Hypertension On-line First

p21-Activated Kinase 1 Participates in Vascular Remodeling In Vitro and In Vivo. Inter-American Society of Hypertension [Scientific Contributions]

Mon, 09 Nov 2009 12:51:27 PST

Abstract—Vascular smooth muscle cell hypertrophy, proliferation, or migration occurs in hypertension, atherosclerosis, and restenosis after angioplasty, leading to pathophysiological vascular remodeling. Angiotensin II and platelet-derived growth factor are well-known participants of vascular remodeling and activate a myriad of downstream protein kinases, including p21-activated protein kinase (PAK1). PAK1, an effector kinase of small GTPases, phosphorylates several substrates to regulate cytoskeletal reorganization. However, the exact role of PAK1 activation in vascular remodeling remains to be elucidated. Here, we have hypothesized that PAK1 is a critical target of intervention for the prevention of vascular remodeling. Adenoviral expression of dominant-negative PAK1 inhibited angiotensin II–stimulated vascular smooth muscle cell migration. It also inhibited vascular smooth muscle cell proliferation induced by platelet-derived growth factor. PAK1 was activated in neointima of the carotid artery after balloon injury in the rat. Moreover, marked inhibition of the neointima hyperplasia was observed in a dominant-negative PAK1 adenovirus-treated carotid artery after the balloon injury. Taken together, these results suggest that PAK1 is involved in both angiotensin II and platelet-derived growth factor–mediated vascular smooth muscle cell remodeling, and inactivation of PAK1 in vivo could be effective in preventing pathophysiological vascular remodeling.

Mitogen-Activated Protein Kinases as Biomarkers of Hypertension or Cardiac Pressure Overload [Editorial Commentaries]

Ocaranza, M. P., Jalil, J. E. — Mon, 09 Nov 2009 12:51:06 PST

Sympathetic Tone in the Young. The Mother Weighs In [Editorial Commentaries]

Rahmouni, K. — Mon, 09 Nov 2009 12:50:51 PST

Extracellular Signal-Regulated Kinase 1/2 Activation, via Downregulation of Mitogen-Activated Protein Kinase Phosphatase 1, Mediates Sex Differences in Desoxycorticosterone Acetate-Salt Hypertension Vascular Reactivity. Inter-American Society of Hypertension [Scientific Contributions]

Mon, 09 Nov 2009 12:50:37 PST

Abstract—Extracellular signal–regulated kinase (ERK)1/2 has been reported to play a role in vascular dysfunction associated with mineralocorticoid hypertension. We hypothesized that, compared with female rats, an upregulation of ERK1/2 signaling in the vasculature of male rats contributes to augmented contractile responses in mineralocorticoid hypertension. Uninephrectomized male and female Sprague-Dawley rats received desoxycorticosterone acetate (DOCA) pellets (200 mg per animal) and saline to drink for 3 weeks. Control uninephrectomized rats received tap water to drink. Blood pressure, measured by telemetry, was significantly higher in male DOCA rats (191±3 mm Hg) compared with female DOCA rats (172±7 mm Hg; n=5). DOCA treatment resulted in augmented contractile responses to phenylephrine in aorta (22±3 mN; n=6) and small mesenteric arteries (13±2 mN; n=6) from male DOCA rats versus uninephrectomized male rats (16±3 and 10±2 mN, respectively; P<0.05) and female DOCA rats (15±1 and 11±1 mN, respectively). ERK1/2 inhibition with PD-98059 (10 µmol/L) abrogated increased contraction to phenylephrine in aorta (14±2 mN) and small mesenteric arteries (10±2 mN) from male DOCA rats, without any effects in arteries from male uninephrectomized or female animals. Compared with the other groups, phosphorylated ERK1/2 levels were increased in the aorta from male DOCA rats, whereas mitogen-activated protein kinase phosphatase 1 expression was decreased. Interleukin-10 plasma levels, which positively regulate mitogen-activated protein kinase phosphatase 1 activity, were reduced in male DOCA-salt rats. We speculate that augmented vascular reactivity in male hypertensive rats is mediated via activation of the ERK1/2 pathway. In addition, mitogen-activated protein kinase phosphatase 1 and interleukin 10 play regulatory roles in this process.

Evidence for Sympathetic Origins of Hypertension in Juvenile Offspring of Obese Rats [Scientific Contributions]

Mon, 09 Nov 2009 12:50:21 PST

Abstract—Maternal obesity in rodents is associated with increased adiposity, impaired glucose tolerance, and hypertension in adult offspring. In this study we investigated the influence of maternal obesity in the rat on blood pressure and blood pressure regulatory pathways in juvenile and adult offspring. Obesity was induced before pregnancy in female Sprague-Dawley rats by feeding a highly palatable energy-dense diet. In juvenile animals (30 days of age), before the onset of obesity and hyperleptinemia, basal nighttime mean arterial pressure was significantly raised in the offspring of obese dams (OffOb) relative to offspring of controls (OffCon; mean arterial pressure, males: OffOb, 121.8±0.6 mm Hg versus OffCon, 115.0±0.5 mm Hg, n=6, P<0.01; females: OffOb, 125.4±0.4 mm Hg versus OffCon, 114.4±0.5 mm Hg, n=6, P<0.001), as was the mean arterial pressure response to restraint stress (P<0.01). The pressor response to a leptin challenge was enhanced in OffOb rats (mean arterial pressure: OffOb, 9.7±0.8 mm Hg versus OffCon, 5.3±1.3 mm Hg; n=8; P<0.05). Renal tissue norepinephrine content (P<0.001) and renin expression (P<0.05) were markedly raised. Analysis of heart rate variability revealed an increased low:high frequency ratio in OffOb versus OffCon rats (P<0.05). At 90 days, hypertension in OffOb rats persisted and was abolished by 1- and β-adrenergic blockade, and cardiovascular responses to phenylephrine or sodium nitroprusside indicated altered baroreceptor function. The exaggerated pressor response to leptin in OffOb rats was maintained. Hypertension in the offspring of obese rats may arise from persistent sympathoexcitatory hyperresponsiveness acquired in early stages of development.

