Vol 48, No 5 | Hypertension

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Case studies and small trials suggest that acupuncture may effectively treat hypertension, but no large randomized trials have been reported. The Stop Hypertension with the Acupuncture Research Program pilot trial enrolled 192 participants with untreated blood pressure (BP) in the range of 140/90 to 179/109 mm Hg. The design of the trial combined rigorous methodology and adherence to principles of traditional Chinese medicine. Participants were weaned off antihypertensives before enrollment and were then randomly assigned to 3 treatments: individualized traditional Chinese acupuncture, standardized acupuncture at preselected points, or invasive sham acupuncture. Participants received ≤12 acupuncture treatments over 6 to 8 weeks. During the first 10 weeks after random assignment, BP was monitored every 14 days, and antihypertensives were prescribed if BP exceeded 180/110 mm Hg. The mean BP decrease from baseline to 10 weeks, the primary end point, did not differ significantly between participants randomly assigned to active (individualized and standardized) versus sham acupuncture (systolic BP: −3.56 versus −3.84 mm Hg, respectively; 95% CI for the difference: −4.0 to 4.6 mm Hg; P=0.90; diastolic BP: −4.32 versus −2.81 mm Hg, 95% CI for the difference: −3.6 to 0.6 mm Hg; P=0.16). Categorizing participants by age, race, gender, baseline BP, history of antihypertensive use, obesity, or primary traditional Chinese medicine diagnosis did not reveal any subgroups for which the benefits of active acupuncture differed significantly from sham acupuncture. Active acupuncture provided no greater benefit than invasive sham acupuncture in reducing systolic or diastolic BP.

Changes in Antihypertensive Prescribing During US Outpatient Visits for Uncomplicated Hypertension Between 1993 and 2004

Hypertension. 2006 | Volume 48, Issue 5: 846–852,

Published Online:September 18, 2006,

https://doi.org/10.1161/01.HYP.0000240931.90917.0c

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Monitoring national patterns of antihypertensive drug therapy is essential to assessing adherence to treatment guidelines and the impact of major scientific publications on physician prescribing. We analyzed data from 2 US National Ambulatory Care Surveys to examine trends between 1993 and 2004 in the prescription of antihypertensive drug classes for uncomplicated hypertension and the association between thiazide and β-blocker prescribing and physician and patient characteristics. Diuretic prescriptions remained level through 2001 (39%; 95% CI: 34% to 44%) but increased to 53% (48% to 58%) in 2003, largely because of a 72% increase in thiazide prescriptions in the first quarter of 2003 (50%; 95% CI: 40% to 59%). However, these increases did not sustain in 2004. β-Blocker prescriptions increased modestly from 1993 (24%; 95% CI: 19% to 29%) to 2004 (33%; 95% CI: 28% to 39%). Prescription of calcium channel blockers and angiotensin-converting enzyme inhibitors declined significantly following the sixth Joint National Committee report, but both subsequently rebounded to prereport levels. Prescription of angiotensin II receptor blockers increased continuously from 1% in 1995 to 23% by 2004. Polytherapy prescriptions, particularly those involving ≥3 drug classes, became increasingly prevalent, accounting for 60% of antihypertensive drug visits by 2004. Prescriptions of thiazides and β-blockers were both more likely in 1998–2004 (versus 1993–1997). Blacks, women, and hospital outpatients were more likely to receive thiazides. Also, cardiologists were more likely to prescribe β-blockers. Evidence-based guidelines for antihypertensive drug therapy do impact physician prescribing, but the impact seems to be short lived. Future interventions are imperative for promoting long-term adherence to published guidelines.

