Hypertension On-line First

[Letters to the Editor] Response to Exercise Generates Lactate and Fluid Intake: Effects on Mitochondrial Function in Heart and Vascular Smooth Muscle

Abhayaratna, W. P., Sakuragi, S., Telford, R. D. — 2009-06-29

[Letters to the Editor] Response to Exercise Generates Lactate and Fluid Intake: Effects on Mitochondrial Function in Heart and Vascular Smooth Muscle

Miyachi, M., Nagata, K. — 2009-06-29

[Letters to the Editor] Exercise Generates Lactate and Fluid Intake: Effects on Mitochondrial Function in Heart and Vascular Smooth Muscle

Thornton, S. N., Hess, K. — 2009-06-29

[Scientific Contribution] A Novel Amiloride-Sensitive H+ Transport Pathway Mediates Enhanced Superoxide Production in Thick Ascending Limb of Salt-Sensitive Rats, Not Na+/H+ Exchange

O'Connor, P. M., Lu, L., Liang, M., Cowley, A. W. — 2009-06-29

Abstract—It has been reported previously that H⁺ efflux via the Na⁺/H⁺ exchange stimulates NAD(P)H oxidase–dependent superoxide (O₂^·-) production in medullary thick ascending limb. We have demonstrated recently that N-methyl-amiloride–sensitive O₂^·- production is enhanced in the thick ascending limb of Dahl salt-sensitive (SS) rats, suggesting that H⁺ efflux through Na⁺/H⁺ exchangers may promote renal oxidative stress and the development of hypertension in these animals. In the current study we demonstrate, using selective and potent inhibitors, that inhibition of Na⁺/H⁺ exchange does not mediate the ability of N-methyl-amiloride to inhibit thick ascending limb O₂^·- production. To determine the mechanism of action of N-methyl-amiloride, we examined H⁺ efflux and O₂^·- production in SS and SS.13^BN thick ascending limbs of prehypertensive, 0.4% NaCl–fed rats. Tissue strips containing the medullary thick ascending limb were isolated from male SS and salt-resistant consomic SS.13^BN rats, loaded with either dihydroethedium or 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester, and imaged in a heated tissue bath. In Na⁺-replete media, activation of Na⁺/H⁺ exchange using an NH₄Cl prepulse did not stimulate thick ascending limb O₂^·- production. In Na⁺-free media containing BaCl₂ in which Na⁺/H⁺ activity was inhibited, an NH₄Cl prepulse stimulated O₂^·- production in medullary thick ascending limb renal tubular segments. This response was enhanced in medullary thick ascending limb of SS rats (slope ethidium/dihydroethedium=0.029±0.004) compared with SS.13^BN rats (slope=0.010±0.004; P<0.04) and could be inhibited by N-methyl-amiloride (slope=0.005±0.002 and 0.006±0.002 for SS and SS.13^BN, respectively). We concluded that only H⁺ efflux through a specific, as-yet-unidentified, amiloride-sensitive H⁺ channel promotes O₂^·- production in the medullary thick ascending limb and that this channel is upregulated in SS rats.

[Scientific Contribution] Role of Pulse Pressure Amplification in Arterial Hypertension. Experts' Opinion and Review of the Data

2009-06-29

[Scientific Contribution] Endothelial Cells Negatively Modulate Reactive Oxygen Species Generation in Vascular Smooth Muscle Cells. Role of Thioredoxin

Xu, S., He, Y., Vokurkova, M., Touyz, R. M. — 2009-06-29

Abstract—In intact vessels, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) act as an integrated system, possibly through reactive oxygen species (ROS). Using a coculture system we tested whether ECs modulate VSMC redox status by regulating activity of NAD(P)H oxidase and antioxidants. VSMC production of O₂^•-, H₂O₂, and NO was assessed using fluoroprobes and amplex-red. NAD(P)H oxidase subunit expression and oxidase activity were determined by Western blotting and chemiluminescence, respectively. Expression of thioredoxin, SOD, growth signaling pathways (PCNA, p21cip1, CDK4, ERK1/2, p38MAPK) was evaluated by immunoblotting. Thioredoxin activity was assessed by the insulin disulfide reduction assay. In cocultured conditions, VSMC ROS production was reduced by 50% without changes in NAD(P)H oxidase expression/activity versus monoculture (P<0.05). This was associated with decreased cell growth (P<0.05). Expression of Cu/Zn SOD and thioredoxin was increased in coculture versus monoculture VSMCs (P<0.01). Pretreatment of ECs with L-NAME (NOS inhibitor), NS-398 (Cox2 inhibitor), and HET0016 (20-HETE inhibitor) did not influence VSMC ROS formation, whereas CDNB, thioredoxin reductase inhibitor, abolished ROS modulating effects of ECs. These findings indicate that in a coculture system recapitulating intact vessels, ECs negatively regulate ROS production in VSMCs through thioredoxin upregulation. Functionally this is associated with growth inhibition. The modulatory actions of ECs are independent of NOS/NO, Cox2, and HETE and do not involve NAD(P)H oxidase. Our data identify novel mechanisms whereby ECs protect against VSMC oxidative stress, a process that may be important in maintaining vascular integrity.

[Scientific Contribution] Cardiac Renin Levels Are Not Influenced by the Amount of Resident Mast Cells

2009-06-29

Abstract—To investigate whether mast cells release renin in the heart, we studied renin and prorenin synthesis by such cells, using the human mast cell lines human mastocytoma 1 and LAD2, as well as fresh mast cells from mastocytosis patients. We also quantified the contribution of mast cells to cardiac renin levels in control and infarcted rat hearts. Human mastocytoma 1 cells contained and released angiotensin I–generating activity, and the inhibition of this activity by the renin inhibitor aliskiren was comparable to that of recombinant human renin. Prorenin activation with trypsin increased angiotensin I–generating activity in the medium only, suggesting release but not storage of prorenin. The adenylyl cyclase activator forskolin, the cAMP analogue 8-db-cAMP, and the degranulator compound 48/80 increased renin release without affecting prorenin. Angiotensin II blocked the forskolin-induced renin release. Angiotensin I–generating activity was undetectable in LAD2 cells and fresh mast cells. Nonperfused rat hearts contained angiotensin I–generating activity, and aliskiren blocked 70% of this activity. A 30-minute buffer perfusion washed away >70% of the aliskiren-inhibitable angiotensin I–generating activity. Prolonged buffer perfusion or compound 48/80 did not decrease cardiac angiotensin I–generating activity further or induce angiotensin I–generating activity release in the perfusion buffer. Results in infarcted hearts were identical, despite the increased mast cell number in such hearts. In conclusion, human mastocytoma 1 cells release renin and prorenin, and the regulation of this release resembles that of renal renin. However, this is not a uniform property of all mast cells. Mast cells appear an unlikely source of renin in the heart, both under normal and pathophysiological conditions.