Induction of Mitogen-Activated Protein Kinases Is Proportional to the Amount of Pressure Overload [Scientific Contributions]

Mon, 09 Nov 2009 12:50:08 PST

Abstract—Pressure overload has been shown to induce mitogen activated protein kinases (MAPKs) and reactivate the atrial natriuretic factor in the heart. To test the sensitivity of these signals to pressure overload, we assayed the activity of MAPKs extracellular signal–regulated kinase, c-Jun N-terminal kinase 1, and p38 in protein lysates from the left ventricle (LV) or white blood cells (WBC) isolated from aortic banded mice with varying levels of pressure overload. In separated mice we measured atrial natriuretic factor mRNA levels by Northern blotting. As expected, a significant induction of atrial natriuretic factor mRNA levels was observed after aortic banding, and it significantly correlated with the trans-stenotic systolic pressure gradient but not with the LV weight:body weight ratio. In contrast, a significant correlation with systolic pressure gradient or LV weight:body weight ratio was observed for all of the MAPK activity detected in LV samples or WBCs. Importantly, LV activation of MAPKs significantly correlated with their activation in WBCs from the same animal. To test whether MAPK activation in WBCs might reflect uncontrolled blood pressure levels in humans, we assayed extracellular signal–regulated kinase, c-Jun N-terminal kinase 1, and p38 activation in WBCs isolated from normotensive volunteers, hypertensive patients with controlled blood pressure values, or hypertensive patients with uncontrolled blood pressure values. Interestingly, in hypertensive patients with controlled blood pressure values, LV mass and extracellular signal–regulated kinase phosphorylation were significantly reduced compared with those in hypertensive patients with uncontrolled blood pressure values. These results suggest that MAPKs are sensors of pressure overload and that extracellular signal–regulated kinase activation in WBCs might be used as a novel surrogate biomarker of uncontrolled human hypertension.

Arteriosclerosis and Atherosclerosis. Guilty by Association [Editorial Commentaries]

Wilkinson, I. B., McEniery, C. M., Cockcroft, J. R. — Mon, 02 Nov 2009 12:54:28 PST

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

McNicholas, C. M., Berecek, K. H. — Mon, 02 Nov 2009 12:54:10 PST

Cardiovascular Responses to Hypothalamic Arcuate Nucleus Stimulation in the Rat. Role of Sympathetic and Vagal Efferents [Scientific Contributions]

Nakamura, T., Bhatt, S., Sapru, H. N. — Mon, 02 Nov 2009 12:53:47 PST

Abstract—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.

Spironolactone Attenuates Experimental Uremic Cardiomyopathy by Antagonizing Marinobufagenin [Scientific Contributions]

Mon, 02 Nov 2009 12:53:24 PST

Abstract—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.

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

Davern, P. J., Chen, D., Head, G. A., Chavez, C. A., Walther, T., Mayorov, D. N. — Mon, 02 Nov 2009 12:53:05 PST

Abstract—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.

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

Mon, 02 Nov 2009 12:52:40 PST

Abstract—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.

Elastase-Induced Intracranial Aneurysms in Hypertensive Mice [Scientific Contributions]

Nuki, Y., Tsou, T.-L., Kurihara, C., Kanematsu, M., Kanematsu, Y., Hashimoto, T. — Mon, 02 Nov 2009 12:52:17 PST

Abstract—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.

Dissociation of Aortic Pulse Wave Velocity With Risk Factors for Cardiovascular Disease Other Than Hypertension. A Systematic Review [Scientific Contributions]

Cecelja, M., Chowienczyk, P. — Mon, 02 Nov 2009 12:52:01 PST

Abstract—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.

Efficacy of Spironolactone Therapy in Patients With True Resistant Hypertension. Inter-American Society of Hypertension [Scientific Contributions]

de Souza, F., Muxfeldt, E., Fiszman, R., Salles, G. — Mon, 26 Oct 2009 12:52:49 PDT