Large Increases in Hypertension Diagnosis and Treatment in Canada After a Healthcare Professional Education Program

Jay Onysko,
Colleen Maxwell,
Michael Eliasziw,
Jenny X. Zhang,
Helen Johansen,
Norm R.C. Campbell and
for the Canadian Hypertension Education Program

Hypertension. 2006 | Volume 48, Issue 5: 853–860,

Published Online:September 18, 2006,

https://doi.org/10.1161/01.HYP.0000242335.32890.c6

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This study was conducted to compare the self-reported prevalence and treatment of hypertension in adult Canadians before and subsequent to the implementation of the Canadian Hypertension Education Program in 1999. Data were obtained from 5 cycles of the Canadian Health Surveys between 1994 and 2003 on respondents aged ≥20 years. Piecewise linear regression was used to calculate the average annual increase in rates, before and after 1999. Between 1994 and 2003, the percentage of adult Canadians aware of being diagnosed with hypertension increased by 51% (from 12.37% to 18.74%; P<0.001), and the percentage prescribed antihypertensive drugs increased by 66% (from 9.57% to 15.86%; P<0.001). After 1999, there was approximately a doubling of the annual rate of increase in the diagnosis of hypertension (from 0.52% of the population per year before 1999 to 1.03% per year after 1999; P<0.001) and the percentage prescribed antihypertensive drugs (from 0.54% of the population per year before 1999 versus 0.98% per year after 1999; P<0.001). The proportion of those aware of the diagnosis of hypertension but not being treated with drugs was reduced by half between 1994 and 2003 (from 31.47% untreated to 15.34% untreated; P<0.001). There was a greater increase in awareness of hypertension and use of antihypertensive drugs among men compared with women after 1999. The large increase in the diagnosis and treatment of hypertension in Canada between 1994 and 2003 is consistent with an overall beneficial effect of the Canadian Hypertension Education Program, including a reduced gender gap in hypertension care.

Importance of Salt in Determining Blood Pressure in Children

Meta-Analysis of Controlled Trials

Feng J. He and
Graham A. MacGregor

Hypertension. 2006 | Volume 48, Issue 5: 861–869,

Published Online:September 25, 2006,

https://doi.org/10.1161/01.HYP.0000245672.27270.4a

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To assess the effect of reducing salt intake on blood pressure in children, we carried out a meta-analysis of controlled trials. Trials were included if participants were children (≤18 years), and duration of salt reduction must have been for ≥2 weeks. Mean effect size was calculated using a fixed-effect model, because there was no significant heterogeneity. Ten trials of children and adolescents with 966 participants were included (median age: 13 years; range: 8 to 16 years; median duration: 4 weeks; range: 2 weeks to 3 years). Salt intake was reduced by 42% (interquartile range [IQR]: 7% to 58%). There were significant reductions in blood pressure: systolic: −1.17 mm Hg (95% CI: −1.78 to −0.56 mm Hg; P<0.001); diastolic: −1.29 mm Hg (95% CI: −1.94 to −0.65 mm Hg; P<0.0001). Three trials of infants with 551 participants were included (median duration: 20 weeks; range: 8 weeks to 6 months). Salt intake was reduced by 54% (IQR: 51% to 79%). There was a significant reduction in systolic blood pressure: −2.47 mm Hg (95% CI: −4.00 to −0.94 mm Hg; P<0.01). This is the first meta-analysis of salt reduction in children, and it demonstrates that a modest reduction in salt intake causes immediate falls in blood pressure and, if continued, may well lessen the subsequent rise in blood pressure with age. This would result in major reductions in cardiovascular disease. These results in conjunction with other evidence provide strong support for a reduction in salt intake in children.

Predictors of Angiotensin-Converting Enzyme Inhibitor–Induced Reduction of Urinary Albumin Excretion in Nondiabetic Patients