[Editorial Commentary] Relentless Progression Toward Sustained Hypertension

Messerli, F. H., Makani, H. — 2009-06-29

[Scientific Contribution] Plasma-Mediated Vascular Dysfunction in the Reduced Uterine Perfusion Pressure Model of Preeclampsia. A Microvascular Characterization

Walsh, S. K., English, F. A., Johns, E. J., Kenny, L. C. — 2009-06-29

Abstract—Preeclampsia is associated with widespread maternal vascular dysfunction, which is thought to be mediated by circulating factor(s). The aim of the study was to characterize vascular function in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia and to investigate the role of plasma factors in mediating any observed changes in vascular reactivity. Mean arterial blood pressure and vascular function were measured in RUPP and control rats. Mesenteric vessels from both virgin and pregnant rats were exposed for 1 hour or overnight to plasma from both RUPP and control rats and their vascular function assessed. RUPP rats were characterized by severe hypertension, restricted fetal growth, and reduced placental weight (P<0.001). Vasorelaxation was impaired in resistance vessels from RUPP compared with control rats (acetylcholine: R_max 70±3 versus 92±1 [NP] and 93±3% [sham], P<0.01; bradykinin: 40±2 versus 62±2 [NP] and 59±4% [sham], P<0.001). Incubation of vessels from pregnant (but not virgin) animals with RUPP plasma overnight resulted in an attenuation of vasorelaxant responses (acetylcholine: 63±7 versus 86±2%, P<0.05; bradykinin: 35±5 versus 55±6%, P<0.001). The residual relaxant response in RUPP plasma-treated vessels was not further attenuated after treatment with N-nitro-L-arginine methyl ester (acetylcholine: 57±7 versus 63±7%, ns; bradykinin: 37±5 versus 35±5%, ns). The RUPP rat model is characterized by an impaired response to vasodilators which may be attributable to one or more circulating factors. This plasma-mediated endothelial dysfunction appears to be a pregnancy-dependent effect. Furthermore, nitric oxide–mediated vasorelaxation appears to be absent in RUPP plasma-treated vessels.

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

2009-06-29

Abstract—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.

[Scientific Contribution] Long-Term Risk of Sustained Hypertension in White-Coat or Masked Hypertension

2009-06-29

Abstract—It is debated whether white-coat (WCHT) and masked hypertension (MHT) are at greater risk of developing a sustained hypertensive state (SHT). In 1412 subjects of the Pressioni Arteriose Monitorate e Loro Associazioni Study, we measured office blood pressure (BP), 24-hour ambulatory BP, and home BP. The condition of WCHT was identified as office BP >140/90 mm Hg and 24-hour BP mean <125/79 mm Hg or home BP <132/82 mm Hg. Corresponding values for MHT diagnosis were office BP <140/90 mm Hg, 24-hour BP ≥125/79 mm Hg, and home BP ≥132/82 mm Hg. SHT was identified when both office and 24-hour BP means or home BP were over threshold values and normotension was under the threshold value. Subjects were reassessed 10 years later to evaluate the BP status of the various conditions defined previously. At the first examination, 758 (54.1%), 225 (16.1%), 124 (8.9%), and 293 (20.9%) subjects were normotensive, WCHT, MHT, and SHT subjects, respectively. At the second examination, 136 normotensives (18.2%), 95 WCHT (42.6%), and 56 MHT (47.1%) subjects became SHT. As compared with normotensives, adjusting for age and sex, the risk of becoming SHT was significantly higher for WCHT and MHT subjects (odds ratio: 2.51 and 1.78, respectively; P<0.0001). Similar results were obtained when the definition of the various conditions was based on home BP. Independent contributors of worsening of hypertension status were not only baseline BP, but also, although to a lesser extent, metabolic variables and age. Subjects with WCHT and MHT are at increased risk of developing SHT. This may contribute to their prognosis that appears to be worse as compared with that of normotensive subjects.

[Scientific Contribution] Growth Arrest Specific Protein 6 Participates in DOCA-Induced Target-Organ Damage

2009-06-29

Abstract—Growth arrest–specific protein 6 (Gas 6) is involved in inflammatory kidney diseases, vascular remodeling, cell adhesion, and thrombus formation. We explored a role for Gas 6 in aldosterone-induced target organ damage. We observed that Gas 6 was upregulated in rats with high aldosterone levels. Mineralocorticoid receptor blockade prevented target organ damage and decreased the elevated Gas 6 expression. Vascular smooth muscle cells given aldosterone increased their Gas 6 expression in vitro. To test the pathophysiological relevance, we investigated the effects of deoxycorticosterone acetate (DOCA) on Gas 6 gene-deleted (^-/-) mice. After 6 weeks DOCA, Gas 6^-/- mice developed similar telemetric blood pressure elevations compared to wild-type mice but were protected from cardiac hypertrophy. Cardiac expression of interleukin 6 and collagen IV was blunted in Gas 6^-/- mice, indicating reduced inflammation and fibrosis. Gas 6^-/- mice also had an improved renal function with reduced albuminuria, compared to wild-type mice. Renal fibrosis and fibronectin deposition in the kidney were also reduced. Gas 6 deficiency reduces the detrimental effects of aldosterone on cardiac and renal remodeling independent of blood pressure reduction. Gas 6 appears to play a role in mineralocorticoid receptor-mediated target organ damage. Furthermore, because warfarin interferes with Gas 6 protein expression, the findings could be of clinical relevance for anticoagulant choices.