Abstract—The role of spironolactone in resistant hypertension management is unclear. The aim of this prospective trial was to evaluate the antihypertensive effect of spironolactone in patients with true resistant hypertension diagnosed by ambulatory blood pressure monitoring. A total of 175 patients had clinical and complementary exams obtained at baseline and received spironolactone in doses of 25 to 100 mg/d. A second ambulatory blood pressure monitoring was performed after a median interval of 7 months. Paired Student t test was used to assess differences in blood pressure before and during spironolactone administration, and multivariate analysis adjusted for age, sex, and number of antihypertensive drugs to assess the predictors of blood pressure fall. There were mean reductions of 16 and 9 mm Hg, respectively, in 24-hour systolic and diastolic blood pressures (95% CIs: 13 to 18 and 7 to 10 mm Hg; P<0.001). Office systolic blood pressure and diastolic blood pressure also decreased (14 and 7 mm Hg). Controlled ambulatory blood pressure was reached in 48% of patients. Factors associated with better response were higher waist circumference, lower aortic pulse wave velocity, and lower serum potassium. No association with plasma aldosterone or aldosterone:renin ratio was found. Adverse effects were observed in 13 patients (7.4%). A third ambulatory blood pressure monitoring performed in 78 patients after a median of 15 months confirmed the persistence of the spironolactone effect. In conclusion, spironolactone administration to true resistant hypertensive patients is safe and effective in decreasing blood pressure, especially in those with abdominal obesity and lower arterial stiffness. Its addition to an antihypertensive regimen as the fourth or fifth drug is recommended.

Pressure-Induced Renal Injury in Angiotensin II Versus Norepinephrine-Induced Hypertensive Rats [Scientific Contributions]

Polichnowski, A. J., Cowley, A. W. — Mon, 26 Oct 2009 12:52:31 PDT

Abstract—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.

Validation of a Case Definition to Define Hypertension Using Administrative Data [Scientific Contributions]

Mon, 26 Oct 2009 12:52:17 PDT

Abstract—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.

Ablation of Transient Receptor Potential Vanilloid 1 Abolishes Endothelin-Induced Increases in Afferent Renal Nerve Activity. Mechanisms and Functional Significance [Scientific Contributions]

Xie, C., Wang, D. H. — Mon, 26 Oct 2009 12:51:54 PDT

Abstract—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.

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

Mon, 26 Oct 2009 12:51:27 PDT

Abstract—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.

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

Agarwal, R. — Mon, 19 Oct 2009 12:45:42 PDT

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

Flynn, J. T. — Mon, 19 Oct 2009 12:45:21 PDT

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

Nagy, G., Nagy, C. B. — Mon, 19 Oct 2009 12:45:02 PDT

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

Danser, A. H. J. — Mon, 19 Oct 2009 12:44:44 PDT

Mineralocorticoid Receptors in Myocardial Infarction [Editorial Commentaries]

Stier, C. T. — Mon, 19 Oct 2009 12:44:29 PDT

Accelarated Skeletal Maturation in Children With Primary Hypertension [Scientific Contributions]

Mon, 19 Oct 2009 12:44:05 PDT

Abstract—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.

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

Campbell, D. J., Karam, H., Menard, J., Bruneval, P., Mullins, J. J. — Mon, 19 Oct 2009 12:43:36 PDT

Abstract—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.

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

Briones, A. M., Touyz, R. M. — Mon, 19 Oct 2009 12:43:16 PDT

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction [Scientific Contributions]

Mihailidou, A. S., Loan Le, T. Y., Mardini, M., Funder, J. W. — Mon, 19 Oct 2009 12:42:54 PDT

Abstract—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.

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

Agarwal, D., Haque, M., Sriramula, S., Mariappan, N., Pariaut, R., Francis, J. — Mon, 19 Oct 2009 12:42:29 PDT

Abstract—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.

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

Schroen, B., Heymans, S. — Mon, 19 Oct 2009 12:42:03 PDT

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

Mon, 19 Oct 2009 12:41:44 PDT

Abstract—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.

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

Lieb, D. C., Kemp, B. A., Howell, N. L., Gildea, J. J., Carey, R. M. — Mon, 19 Oct 2009 12:41:20 PDT

Abstract—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.

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. — Mon, 19 Oct 2009 12:41:02 PDT

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

Mon, 19 Oct 2009 12:40:46 PDT

Abstract—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.

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

Reudelhuber, T. L. — Mon, 12 Oct 2009 12:57:39 PDT

Glutathione S-Transferase-{mu}1 Regulates Vascular Smooth Muscle Cell Proliferation, Migration, and Oxidative Stress [Scientific Contributions]

Yang, Y., Parsons, K. K., Chi, L., Malakauskas, S. M., Le, T. H. — Mon, 12 Oct 2009 12:57:15 PDT

Abstract—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.

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

Yamamoto, K., Ohishi, M., Ho, C., Kurtz, T. W., Rakugi, H. — Mon, 12 Oct 2009 12:56:57 PDT

Abstract—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.

Preservation of Intracellular Renin Expression Is Insufficient to Compensate for Genetic Loss of Secreted Renin [Scientific Contributions]

Xu, D., Borges, G. R., Grobe, J. L., Pelham, C. J., Yang, B., Sigmund, C. D. — Mon, 12 Oct 2009 12:56:41 PDT

Abstract—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.

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

Mon, 12 Oct 2009 12:56:23 PDT

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

Marchesi, C., Ebrahimian, T., Angulo, O., Paradis, P., Schiffrin, E. L. — Mon, 12 Oct 2009 12:55:57 PDT

Abstract—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.

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

Mon, 12 Oct 2009 12:55:38 PDT

Abstract—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.

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

Imig, J. D. — Mon, 12 Oct 2009 12:55:23 PDT

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

Mon, 12 Oct 2009 12:55:02 PDT

Abstract—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.