Hypertension. 2006 | Volume 48, Issue 5: 870–876,

Published Online:September 25, 2006,

https://doi.org/10.1161/01.HYP.0000244082.26293.2d

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Urinary albumin excretion is a predictor for cardiovascular mortality and morbidity. We investigated which parameters determine baseline urinary albumin excretion in nondiabetic subjects, without renal disease. In addition, we evaluated the parameters that predict the albuminuria-lowering efficacy of an angiotensin-converting enzyme inhibitor. In this substudy of the Prevention of Renal and Vascular Endstage Disease Intervention Trial, 384 microalbuminuric patients were included. Patient and biochemical characteristics were obtained at baseline and after 3 months of double-blinded, randomized treatment (fosinopril 20 mg or placebo). Mean age was 51.1±11.5 years, and 65.6% were male. Median urinary albumin excretion was 22.2 mg per 24 hours. At baseline, mean arterial pressure (β_standardized=0.161; P=0.006), urinary sodium excretion (β_standardized=0.154; P=0.011), and estimated renal function were independently associated with albumin excretion. In these predominantly normotensive to prehypertensive subjects, fosinopril reduced albumin excretion by 18.5% versus a 6.1% increase on placebo after 3 months (P<0.001). Fosinopril use and blood pressure reduction independently predicted the change in urinary albumin excretion. Baseline urinary albumin excretion independently predicted the antialbuminuric effect of fosinopril (β_standardized=−0.303; P<0.001). In conclusion, at baseline, sodium intake and blood pressure were positively associated with urinary albumin excretion. Fosinopril reduced albuminuria more than might be expected from its blood pressure–lowering effect alone, and this effect was more outspoken in subjects with higher baseline albumin excretion. Based on our data, we hypothesize that angiotensin-converting enzyme inhibition may result in superior cardiovascular protection when compared with other blood pressure–lowering agents in subjects with higher baseline levels of albuminuria.

Predicting Stroke Using 4 Ambulatory Blood Pressure Monitoring-Derived Blood Pressure Indices

The Ohasama Study

Hypertension. 2006 | Volume 48, Issue 5: 877–882,

Published Online:September 18, 2006,

https://doi.org/10.1161/01.HYP.0000242285.83728.ee

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We investigated the association between stroke and blood pressure (BP) indices (systolic BP [SBP], diastolic BP [DBP], mean BP [MBP], and pulse pressure [PP]) determined by ambulatory BP monitoring. The predictive power for stroke of these indices was compared in the general Japanese population. We obtained ambulatory BP data in 1271 subjects (40% men) aged ≥40 (mean: 61) years. During a mean follow-up of 11 years, 113 strokes were observed. The multivariate adjusted relative hazard and likelihood ratio for a 1-SD increase for each BP index was determined by Cox proportional hazard regression. Comparison of the likelihood ratio between Cox models including 2 indices and those including 1 index indicated that PP was significantly less informative than other indices (P<0.01 when adding MBP, SBP, or DBP to the PP model; P>0.09 when adding PP to the model including another index). However, after removing age from covariates, PP became more informative than DBP and MBP (P<0.0001 when adding PP to the MBP or DBP model, whereas SBP was more informative than PP even after removing age; P<0.05 when adding SBP to the PP model). In conclusion, PP was the weakest predictor of stroke. Exclusion of age from covariates increased the predictive power of PP, suggesting that the stroke risk associated with PP reflected the risk of aging per se.

Implication of Chromosome 18 in Hypertension by Sibling Pair and Association Analyses

Putative Involvement of the RKHD2 Gene

Hypertension. 2006 | Volume 48, Issue 5: 883–891,

Published Online:October 2, 2006,

https://doi.org/10.1161/01.HYP.0000244085.52918.a0

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This study aims to test the implication of regions on chromosomes 9, 17, and 18 in essential hypertension (EH) by combining sibling-pair linkage analysis and case–control association studies. The selection of these chromosomal regions is based on previous evidence of their implication in EH or in related phenotypes by comparative genomics in several rat models and from genome-wide linkage studies in humans. For the affected sibling-pair linkage analysis, 27 microsatellite markers were genotyped in 56 pedigrees from Spain with hypertensive sibling pairs. Linkage analysis showed significant excess allele sharing at the D18S474 marker on 18q21.1, as shown by maximum likelihood of allele sharing methods (logarithm of odds=3.24; P=0.00011) and nonparametric linkage calculations (nonparametric linkage=3.32; P=0.00044). On the contrary, no significant results with any of the markers analyzed on chromosomes 9 and 17 were obtained. We further focused on the Ring finger and KH domain containing 2 (RKHD2) gene located 6 Kb distal from D18S474 and performed a case–control association study based on linkage disequilibrium in 112 hypertensive patients and 156 control subjects. We selected 2 RKHD2-tagged single nucleotide polymorphisms, rs1941958 and rs1893379, covering, in terms of linkage disequilibrium, the entire gene, and observed a significant overrepresentation of the rs1941958G-rs1893379T RKHD2 haplotype in the group of hypertensive patients in comparison with controls (2P=0.0004; odds ratio: 2.32). We also detected epistatic effects between the 2 RKHD2 single nucleotide polymorphisms (2P=0.002; odds ratio: 2.48). Our data confirm the implication of chromosome 18 in EH and support a contribution of RKHD2 to the genetic susceptibility of this complex phenotype.

