derivation of congenic sublines allowed for the separation of salt sensitivity from hypertension QTL regions. Renal expression studies with microarray and Solexa-based sequencing in parental and congenic strains identified 4 differentially expressed genes within the hypertension QTL region, one of which is an unannotated transcript encoding a previously undescribed, small, nonprotein coding RNA. Sequencing selected biological candidate genes within the minimal congenic interval revealed a nonsynonymous variant in SHR transcription factor 4. The minimal congenic interval is syntenic to a region of human chromosome 18 where significant linkage to hypertension was observed in family based linkage studies. These congenic lines provide reagents for identifying causative genes that underlie the chromosome 18 SHR QTLs for hypertension and salt sensitivity. Candidate genes identified in these studies merit further investigation as potentially causative hypertension genes in SHR and human hypertension.

Nocturia, Nocturnal Activity, and Nondipping [Original Articles]

Agarwal, R., Light, R. P., Bills, J. E., Hummel, L. A. — Wed, 19 Aug 2009 13:32:52 PDT

Patients with chronic kidney disease have less than expected decline in blood pressure during sleep (nondipping) and commonly experience the vexing symptom of nocturia. To better understand the relationship among nocturia, nighttime physical activity, and nondipping, we studied 98 patients with chronic kidney disease on 2 occasions, 1 month apart, with 24-hour ambulatory blood pressure monitoring and simultaneous activity monitoring with wrist actigraphy. Patients with nocturia had greater actigraphically recorded nighttime physical activity compared to those with no nocturia. The drop in activity from wake to sleep was reduced to a similar extent whether the patients had nocturia once or twice, but patients who had nocturia ≥3 times had the least reduction from wake to sleep activity (P<0.001 versus those with less degrees of nocturia). Those with nocturia had a lesser drop in systolic ambulatory blood pressure during sleep compared with those without nocturia. The average fall in sleep systolic blood pressure was 9.8 mm Hg (95% CI: 8.0 to 11.6 mm Hg) in those without nocturia compared with 3.4 mm Hg (95% CI: 2.7 to 4.1 mm Hg) in those with any severity of nocturia (P<0.001 for difference). Nondipping in patients with nocturia was mediated by nighttime physical activity. These differences were independent of estimated glomerular filtration rate, albuminuria, or use of diuretics. Thus, nocturia, which may reflect impaired renal tubular function, is associated with nondipping in patients with chronic kidney disease and appears to be mediated by increased nocturnal activity. Whether nocturia itself or the resulting nondipping associated with nocturia is of prognostic importance for cardiorenal events in patients with chronic kidney disease should be tested in future studies.

Vascular Endothelial Growth Factor Receptor 2 Controls Blood Pressure by Regulating Nitric Oxide Synthase Expression [Original Articles]

Facemire, C. S., Nixon, A. B., Griffiths, R., Hurwitz, H., Coffman, T. M. — Wed, 19 Aug 2009 13:32:52 PDT

Drugs and antibodies that interrupt vascular endothelial growth factor (VEGF) signaling pathways improve outcomes in patients with a variety of cancers by inhibiting tumor angiogenesis. A major adverse effect of these treatments is hypertension, suggesting a critical role for VEGF in blood pressure (BP) regulation. However, the physiological mechanisms underlying the control of BP by VEGF are unclear. To address this question, we administered a specific antibody against the major VEGF receptor, VEGFR2, to normal mice and assessed the consequences on BP. Compared with vehicle-treated controls, administration of the anti-VEGFR2 antibody caused a rapid and sustained increase in BP of 10 mm Hg. This increase in BP was associated with a significant reduction in renin mRNA expression in the kidney (P=0.019) and in urinary excretion of aldosterone (P<0.05). Treatment with the anti-VEGFR2 antibody also caused a marked reduction in the expression of endothelial and neuronal NO synthases in the kidney. To examine the role of NO in the hypertension caused by blocking VEGFR2, mice were treated with N-nitro-l-arginine methyl ester (l-NAME) (20 mg/kg per day), an inhibitor of NO production. l-NAME administration abolished the difference in BP between the vehicle- and anti-VEGFR2–treated groups. Our data suggest that VEGF, acting via VEGFR2, plays a critical role in BP control by promoting NO synthase expression and NO activity. Interfering with this pathway is likely to be one mechanism underlying hypertension caused by antiangiogenic agents targeting VEGF.