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

Mon, 05 Oct 2009 12:44:25 PDT

Abstract—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.

Relationship of Carotid Distensibility and Thoracic Aorta Calcification. Multi-Ethnic Study of Atherosclerosis [Scientific Contributions]

Mon, 05 Oct 2009 12:44:02 PDT

Abstract—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.

Renal Proximal Tubular Reabsorption Is Reduced In Adult Spontaneously Hypertensive Rats. Roles of Superoxide and Na+/H+ Exchanger 3 [Scientific Contributions]

Panico, C., Luo, Z., Damiano, S., Artigiano, F., Gill, P., Welch, W. J. — Mon, 05 Oct 2009 12:42:14 PDT

Abstract—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.

Response: Retinal Vessel Narrowing: A Prehypertensive or Masked Hypertensive State? [Letters to the Editor]

Mon, 03 Apr 2006 13:00:13 PDT

Response: Leptin, Endothelin, NADPH Oxidase, and Heart Failure [Letters to the Editor]

Dong, F., Zhang, X., Ren, J. — Mon, 27 Mar 2006 13:01:30 PST

Acknowledgment of Reviewers [Article]

Mon, 06 Feb 2006 13:00:04 PST

Preface [Preface]

Harder, D. R. — Mon, 06 Feb 2006 12:59:37 PST

Response: ClC-Kb Mutation Revisited [Letters to the Editor]

Jeck, N., Waldegger, S., Wissinger, B., Schwab, M., Lang, F. — Mon, 30 Jan 2006 12:47:12 PST

Response: Endothelial Function and Preeclampsia [Letters to the Editor]

Khan, F., Belch, J. J.F., MacLeod, M., Mires, G. — Mon, 09 Jan 2006 12:50:02 PST

Response [Letters to the Editor]

Hu, F. — Tue, 27 Dec 2005 12:51:15 PST

Response [Letters to the Editor]

Takai, S., Miyazaki, M. — Mon, 19 Dec 2005 12:58:58 PST

Mononuclear Leukocyte Mineralocorticoid Receptors. A Possible Link Between Aldosterone and Atherosclerosis [Letters to the Editor]

Armanini, D., Fiore, C., Calo, L. A — Mon, 19 Dec 2005 12:58:47 PST

Magnesium and Arterial Stiffness [Letters to the Editor]

Kisters, K., Gremmler, B., Hausberg, M. — Mon, 05 Dec 2005 12:55:48 PST

Response [Letters to the Editor]

Laurent, S. — Mon, 05 Dec 2005 12:55:33 PST

Response [Letters to the Editor]

Mon, 14 Nov 2005 13:02:19 PST

Response [Letters to the Editor]

Grassi, D., Ferri, C., Blumberg, J. B. — Mon, 14 Nov 2005 12:59:22 PST

Response [Letters to the Editor]

Grassi, D., Desideri, G., Ferri, C., Blumberg, J. B. — Mon, 17 Oct 2005 13:02:07 PDT

Response [Letters to the Editor]

Verbeke, F., Segers, P., Verdonck, P., Vanholder, R., Van Bortel, L. M. — Mon, 17 Oct 2005 13:00:29 PDT

Response [Letters to the Editor]

Garrett, M. R., Rapp, J. P., Joe, B., Meng, H. — Mon, 10 Oct 2005 12:57:53 PDT

Response [Letters to the Editor]

Schoner, W. — Mon, 19 Sep 2005 13:57:08 PDT

Response [Letters to the Editor]

Dolan, E., Stanton, A., O'Brien, E., Staessen, J. A. — Mon, 19 Sep 2005 13:57:51 PDT

Response [Letters to the Editor]

Schoner, W. — Mon, 15 Aug 2005 13:00:36 PDT

Response [Letters to the Editor]

Fyhrquist, F., Devereux, R. B., Kjeldsen, S. E., Dahlof, B. — Mon, 18 Jul 2005 12:48:14 PDT

Inhibition of Rho-Kinase in the Nucleus Tractus Solitarius Enhances Glutamate Sensitivity in Rats [Scientific Contributions]

Tue, 05 Jul 2005 08:01:33 PDT

Abstract--The Rho/Rho-kinase pathway in the central nervous system is involved in the maintenance of dendritic spines, which form the postsynaptic contact sites of excitatory synapses. Inhibition of the Rho-kinase pathway in neuron promotes dendritic spines or branches. In contrast, activation of the Rho/Rho-kinase pathway reduces dendritic spines or branches. Recent studies suggest that morphological changes of dendritic spines occur rapidly, and spine morphology is associated with glutamate sensitivity. The aim of the present study was to determine whether Rho-kinase activity affects glutamate sensitivity in the nucleus tractus solitarii (NTS) of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). We first examined the effects of unilateral glutamate injection in the NTS. There was a significantly smaller decrease in arterial pressure in SHR than in WKY. We then examined the depressor responses evoked by unilateral glutamate injection into the NTS after preinjection of Y-27632, a specific Rho-kinase inhibitor. Preinjection of Y-27632 enhanced the glutamate response in both strains. However, the magnitude of the augmentation was significantly greater in SHR than in WKY. Furthermore, we recorded single-unit activity of NTS neurons from medulla brain slice preparations. N-methyl-D-aspartate (NMDA) or -amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) was applied iontophoretically to the recorded neurons, and neuronal activity was recorded before and after Y-27632 perfusion. Y-27632 perfusion increased the response to NMDA and AMPA. These results suggest that inhibition of Rho-kinase activity in the NTS enhances glutamate sensitivity in WKY and SHR and might improve impaired glutamate sensitivity in SHR.