β-2 Adrenergic Receptor Diplotype Defines a Subset of Salt-Sensitive Hypertension

Hypertension. 2006 | Volume 48, Issue 5: 892–900,

Published Online:October 2, 2006,

https://doi.org/10.1161/01.HYP.0000244688.45472.95

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Two genetic variants of the β-2 adrenergic receptor, 46G>A and 79C>G, affect agonist-mediated receptor downregulation and vascular reactivity. We determined whether these variants were associated with hypertension, per se, blood pressure response to dietary sodium, 2 forms of salt-sensitive hypertension (low renin and nonmodulation), and the activity of the renin–angiotensin–aldosterone system. Included are 280 hypertensive and 65 normotensive white subjects who had the 2 β-2 adrenergic receptor genotypes available. Of all subjects, 171 hypertensive and 48 normotensive subjects had complete data for intermediate phenotyping and blood pressure evaluation on high- and low-sodium balance. The β-2 adrenergic receptor variants were not associated with hypertension per se. However, among hypertensive subjects, the change (from low to high sodium balance) in mean arterial pressure differed significantly by genotype and by diplotype. Compared with all of the other diplotypes combined, 46AA/79CC was associated with a greater change in blood pressure. Furthermore, this diplotype was associated with low-renin (LR) hypertension (identifying 32% of the LR hypertensives), higher plasma aldosterone, and lower plasma renin and serum potassium levels. In conclusion, the 46AA/79CC diplotype is associated with greater blood pressure response to dietary sodium and higher odds of LR hypertension. We propose that the mechanism for the observed association is inadequate suppression of aldosterone with salt intake, implicating the β-2 adrenergic receptor in the regulation of aldosterone secretion. This hypothesis was confirmed in isolated glomerulosa cells, where β-2 adrenergic receptor stimulation increased aldosterone secretion, whereas blockade reduced the stimulated aldosterone response. Importantly, this association could only be detected with an intermediate and not a distant phenotype.

Extensive Genetic Analysis of 10 Candidate Genes for Hypertension in Japanese

Hypertension. 2006 | Volume 48, Issue 5: 901–907,

Published Online:September 18, 2006,

https://doi.org/10.1161/01.HYP.0000242485.23148.bb

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The identification of genes that contribute to essential hypertension has been hampered because of a lack of statistical power and problems with multiple testing. In the present study, we performed association analyses between the 161 single nucleotide polymorphisms of 10 candidate genes and hypertension in a Japanese population recruited from the Suita Study (n=3654). We found that 5 polymorphisms in the 3 genes (SLC9A2, UMOD, and ELN) were associated with hypertension status, and 4 of these 5 polymorphisms were also associated with blood pressure values with a classical criterion of P<0.05. However, when a Bonferroni correction for multiple testing was applied, none of the polymorphisms were associated with blood pressure levels. We also performed association analyses between these 5 polymorphisms and intermediate phenotypes corresponding with the functions of candidate genes, including the renin/aldosterone profile, plasma uric acid levels, and pulse wave velocity. The ELN 3′-untranslated region (−/A) polymorphism was found to significantly affect pulse wave velocity, an indicator of arterial stiffness. Associations of the ELN 3′-untranslated region (−/A) polymorphism with hypertension and pulse wave velocity were reconfirmed in another set of the study population. Thus, ELN seems to contribute to blood pressure regulation by affecting arterial stiffness in Japanese.