[Brief Reviews] Thiazide Effects and Adverse Effects. Insights From Molecular Genetics

Ellison, D. H., Loffing, J. — 2009-06-29

[Scientific Contribution] Change in Blood Pressure and Incident Dementia. A 32-Year Prospective Study

2009-06-29

Abstract—Studies of the association of high blood pressure (BP) with dementia are not consistent. Understanding long-term trajectories in blood pressure of those who do and do not develop dementia can help clarify the issue. The Honolulu Heart Program/Honolulu-Asia Aging Study followed a cohort of Japanese American men for an average of 32 years, with systolic BP (SBP) and diastolic BP (DBP) measured at 6 examinations and dementia assessed at the final 3. In an analysis of 1890 men who completed all 6 of the exams, 112 diagnosed with incident dementia at examination 6 were compared with the 1778 survivors without dementia. Trajectories in SBP and DBP up to and including the sixth examination were estimated with a repeated-measures analysis using 3 splines. From midlife to late life, men who went on to develop dementia had an additional age-adjusted increase in SBP of 0.26 mm Hg (95% CI: 0.01 to 0.51 mm Hg) per year compared with survivors without dementia. Over the late-life examinations, this group had an additional age-adjusted decline in SBP of 1.36 mm Hg (95% CI: 0.64 to 2.07 mm Hg) per year. These associations were strongest for vascular dementia and were reduced substantially in men who were previously taking antihypertensive medication. Similar changes in diastolic BP were observed, but only for vascular dementia, and the findings were not modified by antihypertensive treatment. Over a 32-year period, compared with men who did not, those who did develop dementia had a greater increase, followed by a greater decrease, in SBP. Both of these trends are modified by antihypertensive therapy.

[Scientific Contribution] Prevention of Pulmonary Hypertension by Angiotensin-Converting Enzyme 2 Gene Transfer

2009-06-29

Abstract—In spite of recent advancements in the treatment of pulmonary hypertension, successful control has yet to be accomplished. The abundant presence of angiotensin-converting enzyme 2 (ACE2) in the lungs and its impressive effect in the prevention of acute lung injury led us to test the hypothesis that pulmonary overexpression of this enzyme could produce beneficial outcomes against pulmonary hypertension. Monocrotaline (MCT) treatment of mice for 8 weeks resulted in significant increases in right ventricular systolic pressure, right ventricle:left ventricle plus septal weight ratio, and muscularization of pulmonary vessels. Administration of a lentiviral vector containing ACE2, 7 days before MCT treatment prevented the increases in right ventricular systolic pressure (control: 25±1 mm Hg; MCT: 44±5 mm Hg; MCT+ACE2: 26±1 mm Hg; n=6; P<0.05) and right ventricle:left ventricle plus septal weight ratio (control: 0.25±0.01; MCT: 0.31±0.01; MCT+ACE2: 0.26±0.01; n=8; P<0.05). A significant attenuation in muscularization of pulmonary vessels induced by MCT was also observed in animals overexpressing ACE2. These beneficial effects were associated with an increase in the angiotensin II type 2 receptor:angiotensin II type 1 receptor mRNA ratio. Also, pulmonary hypertension–induced increases in proinflammatory cytokines were significantly attenuated by lentiviral vector–containing ACE2 treatment. Furthermore, ACE2 gene transfer in mice after 6 weeks of MCT treatment resulted in a significant reversal of right ventricular systolic pressure. These observations demonstrate that ACE2 overexpression prevents and reverses right ventricular systolic pressure and associated pathophysiology in MCT-induced pulmonary hypertension by a mechanism involving a shift from the vasoconstrictive, proliferative, and fibrotic axes to the vasoprotective axis of the renin-angiotensin system and inhibition of proinflammatory cytokines.

[In Memoriam] Akira Takeshita (1940-2009)

Hirooka, Y., Sunagawa, K. — 2009-06-22

[Editorial Commentary] (Pro)renin Receptor and Vacuolar H+-ATPase

Jan Danser, A. H. — 2009-06-22

[Scientific Contribution] Impact of Shear Rate Modulation on Vascular Function in Humans

2009-06-22

Abstract—Shear stress is an important stimulus to arterial adaptation in response to exercise and training in humans. We recently observed significant reverse arterial flow and shear during exercise and different antegrade/retrograde patterns of shear and flow in response to different types of exercise. The purpose of this study was to simultaneously examine flow-mediated dilation, a largely NO-mediated vasodilator response, in both brachial arteries of healthy young men before and after 30-minute interventions consisting of bilateral forearm heating, recumbent leg cycling, and bilateral handgrip exercise. During each intervention, a cuff inflated to 60 mm Hg was placed on 1 arm to unilaterally manipulate the shear rate stimulus. In the noncuffed arm, antegrade flow and shear increased similarly in response to each intervention (ANOVA; P<0.001, no interaction between interventions; P=0.71). Baseline flow-mediated dilation (4.6%, 6.9%, and 6.7%) increased similarly in response to heating, handgrip, and cycling (8.1%, 10.4%, and 8.9%, ANOVA; P<0.001, no interaction; P=0.89). In contrast, cuffed arm antegrade shear rate was lower than in the noncuffed arm for all of the conditions (P<0.05), and the increase in flow-mediated dilation was abolished in this arm (4.7%, 6.7%, and 6.1%; 2-way ANOVA: all conditions interacted P<0.05). These results suggest that differences in the magnitude of antegrade shear rate transduce differences in endothelial vasodilator function in humans, a finding that may have relevance for the impact of different exercise interventions on vascular adaptation in humans.