Response [Letters to the Editor]

Mon, 27 Jun 2005 12:48:18 PDT

Response: White Coat Hypertension, Dipping, and Nondipping in Obesity [Letters to the Editor]

Kotsis, V., Stabouli, S., Bouldin, M., Low, A., Toumanidis, S., Zakopoulos, N. — Mon, 13 Jun 2005 12:56:51 PDT

Response: Widely Possible Versus Selectively Perfect [Letters to the Editor]

de Simone, G. — Mon, 16 May 2005 13:04:54 PDT

Response [Letters to the Editor]

Townsend, S., Berkowitz, D. E. — Mon, 16 May 2005 13:04:44 PDT

Ouabain and Serum Sodium [Letters to the Editor]

Gasowski, J., Manunta, P., Bianchi, G., Staessen, J. A. — Mon, 09 May 2005 12:49:48 PDT

Response: Ouabain and Serum Sodium [Letters to the Editor]

He, F. J., MacGregor, G. A. — Mon, 09 May 2005 12:49:34 PDT

Response [Letters to the Editor]

Shibao, C., Gamboa, A., Diedrich, A., Biaggioni, I. — Mon, 25 Apr 2005 12:53:00 PDT

Response [Letters to the Editor]

Pickering, T. G. — Mon, 18 Apr 2005 12:56:42 PDT

Response: Flow-Mediated Dilation: Just a Marker of Local Shear Stress? [Letters to the Editor]

Mon, 10 Jan 2005 12:46:16 PST

Urinary Potassium Excretion and Sodium Sensitivity in Blacks (Response: Reinterpreting Sodium-Potassium Data in Salt Sensitivity Hypertension: A Prospective Debate) [Letters to the Editor]

Aviv, A., Hollenberg, N. K., Weder, A. — Mon, 03 Jan 2005 12:59:21 PST

Response [Letters to the Editor]

Gironacci, M. M. — Mon, 03 Jan 2005 12:59:00 PST

Angiotensin-(1-7) and Bradykinin in Norepinephrine Release in the Central Nervous System of Hypertension [Letters to the Editor]

Tsuda, K., Nishio, I. — Mon, 03 Jan 2005 12:58:50 PST

Response: Prognostic Significance of Serial Electrocardiographic Repolarization Changes [Letters to the Editor]

Fagard, R. H., on behalf of the Syst-Eur investigators — Mon, 06 Dec 2004 12:49:46 PST

Response [Letters to the Editor]

Schneider, M. P., Schmieder, R. E. — Mon, 06 Dec 2004 12:50:12 PST

Response: Physical Activity and Fitness in Arterial Stiffness: What Role Does Exposure Measurement Error Occupy? [Letters to the Editor]

Mon, 29 Nov 2004 12:58:10 PST

Response [Letters to the Editor]

Mon, 18 Oct 2004 13:03:10 PDT

Response [Letters to the Editor]

Jones, D. W. — Mon, 18 Oct 2004 13:02:49 PDT

Response: Is It Essential to Change the Term "Essential Hypertension" [Letters to the Editor]

Materson, B. J. — Mon, 20 Sep 2004 12:54:27 PDT

Response: Blood Pressure, Resting Energy Expenditure, and Creatine Kinase Activity: [Letters to the Editor]

Luke, A., Adeyemo, A., Kramer, H., Forrester, T., Cooper, R. S. — Mon, 26 Jul 2004 12:41:03 PDT

Response: Neural Sympathetic Activity in Essential Hypertension [Letters to the Editor]

Schlaich, M. P., Esler, M. D. — Mon, 07 Jun 2004 12:40:12 PDT

Neuroendocrine Transcriptome in Genetic Hypertension. Multiple Changes in Diverse Adrenal Physiological Systems [Scientific Contributions]

Mon, 19 Apr 2004 12:42:53 PDT

Abstract--The genetic basis of hypertension in the genetically/hereditary hypertensive (BPH/2) mouse strain is incompletely understood, although a recent genome scan uncovered evidence for several susceptibility loci. To probe the neuroendocrine transcriptome in this disease model, 12 488 probe set microarray experiments were performed on mRNA transcripts from adrenal glands of juvenile (prehypertensive) and adult BPH/2 (hypertensive), as well as the genetically/hereditary low-blood pressure (BPL/1), strains at both time points. To determine the impact of strain (BPH/2 versus BPL/1), age (juvenile versus adult), and the interaction of strain and age on gene expression levels, we performed standard 2-factor ANOVA and computed a concordance coefficient to assess the reproducibility of gene expression measurements among replicates. Of genes with significant (P<0.05) differential expression, 2647 showed strain differences, 982 showed age differences, and 757 exhibited strain-by-age interaction. Fold-changes in gene expression assayed by microarray were confirmed in a subset by real-time polymerase chain reaction (R=0.739, P=0.0094). We used a systems biology approach to evaluate alterations in contributing biochemical pathways and we statistically quantified these global pathway disturbances using the Kolmogorov-Smirnov goodness-of-fit test. We found widespread, indeed global, alterations in patterns of gene expression in diverse systems of BPH/2: in sympathochromaffin transcripts suggesting increased sympathetic stimulation; in vasoconstrictor/vasodilator systems; global reductions in carbohydrate intermediary metabolism; and increases in oxidative stress, with changes in oxygen radical forming and disposition enzymes. These analyses highlight widespread derangements in diverse physiological pathways, providing multiple avenues for further investigation into the pathogenesis of genetic hypertension.