Genome-Wide Scan for Premature Hypertension Supports Linkage to Chromosome 2 in a Large Kyrgyz Family

Hypertension. 2006 | Volume 48, Issue 5: 908–913,

Published Online:September 25, 2006,

https://doi.org/10.1161/01.HYP.0000244107.13957.2b

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We report a genome-wide scan for susceptibility loci to hypertension in a single Kyrgyz family where 10 of the affected relatives developed hypertension before the age of 35 years, and some members have suffered stroke. The early onset of disease and the geographic isolation of the Kyrgyz population are both expected to select for an increased influence of genetic factors in hypertension. We genotyped 44 individuals from this Krygyz family with 374 microsatellite markers, covering a 10-centimorgan map. Nonparametric analysis suggests that affected status is linked to loci in the chromosome 2q23 to q37 genomic interval, whereas 2-point parametric analysis returned a logarithm of odds score of 2.67 for marker D2S2330 (2q24.3). Multipoint linkage analysis substantiated the evidence for a hypertension susceptibility allele in the chromosome 2q23 to q36 region. Fine mapping and haplotype analysis implicate that the genetic lesion resides between markers D2S2380 (166.5 cM) and D2S335 (175.9 cM). This finding supports other recent studies of early onset hypertension suggesting that the region 2q24.3 to q31.1 encompasses a novel locus for premature hypertension.

Circulating Activities of Angiotensin-Converting Enzyme, Its Homolog, Angiotensin-Converting Enzyme 2, and Neprilysin in a Family Study

Hypertension. 2006 | Volume 48, Issue 5: 914–920,

Published Online:September 25, 2006,

https://doi.org/10.1161/01.HYP.0000244543.91937.79

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The renin–angiotensin system is a key regulator of blood pressure (BP), with inhibitors of angiotensin-converting enzyme (ACE) used clinically to treat hypertension and other cardiovascular conditions. ACE2 is a newly identified member of this system, which converts angiotensin II to angiotensin (1-7), and of which the occurrence in plasma has not been investigated. The aim of this study was to determine the heritability of circulating ACE, ACE2, and neprilysin (NEP), which may also be a regulator of BP, in a family study, and to determine covariates that contribute to the variation in plasma activity. ACE, ACE2, and NEP activities were measured in plasma from 534 subjects in the Leeds Family Study using selective fluorogenic substrates. Genetic factors accounted for 24.5%, 67%, and 22.7% of the phenotypic variation in circulating ACE, ACE2, and NEP, respectively. ACE insertion/deletion polymorphism and other measured covariates accounted for 23.8% of variance in circulating ACE. High-density lipoprotein cholesterol was a significant determinant of circulating ACE2. Measured covariates accounted for 17.3% of variation in circulating NEP. ACE and NEP were associated with systolic and diastolic BP in univariate analyses; however, only ACE was independently associated with systolic and diastolic BP after accounting for covariates and shared childhood household.

Genetic Determinants of Systolic and Pulse Pressure in an Intercross Between Normotensive Inbred Rats

Hypertension. 2006 | Volume 48, Issue 5: 921–926,

Published Online:October 2, 2006,

https://doi.org/10.1161/01.HYP.0000244758.50351.29

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By continuous monitoring of abdominal aortic blood pressure via telemetry in conscious rats, we have observed that systolic, diastolic, and pulse pressures of male Brown–Norway rats were all significantly lower than that of male Wistar–Kyoto rats, despite the fact that all of the values in both strains were within normotensive ranges. Further analyses performed in 166 animals from the progeny of an F2 intercross between Brown–Norway and Wistar–Kyoto rats revealed that, despite a high correlation between systolic blood pressure and diastolic blood pressure, there was no correlation between pulse pressure and diastolic blood pressure, and the value of the correlation between systolic blood pressure and pulse pressure was lower than that of systolic blood pressure with diastolic blood pressure. Two major and highly significant (P<0.001) quantitative trait loci linked to pulse pressure were found on chromosome 4 (Pp1) and 16 (Pp2). Only suggestive quantitative trait loci were found for systolic blood pressure, but the strongest one (Sbp1) had the same peak and linkage probability profile as Pp1. Altogether, these data show that genetic determinants affecting pulse pressure in normotensive animals are either stronger or independent from the ones affecting systolic blood pressure and are of interest in light of evidence showing that pulse pressure is highly heritable in humans and that elevated pulse pressure is a predictor of cardiovascular risk.