[Brief Review] Protective Importance of the Myogenic Response in the Renal Circulation

Bidani, A. K., Griffin, K. A., Williamson, G., Wang, X., Loutzenhiser, R. — 2009-06-22

[Brief Review] Large and Small Artery Cross-Talk and Recent Morbidity-Mortality Trials in Hypertension

Laurent, S., Briet, M., Boutouyrie, P. — 2009-06-22

[Scientific Contribution] Amplification of the Pressure Pulse in the Upper Limb in Healthy, Middle-Aged Men and Women

2009-06-22

Abstract—Central-to-peripheral amplification of the pressure pulse leads to discrepancies between central and brachial blood pressures. This amplification depends on an individual's hemodynamic and (patho)physiological characteristics. The aim of this study was to assess the magnitude and correlates of central-to-peripheral amplification in the upper limb in a healthy, middle-aged population (the Asklepios Study). Carotid, brachial, and radial pressure waveforms were acquired noninvasively using applanation tonometry in 1873 subjects (895 women) aged 35 to 55 years. Carotid, brachial, and radial pulse pressures were calculated, as well as the absolute and relative (with carotid pulse pressure as reference) amplifications. With subjects classified per semidecade of age, carotid-to-radial amplification varied from 25% in the youngest men to 8% in the oldest women. Amplification was higher in men (20±14%) than in women (13±12%; P<0.001) and decreased with age (P<0.001) in both. Amplification over the brachial-to-radial path contributed substantially to the total amplification. In univariate analysis, the strongest correlation was found with the carotid augmentation index (-0.51 in women; -0.47 in men; both P<0.001). In a multiple linear regression model with carotid-to-radial amplification as the dependent variable, carotid augmentation index, total arterial compliance, and heart rate were identified as the 3 major determinants of upper limb pressure amplification (R²=0.36). We conclude that, in healthy middle-aged subjects, the central-to-radial amplification of the pressure pulse is substantial. Amplification is higher in men than in women, decreases with age, and is primarily associated with the carotid augmentation index.

[Scientific Contribution] Novel Role of Fumarate Metabolism in Dahl-Salt Sensitive Hypertension

2009-06-22

Abstract—In a previous proteomic study, we found dramatic differences in fumarase in the kidney between Dahl salt-sensitive rats and salt-insensitive consomic SS-13^BN rats. Fumarase catalyzes the conversion between fumarate and L-malate in the tricarboxylic acid cycle. Little is known about the pathophysiological significance of fumarate metabolism in cardiovascular and renal functions, including salt-induced hypertension. The fumarase gene is located on the chromosome substituted in the SS-13^BN rat. Sequencing of fumarase cDNA indicated the presence of lysine at amino acid position 481 in Dahl salt-sensitive rats and glutamic acid in Brown Norway and SS-13^BN rats. Total fumarase activity was significantly lower in the kidneys of Dahl salt-sensitive rats compared with SS-13^BN rats, despite an apparent compensatory increase in fumarase abundance in Dahl salt-sensitive rats. Intravenous infusion of a fumarate precursor in SS-13^BN rats resulted in a fumarate excess in the renal medulla comparable to that seen in Dahl salt-sensitive rats. The infusion significantly exacerbated salt-induced hypertension in SS-13^BN rats (140±3 vs125±2 mm Hg in vehicle control at day 5 on a 4% NaCl diet; P<0.05). In addition, the fumarate infusion increased renal medullary tissue levels of H₂O₂. Treatment of cultured human renal epithelial cells with the fumarate precursor also increased cellular levels of H₂O₂. These data suggest a novel role for fumarate metabolism in salt-induced hypertension and renal medullary oxidative stress.

[Scientific Contributions] Failures in Mitochondrial tRNAMet and tRNAGln Metabolism Caused by the Novel 4401A>G Mutation Are Involved in Essential Hypertension in a Han Chinese Family

Li, R., Liu, Y., Li, Z., Yang, L., Wang, S., Guan, M.-X. — 2009-06-22

Abstract—We report here on the clinical, genetic, and molecular characterization of 1 Han Chinese family with maternally transmitted hypertension. Three of 7 matrilineal relatives in this 4-generation family exhibited the variable degree of essential hypertension at the age at onset, ranging from 35 to 60 years old. Sequence analysis of the complete mitochondrial DNA in this pedigree identified the novel homoplasmic 4401A>G mutation localizing at the spacer immediately to the 5' end of tRNA^Met and tRNA^Gln genes and 39 other variants belonging to the Asian haplogroup C. The 4401A>G mutation was absent in 242 Han Chinese controls. Approximately 30% reductions in the steady-state levels of tRNA^Met and tRNA^Gln were observed in 2 lymphoblastoid cell lines carrying the 4401A>G mutation compared with 2 control cell lines lacking this mutation. Failures in mitochondrial metabolism are apparently a primary contributor to the reduced rate of mitochondrial translation and reductions in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate–promoted respiration, or N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate-promoted respiration in lymphoblastoid cell lines carrying the 4401A>G mutation. The homoplasmic form, mild biochemical defect, late onset, and incomplete penetrance of hypertension in this family suggest that the 4401A>G mutation itself is insufficient to produce a clinical phenotype. Thus, the other modifier factors, eg, nuclear modifier genes and environmental and personal factors, may also contribute to the development of hypertension in these subjects carrying this mutation. These data suggest that mitochondrial dysfunctions, caused by the 4401A>G mutation, are involved in the development of hypertension in this Chinese pedigree.

[Scientific Contributions] The (Pro)Renin Receptor. Site-Specific and Functional Linkage to the Vacuolar H+-ATPase in the Kidney

2009-06-22

Abstract—The (pro)renin receptor ([P]RR) is a transmembrane protein that binds both renin and prorenin with high affinity, increasing the catalytic cleavage of angiotensinogen and signaling intracellularly through mitogen-activated protein kinase activation. Although initially reported as having no homology with any known membrane protein, other studies have suggested that the (P)RR is an accessory protein, named ATP6ap2, that associates with the vacuolar H⁺-ATPase, a key mediator of final urinary acidification. Using in situ hybridization, immunohistochemistry, and electron microscopy, together with serial sections stained with nephron segment–specific markers, we found that (P)RR mRNA and protein were predominantly expressed in collecting ducts and in the distal nephron. Within collecting ducts, the (P)RR was most abundant in microvilli at the apical surface of A-type intercalated cells. Dual-staining immunofluorescence demonstrated colocalization of the (P)RR with the B1/2 subunit of the vacuolar H⁺-ATPase, the ion exchanger that secretes H⁺ ions into the urinary space and that associates with an accessory subunit homologous to the (P)RR. In collecting duct/distal tubule lineage Madin-Darby canine kidney cells, extracellular signal–regulated kinase 1/2 phosphorylation, induced by either renin or prorenin, was attenuated by the selective vacuolar H⁺-ATPase inhibitor bafilomycin. The predominant expression of the (P)RR at the apex of acid-secreting cells in the collecting duct, along with its colocalization and homology with an accessory protein of the vacuolar H⁺-ATPase, suggests that the (P)RR may function primarily in distal nephron H⁺ transport, recently noted to be, at least in part, an angiotensin II–dependent phenomenon.