Insights Into the Mechanisms and Mediators of the Effects of Air Pollution Exposure on Blood Pressure and Vascular Function in Healthy Humans [Original Articles]

Wed, 19 Aug 2009 13:32:52 PDT

Fine particulate matter air pollution plus ozone impairs vascular function and raises diastolic blood pressure. We aimed to determine the mechanism and air pollutant responsible. The effects of pollution on heart rate variability, blood pressure, biomarkers, and brachial flow-mediated dilatation were determined in 2 randomized, double-blind, crossover studies. In Ann Arbor, 50 subjects were exposed to fine particles (150 µg/m³) plus ozone (120 parts per billion) for 2 hours on 3 occasions with pretreatments of an endothelin antagonist (Bosentan, 250 mg), antioxidant (Vitamin C, 2 g), or placebo. In Toronto, 31 subjects were exposed to 4 different conditions (particles plus ozone, particles, ozone, and filtered air). In Toronto, diastolic blood pressure significantly increased (2.9 and 3.6 mm Hg) only during particle-containing exposures in association with particulate matter concentration and reductions in heart rate variability. Flow-mediated dilatation significantly decreased (2.0% and 2.9%) only 24 hours after particle-containing exposures in association with particulate matter concentration and increases in blood tumor necrosis factor . In Ann Arbor, diastolic blood pressure significantly similarly increased during all of the exposures (2.5 to 4.0 mm Hg), a response not mitigated by pretreatments. Flow-mediated dilatation remained unaltered. Particulate matter, not ozone, was responsible for increasing diastolic blood pressure during air pollution inhalation, most plausibly by instigating acute autonomic imbalance. Only particles from urban Toronto additionally impaired endothelial function, likely via slower proinflammatory pathways. Our findings demonstrate credible mechanisms whereby fine particulate matter could trigger acute cardiovascular events and that aspects of exposure location may be an important determinant of the health consequences.

Resveratrol Prevents Monocrotaline-Induced Pulmonary Hypertension in Rats [Original Articles]

Wed, 19 Aug 2009 13:32:52 PDT

Proliferation of pulmonary arterial smooth muscle cells, endothelial dysfunction, oxidative stress, and inflammation promotes the development of pulmonary hypertension. Resveratrol is a polyphenolic compound that exerts antioxidant and anti-inflammatory protective effects in the systemic circulation, but its effects on pulmonary arteries remain poorly defined. The present study was undertaken to investigate the efficacy of resveratrol to prevent pulmonary hypertension. Rats injected with monocrotaline progressively developed pulmonary hypertension. Resveratrol treatment (25 mg/kg per day, PO, from day 1 postmonocrotaline) attenuated right ventricular systolic pressure and pulmonary arterial remodeling, decreased expression of inflammatory cytokines (tumor necrosis factor-, interleukin 1β, interleukin 6, and platelet-derived growth factor-/β), and limited leukocyte infiltration in the lung. Resveratrol also inhibited proliferation of pulmonary arterial smooth muscle cells. Treatment of rats with resveratrol increased expression of endothelial NO synthase, decreased oxidative stress, and improved endothelial function in small pulmonary arteries. Pulmonary hypertension was associated with an upregulation of NAD(P)H oxidase in small pulmonary arteries, which was significantly attenuated by resveratrol treatment. Our studies show that resveratrol exerts anti-inflammatory, antioxidant, and antiproliferative effects in the pulmonary arteries, which may contribute to the prevention of pulmonary hypertension.

Pharmacological Characterization of SAR407899, a Novel Rho-Kinase Inhibitor [Original Articles]

Wed, 19 Aug 2009 13:32:52 PDT

Recent advances in basic and clinical research have identified Rho kinase as an important target potentially implicated in a variety of cardiovascular diseases. Rho kinase is a downstream mediator of RhoA that leads to stress fiber formation, membrane ruffling, smooth muscle contraction, and cell motility. Increased Rho-kinase activity is associated with vasoconstriction and elevated blood pressure. We identified a novel inhibitor of Rho kinase (SAR407899) and characterized its effects in biochemical, cellular, tissue-based, and in vivo assays. SAR407899 is an ATP-competitive Rho-kinase inhibitor, equipotent against human and rat-derived Rho-kinase 2 with inhibition constant values of 36 nM and 41 nM, respectively. It is highly selective in panel of 117 receptor and enzyme targets. SAR407899 is 8-fold more active than fasudil. In vitro, SAR407899 demonstrated concentration-dependent inhibition of Rho-kinase–mediated phosphorylation of myosin phosphatase, thrombin-induced stress fiber formation, platelet-derived growth factor–induced proliferation, and monocyte chemotactic protein-1–stimulated chemotaxis. SAR407899 potently (mean IC₅₀ values: 122 to 280 nM) and species-independently relaxed precontracted isolated arteries of different species and different vascular beds. In vivo, over the dose range 3 to 30 mg/kg PO, SAR407899 lowered blood pressure in a variety of rodent models of arterial hypertension. The antihypertensive effect of SAR407899 was superior to that of fasudil and Y-27632. In conclusion, SAR407899 is a novel and potent selective Rho-kinase inhibitor with promising antihypertensive activity.