Chronic Low-Dose Angiotensin II Infusion Increases Venomotor Tone by Neurogenic Mechanisms

Andrew J. King and
Gregory D. Fink

Hypertension. 2006 | Volume 48, Issue 5: 927–933,

Published Online:September 25, 2006,

https://doi.org/10.1161/01.HYP.0000243799.84573.f8

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The purpose of this study was to identify changes in venomotor tone in the chronic low-dose angiotensin II (Ang II) model of hypertension and to establish the contribution of sympathetic nerve activation to these venomotor tone changes. Male Sprague–Dawley rats were acclimatized to a 0.4% or 2.0% NaCl diet for 7 days and then catheterized to allow chronic and repeated measures of arterial pressure, central venous pressure, and mean circulatory filling pressure (MCFP), an index of venous smooth muscle tone, in conscious undisturbed rats. After 4 days of recovery and a 3-day control period, an Ang II or physiological saline-filled osmotic minipump was implanted subcutaneously to deliver Ang II (150 ng/kg per minute) or vehicle control for 14 days. MCFP was measured in duplicate before and after acute ganglionic blockade with hexamethonium (30 mg/kg IV) on control day 2 and Ang II infusion on days 1, 3, 7, and 14. Blood volume was also measured on these days and was unchanged for the duration of the study in all of the groups. Arterial pressure was increased for the duration of Ang II infusion in rats on both 0.4% and 2% NaCl diets, but the increase was significantly greater in the 2% NaCl group and completely abolished by hexamethonium. MCFP was significantly increased for the entire Ang II infusion period only in rats fed 2% NaCl, and this increase was completely abolished by hexamethonium. We conclude that the combination of chronic low-dose Ang II infusion and high dietary salt intake engages the sympathetic nervous system to increase venomotor tone.

Role of Extracellular Superoxide Dismutase in the Mouse Angiotensin Slow Pressor Response

Hypertension. 2006 | Volume 48, Issue 5: 934–941,

Published Online:October 2, 2006,

https://doi.org/10.1161/01.HYP.0000242928.57344.92

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Low rates of angiotensin II (Ang II) infusion raise blood pressure, renal vascular resistance (RVR), NADPH oxidase activity, and superoxide. We tested the hypothesis that these effects are ameliorated by extracellular superoxide dismutase (EC-SOD). EC-SOD knockout (−/−) and wild type (+/+) mice were equipped with blood pressure telemeters and infused subcutaneously with Ang II (400 ng/kg per minute) or vehicle for 2 weeks. During vehicle infusion, EC-SOD −/− mice had significantly (P<0.05) higher MAP (+/+: 107±3 mm Hg versus −/−: 114±2 mm Hg; n=11 to 14), RVR, lipid peroxidation, renal cortical p22^phox expression, and NADPH oxidase activity. Ang II infusion in EC-SOD +/+ mice significantly (P<0.05) increased MAP, RVR, p22^phox, NADPH oxidase activity, and lipid peroxidation. Ang II reduced SOD activity in plasma, aorta, and kidney accompanied by reduced renal EC-SOD expression. During Ang II infusion, both groups had similar values for MAP (+/+ Ang II: 125±3 versus −/− Ang II: 124±3 mmHg; P value not significant), RVR, NADPH oxidase activity, and lipid peroxidation. SOD activity in the kidneys of Ang II–infused mice was paradoxically higher in EC-SOD −/− mice (+/+: 8.8±1.2 U/mg protein⁻¹ versus −/−: 13.7±1.6 U/mg protein⁻¹; P<0.05) accompanied by a significant upregulation of mRNA and protein for Cu/Zn-SOD. In conclusion, EC-SOD protects normal mice against oxidative stress by attenuating renal p22^phox expression, NADPH oxidase activation, and the accompanying renal vasoconstriction and hypertension. However, during an Ang II slow pressor response, renal EC-SOD expression is reduced and, in its absence, renal Cu/Zn-SOD is upregulated and may prevent excessive Ang II–induced renal oxidative stress, renal vasoconstriction, and hypertension.