Prevention of Cardiac Hypertrophy by Angiotensin II Type 2 Receptor Gene Transfer [Scientific Contributions]

Mon, 19 Apr 2004 12:42:24 PDT

Abstract--The role of the angiotensin II type-2 receptor (AT₂R) in cardiac hypertrophy remains elusive despite its demonstrated involvement in cardiovascular development. We have previously shown that a lentiviral vector gene delivery system is able to transduce cardiac tissue with high efficiency in vivo. Using such an approach, our objectives in the present study were 2-fold: (1) to overexpress the AT₂R in cardiac tissue after completion of natural embryonic development of the heart and (2) to determine the effects of this overexpression on cardiac hypertrophy and basal blood pressure (BP). A lentiviral vector encoding the AT₂R (lenti-AT₂R) was administered (1.5x10⁸ transducing units) into the left ventricular space of 5-day-old spontaneously hypertensive rats (SHRs). AT₂R transgene expression increased in these animals and persisted for 30 weeks. In contrast, the expression of the angiotensin II type-1 receptor remained unchanged following lenti-AT₂R treatment. At 21 weeks following gene transduction, the lenti-AT₂R-treated SHRs exhibited decreased left ventricular wall thickness compared with control animals. In contrast, basal BP did not differ between the two SHR groups. Finally, heart weight to body weight ratios indicated a significant decrease in lenti-AT₂R-treated SHRs compared with SHR controls. Our data indicate that AT₂R overexpression attenuates cardiac hypertrophy in the SHR. This beneficial outcome was observed despite the existence of elevated BP.

Response: High Blood Pressure in Acute Stroke and Subsequent Outcome: A Systematic Review [Letters to the Editor]

Willmot, M., Leonardi-Bee, J., Bath, P. M.W. — Mon, 19 Apr 2004 12:41:25 PDT

Response: Assessing the Sensitivity of Spontaneous Baroreflex Control of the Heart: Deeper Insight Into Complex Physiology [Letters to the Editor]

Taylor, J. A., Lipman, R. D. — Mon, 05 Apr 2004 12:49:17 PDT

Heme Oxygenase-1 Gene Expression Modulates Angiotensin II-Induced Increase in Blood Pressure [Scientific Contributions]

Yang, L., Quan, S., Nasjletti, A., Laniado-Schwartzman, M., Abraham, N. G. — Mon, 05 Apr 2004 12:48:33 PDT

Abstract--The heme-heme oxygenase (HO) system has been implicated in the regulation of vascular reactivity and blood pressure. This study examines the notion that overexpression of HO decreases pressor responsiveness to angiotensin II (Ang II). Five-day-old Sprague-Dawley rats received an intraleft ventricular injection of 5x10⁹ cfu/mL of retroviruses containing human HO-1 sense (LSN-HHO-1), rat HO-1 antisense (LSN-RHO-1-AS), or control retrovirus (LXSN). Three months later, rats were instrumented with femoral arterial and venous catheters for mean arterial pressure (MAP) determination and Ang II administration, respectively. Rats injected with LSN-HHO-1, but not with LXSN, expressed human HO-1 mRNA and protein in several tissues. BP increased with administration of Ang II in rats expressing and not expressing human HO-1. However, the Ang II-induced pressor response (mm Hg) in LSN-HHO-1 rats (16±3, 27±3, and 38±3 at 0.5, 2, and 10 ng) was surpassed (P<0.05) in LXSN rats (23±1, 37±2, and 52±2 at 0.5, 2, and 10 ng). Importantly, treating LSN-HHO-1 rats with the HO inhibitor tin mesoporphyrin (SnMP) enhanced (P<0.05) the Ang II-induced pressor response to a level not different from that observed in LXSN rats. Rats injected with LSN-RHO-1-AS showed a decrease in renal HO-1 protein expression and HO activity relative to control LXSN rats. Administration of Ang II (0.1 to 2 ng) caused small (4 to 5 mm Hg) but significant increases in MAP in rats injected with LSN-RHO-1-AS (P<0.05) compared with rats injected with LXSN. These data demonstrate that overexpression of HO-1 brings about a reduction in pressor responsiveness to Ang II, which is most likely due to increased generation of an HO-1 product, presumably CO, with the ability to inhibit vascular reactivity to constrictor stimuli.