[Scientific Contribution] Arginase II Knockout Mouse Displays a Hypertensive Phenotype Despite a Decreased Vasoconstrictory Profile

2009-06-22

Abstract—Arginase upregulation is associated with aging and cardiovascular diseases. In this study we report on the cardiovascular phenotype of the arginase II knockout (KO) mouse. We demonstrate that vascular sensitivity and reactivity altered over time in these animals such that no influence on responses to vasoconstrictor activity was observed in 7-week-old KO mice, but dampened responses to norepinephrine and phenylephrine were observed by 10 and 15 weeks with Rho kinase influencing these effects in the 15-week-old animals. Despite these dampened vasoconstrictory responses, KO mice demonstrated increased mean arterial pressure from 8 weeks old. This hypertensive phenotype was associated with an increase in left ventricular weight, left ventricular systolic pressure, and diminished diastolic function. KO mice also show enhanced plasma norepinephrine turnover, suggesting an increased sympathetic outflow. In conclusion, our data suggest that global loss of arginase II activity results in hypertension. We suggest that this strain of mouse warrants further investigation as a potentially novel model of hypertension.

[Scientific Contribution] Volume-Associated Ambulatory Blood Pressure Patterns in Hemodialysis Patients

Agarwal, R. — 2009-06-15

Abstract—Although volume excess causes hypertension, whether it also affects circadian patterns of arterial pressures among hemodialysis patients remains unknown. To test the notion of whether volume overload is associated with a unique blood pressure (BP) "signature," a posthoc analysis was performed among 145 patients participating in the Dry-Weight Reduction in Hypertensive Hemodialysis Patients randomized, controlled trial. Using 400 ambulatory BP recordings over 8 weeks composed of 35 302 measurements, the trended cosinor model was found to be the best descriptor of BP chronobiology. The trended cosinor model may be described as a pattern of sinusoidal oscillation around a straight line with an upward trend during the interdialytic period that has an intercept at the postdialysis time. Augmented volume removal therapy reduced the intercept systolic BP and increased the rate of rise in systolic BP over the interdialytic interval but had no effect on the systolic BP fluctuation (amplitude). Thus, an elevated intercept and blunted slope pattern characterize the "volume-overload BP pattern" on ambulatory BP monitoring. Similar changes were seen for diastolic BP. Augmented volume removal therapy neither restored dipping nor was associated with a lag phenomenon for either the wake or the sleep systolic BP. Lowering of systolic BP was greater than diastolic BP such that pulse pressure was reduced. An observational cohort of 37 patients followed for 6 months confirmed these findings. Randomized trials are now needed to evaluate the clinical impact of augmented volume removal therapy on hard outcomes, because reduction of pulse pressure with this simple expedient has the potential to improve survival in hemodialysis patients.

[Scientific Contribution] Differential Effects of Antihypertensive Treatment on the Retinal Microcirculation. An Anglo-Scandinavian Cardiac Outcomes Trial Substudy

2009-06-15

Abstract—Changes in the retinal microcirculation are associated with hypertension and predict cardiovascular mortality. There are few data describing the impact of antihypertensive therapy on retinal vascular changes. This substudy of the Anglo-Scandinavian Cardiac Outcomes Trial compared the effects of an amlodipine-based regimen (373 patients) with an atenolol-based regimen (347 patients) on retinal microvascular measurements made from fundus photographs. The retinal photographs were taken at a stage in the trial when treatments were stable and blood pressure was well controlled. Amlodipine-based treatment was associated with a smaller arteriolar length:diameter ratio than atenolol-based treatment (13.32 [10.75 to 16.04] versus 14.12 [11.27 to 17.81], median [interquartile range]; P<0.01). The association remained significant after adjustment for age, sex, cholesterol, systolic and diastolic blood pressures, body mass index, smoking, and statin treatment. This effect appeared to be largely attributable to shorter retinal arteriolar segment lengths in the amlodipine-treated group and is best explained by the vasodilator effects of amlodipine causing the visible emergence of branching side vessels. Photographic assessment of the retinal vascular network may be a useful approach to evaluating microvascular structural responses in clinical trials of antihypertensive therapy.

[Scientific Contribution] Direct Chronic Effect of Steroid Hormones in Attenuating Uterine Arterial Myogenic Tone. Role of Protein Kinase C/Extracellular Signal-Regulated Kinase 1/2

Xiao, D., Huang, X., Yang, S., Zhang, L. — 2009-06-15

Abstract—Pregnancy is associated with a significant decrease in uterine vascular tone and an increase in uterine blood flow. The present study tested the hypothesis that estrogen and progesterone differentially regulate the extracellular signal–regulated kinase (ERK)1/2 and protein kinase C (PKC) signaling pathways in vascular smooth muscle, resulting in a decrease in uterine vascular myogenic tone in pregnancy. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep. Chronic treatment (48 hours) of nonpregnant uterine arteries with 17β-estradiol and progesterone caused a significant decrease in PKC-mediated contractions and pressure-induced myogenic tone. In accordance, treatment of near-term pregnant uterine arteries for 48 hours with ICI 182780 and RU 486 significantly increased PKC-induced contractions and myogenic tone. In contrast, acute treatment for 30 minutes had no effect on uterine artery contractility. An ERK1/2 inhibitor, PD098059, restored the chronic effect of steroids on PKC-mediated contractions in nonpregnant sheep. ERK1/2 protein and mRNA levels were greater in near-term pregnant as compared with nonpregnant uterine arteries. 17β-Estradiol and progesterone increased ERK1/2 protein in nonpregnant sheep. In agreement, ICI 182780 and RU 486 caused significant decreases in ERK1/2 protein in near-term pregnant sheep. Western blot showed 6 PKC isozymes, , β_I, β_II, , , and , in the uterine arteries. 17β-Estradiol and progesterone decreased the particulate:cytosolic ratios of PKC, , and , respectively, in nonpregnant sheep. ICI 182780 and RU 486 increased the ratios in near-term pregnant sheep. The results indicate a direct chronic effect of the steroid hormones in the upregulation of ERK1/2 expression and downregulation of the PKC signaling pathway, resulting in attenuated myogenic tone of the uterine artery in pregnancy.