Angiotensin II Type 2 Receptor Expression After Vascular Injury

Differing Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin Receptor Blockade

Hypertension. 2006 | Volume 48, Issue 5: 942–949,

Published Online:September 18, 2006,

https://doi.org/10.1161/01.HYP.0000241061.51003.b7

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It has been suggested that the effects of angiotensin II type 1 receptor (AT₁R) blockers are in part because of angiotensin II type 2 receptor (AT₂R) signaling. Interactions between the AT₂R and kinins modulate cardiovascular function. Because AT₂R expression increases after vascular injury, we hypothesized that the effects on vascular remodeling of the AT₁R blocker valsartan and the ACE inhibitor benazepril require AT₂R signaling through the bradykinin 1 and 2 receptors (B₁R and B₂R). To test this hypothesis, Brown Norway rats were assigned to 8 treatments (n=16): valsartan, valsartan+PD123319 (AT₂R inhibitor), valsartan+des-arg⁹-[Leu⁸]-bradykinin (B₁R inhibitor), valsartan+HOE140 (B₂R inhibitor), benazepril, benazepril+HOE140, amlodipine, and vehicle. After 1 week of treatment, carotid balloon injury was performed. Two weeks later, carotids were harvested for morphometry and analysis of receptor expression by immunohistochemistry and Western blotting. Valsartan and benazepril significantly reduced the intima:media ratio compared with vehicle. Blockade of AT₂R, B₁R, or B₂R in the presence of valsartan prevented the reduction seen with valsartan alone. B₂R blockade inhibited the effect of benazepril. Injury increased AT₁R, AT₂R, B₁R, and B₂R expression. Treatment with valsartan but not benazepril significantly increased intima AT₂R expression 2-fold compared with vehicle, which was not reversed by inhibition of AT₂R, B₁R, and B₂R. Functionally, valsartan increased intimal cGMP levels compared with vehicle, and this increase was inhibited by blocking the AT₂R, B₁R, and B₂R. Results suggest that AT₂R expression and increased cGMP represent a molecular mechanism that differentiates AT₁R blockers, such as valsartan, from angiotensin-converting enzyme inhibitors like benazepril.

NO Modulates NADPH Oxidase Function Via Heme Oxygenase-1 in Human Endothelial Cells

Hypertension. 2006 | Volume 48, Issue 5: 950–957,

Published Online:September 18, 2006,

https://doi.org/10.1161/01.HYP.0000242336.58387.1f

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NO is known to induce expression of heme oxygenase-1, an antioxidant enzyme in blood vessels. We tested whether NO might modulate the endothelial NADPH oxidase function via heme oxygenase-1. In human microvascular endothelial cells, the NO donor DETA-NONOate (0.1 to 1 mmol/L) strongly induced expression of heme oxygenase-1 but not Cu/Zn superoxide dismutase. This was associated with a reduction of the superoxide-generating capacity of NADPH oxidase, an effect that depended on de novo gene transcription and heme oxygenase-1 activity. Activation of NADPH oxidase by tumor necrosis factor (TNF) α increased generation of reactive oxygen species. DETA-NONOate alone had little effect on TNF-stimulated reactive oxygen species, but it enhanced the TNF response when: (1) heme oxygenase-1 expression was blocked with specific small-interfering RNA; (2) heme oxygenase-1 activity was blocked by zinc-protoporphyrin; or (3) NADPH oxidase activity was blocked by diphenyleneiodonium. Moreover, the heme oxygenase-1 end product bilirubin directly inhibited fully functional NADPH oxidase and seemed to interrupt the assembly and activation of the oxidase. In conclusion, NO may modulate superoxide production by NADPH oxidase in human vascular endothelial cells, at least partly by inducing heme oxygenase-1. Our results indicate that suppression of NADPH oxidase-dependent reactive oxygen species formation may represent a novel mechanism underlying the cardiovascular protective actions of heme oxygenase-1 and bilirubin.