Gene Therapy and Heme Oxygenase Coming of Age [Editorial Commentary]

Roman, R. J. — Mon, 05 Apr 2004 12:47:55 PDT

Statins Augment Collateral Growth in Response to Ischemia But They Do Not Promote Cancer and Atherosclerosis [Scientific Contributions]

Mon, 05 Apr 2004 12:47:23 PDT

Abstract--3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are widely prescribed to lower cholesterol. Recent reports suggest that statins may promote angiogenesis in ischemic tissues. It remains to be elucidated whether statins potentially enhance unfavorable angiogenesis associated with tumor and atherosclerosis. Here, we induced hind limb ischemia in wild-type mice by resecting the right femoral artery and subsequently inoculated cancer cells in the same animal. Cerivastatin enhanced blood flow recovery in the ischemic hind limb as determined by laser Doppler imaging, whereas tumor growth was significantly retarded. Cerivastatin did not affect capillary density in tumors. Cerivastatin, pitavastatin, and fluvastatin inhibited atherosclerotic lesion progression in apolipoprotein E-deficient mice, whereas they augmented blood flow recovery and capillary formation in ischemic hind limb. Low-dose statins were more effective than high-dose statins in both augmentation of collateral flow recovery and inhibition of atherosclerosis. These results suggest that statins may not promote the development of cancer and atherosclerosis at the doses that augment collateral flow growth in ischemic tissues.

Statin Therapy: Having the Good Without the Bad [Editorial Commentary]

Liao, J. K. — Mon, 29 Mar 2004 13:01:51 PST

Response [Letters to the Editor]

Chobanian, A. V., Roccella, E. J. — Mon, 22 Mar 2004 12:43:04 PST

Response: Rapid Nongenomic Effects of Aldosterone on Human Forearm Vasculature [Letters to the Editor]

Schmidt, B. M.W., Schmieder, R. E. — Mon, 23 Feb 2004 13:05:15 PST

Response: Does Hypomagnesemia Have an Adaptive Role in Hypertension? [Letters to the Editor]

Northcott, C. A., Watts, S. W. — Mon, 23 Feb 2004 13:03:05 PST

Response [Letters to the Editor]

Chobanian, A. V., Roccella, E. J. — Mon, 23 Feb 2004 13:02:09 PST

Response [Letters to the Editor]

Chobanian, A. V., Roccella, E. J. — Mon, 23 Feb 2004 13:01:42 PST

Response: Gold Standards for Baroreflex Gain [Letters to the Editor]

Lipman, R. D., Taylor, J. A. — Mon, 23 Feb 2004 12:57:51 PST

Response: Terminology for Describing the Elastic Behavior of Arteries [Letters to the Editor]

Budge, M. M., Gosling, R. G. — Mon, 23 Feb 2004 12:57:26 PST

Response [Letters to the Editor]

Mon, 16 Feb 2004 12:30:38 PST

Response: Aspirin Administered at Bedtime as Opposed to Upon Wakening Has an Effect on Ambulatory Blood Pressure: Further Evidence [Letters to the Editor]

Mon, 16 Feb 2004 12:30:11 PST

Response: Insulin-Leptin Interplay May Differ Among Tissues: [Letters to the Editor]

Vecchione, C., Lembo, G. — Mon, 09 Feb 2004 12:44:34 PST

Response: Adiponectin Concentrations in Preeclampsia [Letters to the Editor]

Sattar, N., Ramsey, J., Jamieson, N., Greer, I. A. — Mon, 02 Feb 2004 12:54:44 PST

Response: Is Low-Heat Shock Protein 70 a Primary or a Secondary Event in the Development of Atherosclerosis? [Letters to the Editor]

Pockley, A. G., Georgiades, A., Thulin, T., de Faire, U., Frostegard, J. — Mon, 02 Feb 2004 12:53:44 PST

Response [Letters to the Editor]

Mon, 26 Jan 2004 12:41:27 PST

Response [Letters to the Editor]

Egan, B. M. — Mon, 19 Jan 2004 13:16:29 PST

Guidelines for Hypertension: Are Quality-Assurance Measures on Target? [Scientific Contributions]

Singer, G. M., Izhar, M., Black, H. R. — Mon, 19 Jan 2004 13:14:50 PST

Abstract--Guideline committees recommend targets of treatment based on trial data on efficacy and effectiveness. Quality-assurance initiatives apply these parameters in the general practice setting. Therefore, targets must be feasible and achievable by the practicing physicians who are judged by these targets as goals for care. We evaluated 437 patients in the Rush University Hypertension Clinic using the Health Employer Data Information Set (HEDIS) measures for 2000 to assess goal achievement in a practice-based setting. We compared guideline achievement of uncomplicated hypertensive and diabetic subjects to standards dictated by HEDIS, the 6th Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI), and the American Diabetic Association (ADA)/National Kidney Foundation (NKF). Overall, 276 (63%) patients achieved SBP goal, with 376 (86%) achieving DBP goal and 358 (59%) achieving both goals. However, in the 20% of patients who were diabetic, only 52% had a BP of <140 mm Hg and <90 mm Hg, whereas only 22% achieved the more stringent goals of JNC VI of <130 mm Hg systolic and <85 mm Hg diastolic and only 15% achieved the ADA/NKF goals of <130 mm Hg systolic and <80 mm Hg diastolic. Although goal was achievable in most uncomplicated hypertension, hypertension in diabetes was more difficult to control, despite being more likely to receive enhanced benefit from effective management. Goal-oriented strategy, especially in diabetic subjects, should be aggressively sought rather than relaxing goals to promote achievement.