[Scientific Contribution] Regulation of Renovascular Adenosine 3',5'-Cyclic Monophosphate in Spontaneously Hypertensive Rats

Jackson, E. K., Mi, Z. — 2009-06-15

Abstract—This study tested the hypothesis that regulation of 3',5'-cAMP levels in the kidney vasculature is abnormal in spontaneously hypertensive rats. In isolated, perfused kidneys from adult rats (16 weeks of age), isoproterenol similarly increased renal venous 3',5'-cAMP secretion from kidneys of hypertensive versus normotensive Wistar-Kyoto rats. However, a broad-spectrum phosphodiesterase inhibitor (isobutyl-1-methylxanthine) augmented isoproterenol (3 µmol/L)-induced increases in renal venous 3',5'-cAMP secretion more so in kidneys from adult hypertensive versus age-matched normotensive rats (31-fold and 5-fold, respectively; P<0.0001). In contrast to isoproterenol, broad-spectrum phosphodiesterase inhibition augmented forskolin-induced increases in renal venous 3',5'-cAMP secretion similarly in kidneys from adult hypertensive versus age-matched normotensive rats. In kidneys from adults of both strains, the effects of isobutyl-1-methylxanthine on isoproterenol-induced 3',5'-cAMP responses were mimicked by the inhibition of phosphodiesterase 4 (RO 20-1724) but not by the inhibition of phosphodiesterase 1 (3,8-methoxymethyl-3-isobutyl-1-methylxanthine) or phosphodiesterase 3 (milrinone). In kidneys from young (5 weeks of age), adult, and old (39 weeks of age) rats, RO 20-1724 augmented isoproterenol-induced renal 3',5'-cAMP secretion more so in kidneys from hypertensive rats. In adult hypertensive rats, arterial blood pressure and renal vascular resistance were elevated compared with age-matched normotensive rats, and intravenous infusions of RO 20-1724 reduced blood pressure and renal vascular resistance in hypertensive rats but had little effect on these variables in normotensive rats. We conclude that, in the renal vasculature of spontaneously hypertensive rats (young, adult, and old), there is increased activity of a compartment of phosphodiesterase 4. Selective inhibition of renal vascular phosphodiesterase 4 may represent a new strategy for improving renal hemodynamics in genetic hypertension.

[Brief Review] Unveiling the Role of Multidrug Resistance Proteins in Hypertension

Delou, J. M. A., Lopes, A. G., Capella, M. A.M. — 2009-06-15

[Editorial Commentary] Mitochondrial Thioredoxin. Novel Regulator for NADPH Oxidase and Angiotensin II- Induced Hypertension

Fukai, T. — 2009-06-08

[Scientific Contribution] Pulse Wave Velocity Assessment by External Noninvasive Devices and Phase-Contrast Magnetic Resonance Imaging in the Obese

2009-06-08

Abstract—Carotid-femoral pulse wave velocity (PWV) is considered the gold-standard measurement of arterial stiffness. Obesity, however, can render inaccurate the measurement of PWV by external noninvasive devices. Phase-contrast MRI allows the determination of aortic PWV in multiple aortic locations with intra-arterial distance measurements, as well as the assessment of aortic mechanical properties. The purpose of this study was to assess the reliability of external carotid-femoral PWV values measured by well-validated external devices in comparison with MRI acquisitions of PWV and aortic mechanical properties in a population of obese subjects. PWV was measured with PulsePen and Complior II devices in 32 volunteers (18 men and 14 women), aged 46 to 65 years (mean: 55.7±5.1 years), presenting with isolated abdominal obesity, with a waist circumference >102 cm for men and >88 cm for women, and a body mass index between 27 and 35. These results were then compared with MRI PWV values and cross-sectional MRI thoracic aorta distensibility values. MRI PWV values were positively correlated with PWV measured by both PulsePen (r=0.47; P=0.005) and Complior (r=0.43; P=0.01). Aortic cross-sectional stiffness was positively correlated with PulsePen PWV (r=0.42; P=0.02). The same trend was also observed with Complior PWV (r=0.33; P=0.06). This is the first study comparing transcutaneous PWV measurements with MRI aortic elastic properties in obese subjects. Our results indicate that, for body mass index values ≤35 kg m^-2, PWV measured externally with Complior or PulsePen validly reflect values obtained directly in the thoracic aorta through MRI.

[Scientific Contribution] Estrous Cycle-Dependent Neurovascular Dysfunction Induced by Angiotensin II in the Mouse Neocortex

Capone, C., Anrather, J., Milner, T. A., Iadecola, C. — 2009-06-08

Abstract—Female mice are protected from the cerebrovascular dysfunction induced by angiotensin II (Ang II), an effect attributed to estrogen. We examined whether such cerebrovascular protection from Ang II is related to the estrous cycle. Cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized (urethane-chloralose) C57BL/6 female mice equipped with a cranial window. The phase of the estrous cycle was determined by vaginal smear cytology and plasma estrogen measurement. Ang II (0.25 µg/kg per minute, IV, 30 to 45 minutes) elevated arterial pressure (15 to 20 mm Hg) equally across the estrous cycle. However, in proestrus and estrus, phases in which estrogen is relatively high, Ang II did not impair the increase in the cerebral blood flow induced by neural activity or by endothelium-dependent vasodilators (P>0.05 from vehicle). In contrast, in diestrus (lower estrogen), Ang II induced a marked cerebrovascular dysfunction comparable to that of male mice. For example, the cerebral blood flow responses to whisker stimulation and to the endothelium-dependent vasodilator acetylcholine were attenuated by 41±12% and 49±12%, respectively (P<0.05; n=6 per group). The protection from the cerebrovascular effects of Ang II in proestrus was abolished by the estrogen receptor inhibitor ICI182,780. Ang II also increased production of free radicals in cerebral blood vessels in diestrus (+116±13%; P<0.05) but not in proestrus and estrus (P>0.05 from control). Topical treatment with ICI182,780 reestablished Ang II–induced oxidative stress in proestrus (P>0.05 from diestrus). We conclude that the protection from the neurovascular dysfunction induced by acute administration of Ang II in females depends on the estrous cycle and may underlie the increased propensity to cerebrovascular damage associated with low estrogen states.

[Scientific Contribution] Attenuation of Angiotensin II-Induced Vascular Dysfunction and Hypertension by Overexpression of Thioredoxin 2

2009-06-08

Abstract—Reactive oxygen species increase in the cardiovascular system during hypertension and in response to angiotensin II. Because mitochondria contribute to reactive oxygen species generation, we sought to investigate the role of thioredoxin 2, a mitochondria-specific antioxidant enzyme. Mice were created with overexpression of human thioredoxin 2 (Tg^hTrx2 mice) and backcrossed to C57BL/6J mice for ≥6 generations. Twelve-week-old male Tg^hTrx2 or littermate wild-type mice were made hypertensive by infusion of angiotensin II (400 ng/kg per minute) for 14 days using osmotic minipumps. Systolic arterial blood pressure was not different between Tg^hTrx2 and wild-type animals under baseline conditions (101±1 respective 102±1 mm Hg). The angiotensin II–induced hypertension in wild-type mice (145±2 mm Hg) was significantly attenuated in Tg^hTrx2 mice (124±1 mm Hg; P<0.001). Aortic endothelium-dependent relaxation was significantly reduced in wild-type mice after angiotensin II infusion but nearly unchanged in transgenic mice. Elevated vascular superoxide and hydrogen peroxide levels, as well as expression of NADPH oxidase subunits in response to angiotensin II infusion, were significantly attenuated in Tg^hTrx2 mice. Mitochondrial superoxide anion levels were augmented after angiotensin II infusion in wild-type mice, and this was blunted in Tg^hTrx2 mice. Angiotensin II infusion significantly increased myocardial superoxide formation, heart weight, and cardiomyocyte size in wild-type but not in Tg^hTrx2 mice. These data indicate a major role for mitochondrial thioredoxin 2 in the development of cardiovascular alterations and hypertension during chronic angiotensin II infusion. Thioredoxin 2 may represent an important therapeutic target for the prevention and treatment of hypertension and oxidative stress.

[Scientific Contribution] Ventral Lamina Terminalis Mediates Enhanced Cardiovascular Responses of Rostral Ventrolateral Medulla Neurons During Increased Dietary Salt

Adams, J. M., Bardgett, M. E., Stocker, S. D. — 2009-06-08

Abstract—Increased dietary salt enhances sympathoexcitatory and sympathoinhibitory responses evoked from the rostral ventrolateral medulla (RVLM). The purpose of the present study was to determine whether neurons of the forebrain lamina terminalis (LT) mediated these changes in the RVLM. Male Sprague-Dawley rats with and without LT lesions were fed normal chow and given access to water or 0.9% NaCl for 14 to 15 days. Unilateral injection of L-glutamate into the RVLM produced significantly larger increases in renal sympathetic nerve activity and arterial blood pressure of sham rats ingesting 0.9% NaCl versus water. However, these differences were not observed between ventral LT-lesioned rats drinking 0.9% NaCl versus water. Similar findings were observed when angiotensin II or -aminobutyric acid was injected into the RVLM. Interestingly, a subset of animals drinking 0.9% but with damage restricted to the organum vasculosum of the lamina terminalis did not show enhanced responses to L-glutamate or -aminobutyric acid. In marked contrast, RVLM injection of L-glutamate or -aminobutyric acid produced exaggerated sympathetic nerve activity and arterial blood pressure responses in animals drinking 0.9% NaCl versus water after an acute ventral LT lesion or chronic lesion of the subfornical organ. Additional experiments demonstrated that plasma sodium concentration and osmolality were increased at night in rats ingesting 0.9% NaCl. These findings suggest that neurons of the ventral LT mediate the ability of increased dietary salt to enhance the responsiveness of RVLM sympathetic neurons.

[Scientific Contribution] Comparison of the Effects of Antihypertensive Agents on Central Blood Pressure and Arterial Stiffness in Isolated Systolic Hypertension

2009-06-01

Abstract—Isolated systolic hypertension is an important risk factor for cardiovascular disease and results primarily from elastic artery stiffening. Although various drug therapies are used to lower peripheral blood pressure (BP) in patients with isolated systolic hypertension, the effects of the 4 major classes of antihypertensive agents on central BP, pulse pressure (PP) amplification, and arterial stiffness in this condition are not clear. Fifty-nine patients over the age of 60 years with untreated isolated systolic hypertension (systolic BP ≥140 mm Hg and diastolic BP ≤90 mm Hg) were randomly assigned to receive 1 of the following 4 antihypertensive agents: perindopril, atenolol, lercanidipine, or bendrofluazide. BP was measured using a mercury sphygmomanometer, and augmentation index and carotid-femoral (aortic) pulse wave velocity were measured at baseline, after 2 weeks of placebo therapy, and at the end of 10 weeks of active therapy. Peripheral systolic BP and peripheral PP were reduced similarly after treatment with all 4 classes of drug. However, central PP was only reduced significantly by perindopril, lercanidipine, and bendrofluazide, whereas atenolol had no effect. Lercanidipine reduced the augmentation index, whereas atenolol increased it. Aortic pulse wave velocity was not changed by any of the drugs. In summary, despite similar reductions in peripheral systolic and PPs with the 4 classes of drug, changes in central pressure and augmentation index varied. Because central PP and increased wave reflections are considered important risk factors in patients with isolated systolic hypertension, the choice of therapy may be influenced by these findings in the future.

[Scientific Contribution] Blood Pressure Variables and Cardiovascular Risk. New Findings From ADVANCE

2009-05-26

Abstract—The relative importance of various blood pressure indices on cardiovascular risk in people with type 2 diabetes mellitus has not been established. This study compares the strengths of the associations between different baseline blood pressure variables (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], and mean arterial pressure) and the 4.3-year risk of major cardiovascular events in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. Mean (SD) age for the 11 140 participants was 65.8 years (6.4 years). During follow-up, 1000 major cardiovascular events, 559 major coronary events, and 468 cardiovascular deaths were recorded. After adjustment for age, sex, and treatment allocation, the hazard ratios (95% CIs) associated with 1 increment in SD for the risk of major cardiovascular events were 1.17 (1.10 to 1.24) for SBP; 1.20 (1.13 to 1.28) for PP; 1.12 (1.05 to 1.19) for mean arterial pressure; and 1.04 (0.98 to 1.11) for DBP. The areas under the receiver operating characteristic curve were slightly higher for SBP and PP compared with mean arterial pressure and DBP for major cardiovascular and coronary events. Using achieved instead of baseline blood pressure values marginally improved the effect estimates for SBP, DBP, and mean arterial pressure, with no significant differences in the areas under the receiver operating characteristic curve between models with SBP and those with PP. In conclusion, SBP and PP are the 2 best and DBP is the least effective determinant of the risk of major cardiovascular outcomes in the relatively old patients with type 2 diabetes mellitus participating in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. However, SBP may be the simplest and most useful predictor across a wider range of age groups and populations.