Acromegalic Patients Show the Presence of Hypertrophic Remodeling of Subcutaneous Small Resistance Arteries [Scientific Contributions]

Mon, 19 Jan 2004 13:14:17 PST

Abstract--Structural alterations of small resistance arteries in patients with essential hypertension (EH) are mostly characterized by inward eutrophic remodeling. However, we have observed the presence of hypertrophic remodeling in patients with renovascular hypertension, as well as in patients with noninsulin-dependent diabetes mellitus, suggesting a relevant effect of humoral growth factors on vascular structure. Growth hormone may stimulate in vitro proliferation of vascular smooth muscle cells. However, no data are presently available about small artery structure in acromegalic patients. Therefore, we have investigated the structure of subcutaneous small arteries in 12 normotensive (NT) subjects, in 12 EH subjects, and in 9 acromegalic patients (APs). All subjects underwent biopsy of the subcutaneous fat; then, small resistance arteries were dissected and mounted on a micromyograph. The normalized internal diameter, media thickness, media-to-lumen ratio, the media cross-sectional area together with remodeling, and growth indices were calculated. Demographic variables were similar in the three groups, except for blood pressure. The media-to-lumen ratio was significantly greater in EH and AP, compared with NT. No difference was observed between EH and AP. The media cross-sectional area was significantly greater in AP compared with EH and with NT. The calculation of remodeling and growth index suggests the presence of eutrophic remodeling in EH (growth index 0%) and of hypertrophic remodeling in AP (growth index 40%). In conclusion, our data suggest the presence of hypertrophic remodeling of subcutaneous small resistance arteries of AP, probably as a consequence of growth-stimulator properties of IGF-1.

Response: Vitamin C in Heart Failure: Hope! [Letters to the Editor]

Mon, 19 Jan 2004 13:05:34 PST

Aldosterone Antagonism and Arterial Stiffness [Letters to the Editor]

White, W. B., Duprez, D. — Mon, 12 Jan 2004 12:54:08 PST

Response [Letters to the Editor]

Redon, J., Tormos, M. C., Chaves, F. J., Espinosa, O., Iradi, A., Saez, G. T. — Mon, 12 Jan 2004 12:50:46 PST

Response: Augmentation Index and the Radial-to-Aortic Transfer Function [Letters to the Editor]

Millasseau, Ritter, Chowienczyk — Mon, 22 Sep 2003 12:53:53 PDT

Response: Hypotension and Reduced Catecholamines in Neuropeptide Y Transgenic Rats [Letters to the Editor]

Michalkiewicz, Knestaut, Bytchkova, Michalkiewicz — Mon, 22 Sep 2003 12:50:57 PDT

Response [Letters to the Editor]

Taddei, Virdis, Ghiadoni, Versari, Salvetti, Magagna, Salvetti — Tue, 02 Sep 2003 12:39:16 PDT

Acknowledgment to Reviewers [Acknowledgment to Reviewers]

Mon, 18 Aug 2003 12:38:55 PDT

Response [Letters to the Editor]

Palmer, Mancia — Mon, 18 Aug 2003 12:34:14 PDT

Response: Aortic Augmentation Index and Radial-to-Aortic Transfer Function [Letters to the Editor]

Millasseau, Ritter, Chowienczyk — Mon, 04 Aug 2003 12:52:46 PDT

Response: Hypertension and Low-Level Lead Exposure in African Americans: A Public Health Reality [Letters to the Editor]

Vupputuri, Batuman, He — Mon, 28 Jul 2003 12:59:28 PDT

Correction [Correction]

Mon, 07 Jul 2003 12:44:59 PDT

Correction [Correction]

Mon, 30 Jun 2003 12:48:24 PDT

Response: Does the Bradykinin B2 Receptor Function as a Protease-Activated Receptor? [Letters to the Editor]

Marceau, Houle, Molinaro, Adam — Mon, 30 Jun 2003 12:47:10 PDT

Response [Letters to the Editor]

Morris, Lin, Wang — Mon, 23 Jun 2003 12:49:02 PDT

News From the American Heart Association [News From the American Heart Association]

Mon, 02 Jun 2003 12:50:01 PDT

Meetings Calendar [Meetings Calendar]

Mon, 02 Jun 2003 12:49:40 PDT

Response [Letters to the Editor]

Lantelme, Mestre, Milon — Mon, 21 Apr 2003 13:00:17 PDT

Response: What Is Old Is Not Always Best [Letters to the Editor]

Myerson, Pennell — Mon, 21 Apr 2003 12:59:51 PDT

Response: Multifactorial Disease: Glu298asp of Endothelial Nitric Oxide Synthase [Letters to the Editor]

Noiri, Fujita, Tokunaga — Mon, 14 Apr 2003 12:49:58 PDT

Response: Pulse Wave Velocity, Heart Rate, and Blood Pressure [Letters to the Editor]

Lantelme, Mestre, Gressard, Milon, Lievre — Mon, 28 Oct 2002 12:36:43 PST

Response: Heart Rate and Pulse Wave Velocity [Letters to the Editor]

Lantelme, Mestre, Lievre, Gressard, Milon — Mon, 21 Oct 2002 12:57:38 PDT

Response: Endothelin Antagonism and Insulin's Vascular Effects [Letters to the Editor]

Miller, Busija — Mon, 21 Oct 2002 12:55:51 PDT

Response: How to Measure Blood Pressure Variability [Letters to the Editor]

Mancia, Sega — Mon, 16 Sep 2002 12:53:42 PDT

Response [Letters to the Editor]

Zhuo, Mendelsohn, Ohishi — Mon, 09 Sep 2002 12:40:03 PDT