[Brief Review] Wall-to-Lumen Ratio of Retinal Arterioles as a Tool to Assess Vascular Changes

Ritt, M., Schmieder, R. E. — 2009-05-18

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

2006-04-03

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

Dong, F., Zhang, X., Ren, J. — 2006-03-27

[Article] Acknowledgment of Reviewers

2006-02-06

[Preface] Preface

Harder, D. R. — 2006-02-06

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

Jeck, N., Waldegger, S., Wissinger, B., Schwab, M., Lang, F. — 2006-01-30

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

Khan, F., Belch, J. J.F., MacLeod, M., Mires, G. — 2006-01-09

[Letters to the Editor] Response

Hu, F. — 2005-12-27

[Letters to the Editor] Response

Takai, S., Miyazaki, M. — 2005-12-19

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

Armanini, D., Fiore, C., Calo, L. A — 2005-12-19

[Letters to the Editor] Magnesium and Arterial Stiffness

Kisters, K., Gremmler, B., Hausberg, M. — 2005-12-05

[Letters to the Editor] Response

Laurent, S. — 2005-12-05

[Letters to the Editor] Response

2005-11-14

[Letters to the Editor] Response

Grassi, D., Ferri, C., Blumberg, J. B. — 2005-11-14

[Letters to the Editor] Response

Grassi, D., Desideri, G., Ferri, C., Blumberg, J. B. — 2005-10-17

[Letters to the Editor] Response

Verbeke, F., Segers, P., Verdonck, P., Vanholder, R., Van Bortel, L. M. — 2005-10-17

[Letters to the Editor] Response

Garrett, M. R., Rapp, J. P., Joe, B., Meng, H. — 2005-10-10

[Letters to the Editor] Response

Schoner, W. — 2005-09-19

[Letters to the Editor] Response

Dolan, E., Stanton, A., O'Brien, E., Staessen, J. A. — 2005-09-19

[Letters to the Editor] Response

Schoner, W. — 2005-08-15

[Letters to the Editor] Response

Fyhrquist, F., Devereux, R. B., Kjeldsen, S. E., Dahlof, B. — 2005-07-18

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

2005-07-05

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.

[Letters to the Editor] Response

2005-06-27

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

Kotsis, V., Stabouli, S., Bouldin, M., Low, A., Toumanidis, S., Zakopoulos, N. — 2005-06-13

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

de Simone, G. — 2005-05-16

[Letters to the Editor] Response

Townsend, S., Berkowitz, D. E. — 2005-05-16

[Letters to the Editor] Ouabain and Serum Sodium

Gasowski, J., Manunta, P., Bianchi, G., Staessen, J. A. — 2005-05-09

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

He, F. J., MacGregor, G. A. — 2005-05-09

[Letters to the Editor] Response

Shibao, C., Gamboa, A., Diedrich, A., Biaggioni, I. — 2005-04-25

[Letters to the Editor] Response

Pickering, T. G. — 2005-04-18

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

2005-01-10

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

Aviv, A., Hollenberg, N. K., Weder, A. — 2005-01-03

[Letters to the Editor] Response

Gironacci, M. M. — 2005-01-03

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

Tsuda, K., Nishio, I. — 2005-01-03

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

Fagard, R. H., on behalf of the Syst-Eur investigators — 2004-12-06

[Letters to the Editor] Response

Schneider, M. P., Schmieder, R. E. — 2004-12-06

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

2004-11-29

[Letters to the Editor] Response

2004-10-18

[Letters to the Editor] Response

Jones, D. W. — 2004-10-18

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

Materson, B. J. — 2004-09-20

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

Luke, A., Adeyemo, A., Kramer, H., Forrester, T., Cooper, R. S. — 2004-07-26

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

Schlaich, M. P., Esler, M. D. — 2004-06-07

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

2004-04-19

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.

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

2004-04-19

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.

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

Willmot, M., Leonardi-Bee, J., Bath, P. M.W. — 2004-04-19

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

Taylor, J. A., Lipman, R. D. — 2004-04-05

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

Yang, L., Quan, S., Nasjletti, A., Laniado-Schwartzman, M., Abraham, N. G. — 2004-04-05

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.

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

Roman, R. J. — 2004-04-05

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

2004-04-05

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.

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

Liao, J. K. — 2004-03-29

[Letters to the Editor] Response

Chobanian, A. V., Roccella, E. J. — 2004-03-22

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

Schmidt, B. M.W., Schmieder, R. E. — 2004-02-23

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

Northcott, C. A., Watts, S. W. — 2004-02-23

[Letters to the Editor] Response

Chobanian, A. V., Roccella, E. J. — 2004-02-23

[Letters to the Editor] Response

Chobanian, A. V., Roccella, E. J. — 2004-02-23

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

Lipman, R. D., Taylor, J. A. — 2004-02-23

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

Budge, M. M., Gosling, R. G. — 2004-02-23

[Letters to the Editor] Response

2004-02-16

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

2004-02-16

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

Vecchione, C., Lembo, G. — 2004-02-09

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

Sattar, N., Ramsey, J., Jamieson, N., Greer, I. A. — 2004-02-02

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

Pockley, A. G., Georgiades, A., Thulin, T., de Faire, U., Frostegard, J. — 2004-02-02

[Letters to the Editor] Response

2004-01-26

[Letters to the Editor] Response

Egan, B. M. — 2004-01-19

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

Singer, G. M., Izhar, M., Black, H. R. — 2004-01-19

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.

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

2004-01-19

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.

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