Angiotensin II Stimulates Endothelial NO Synthase Phosphorylation in Thoracic Aorta of Mice With Abdominal Aortic Banding Via Type 2 Receptor

Hypertension. 2006 | Volume 48, Issue 5: 958–964,

Published Online:September 25, 2006,

https://doi.org/10.1161/01.HYP.0000244108.30909.27

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Abdominal aortic banding in mice induces upregulation of angiotensin II (Ang II) type 2 (AT₂) receptors in the pressure-overloaded thoracic aorta. To clarify mechanisms underlying the vascular AT₂ receptor-dependent NO production, we measured aortic levels of endothelial NO synthase (eNOS), eNOS phosphorylated at Ser⁶³³ and Ser¹¹⁷⁷, protein kinase B (Akt), and Akt phosphorylated at Ser⁴⁷³ in thoracic aortas of mice after banding. Total eNOS, both forms of phosphorylated eNOS, Akt, and phosphorylated Akt levels, as well as cGMP contents, were significantly increased 4 days after banding. The administration of PD123319 (an AT₂ receptor antagonist) or icatibant (a bradykinin B₂ receptor antagonist) abolished the banding-induced upregulation of both forms of phosphorylated eNOS, as well as elevation of cGMP, but did not affect the upregulation of eNOS, Akt, and phosphorylated Akt. In the in vitro experiments using aortic rings prepared from banded mice, Ang II produced significant increases in both forms of phosphorylated eNOS, as well as cGMP, and these effects were blocked by PD123319 and icatibant. Ang II–induced eNOS phosphorylation and cGMP elevation in aortic rings were inhibited by protein kinase A (PKA) inhibitors H89 and KT5720 but not by phosphatidylinositol 3-kinase inhibitors wortmannin and LY24002. The contractile response to Ang II was attenuated in aortic rings from banded mice via AT₂ receptor, and this attenuation was blocked by PKA inhibitors. These results suggest that the activation of AT₂ receptor by Ang II induces phosphorylation of eNOS at Ser⁶³³ and Ser¹¹⁷⁷ via a PKA-mediated signaling pathway, resulting in sustained activation of eNOS.

Late-Onset Endothelin-A Receptor Blockade Reduces Podocyte Injury in Homozygous Ren-2 Rats Despite Severe Hypertension

Hypertension. 2006 | Volume 48, Issue 5: 965–971,

Published Online:October 2, 2006,

https://doi.org/10.1161/01.HYP.0000245117.57524.d6

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We have recently found in male homozygous hypertensive Ren-2 transgenic rats (TGRs) fed a high-salt diet that early onset selective endothelin (ET) A (ET_A) or nonselective ET_A/ET B (ET_B) receptor blockade improved survival rate and reduced proteinuria, glomerulosclerosis, and cardiac hypertrophy, whereas selective ET_A receptor blockade also significantly attenuated the rise in blood pressure. Because antihypertensive therapy in general is known to be more efficient when started at early age, our study was performed to determine whether onset of ET receptor blockade at a later age in animals with established hypertension will have similar protective effects as does early-onset therapy. Male homozygous TGRs and age-matched normotensive Hannover Sprague–Dawley rats were fed a high-salt diet between days 51 and 90 of age. TGRs received vehicle (untreated), the selective ET_A receptor blocker atrasentan (ABT-627), or the nonselective ET_A/ET_B receptor blocker bosentan. Survival rates in untreated and bosentan-treated TGRs were 50% and 64%, respectively, whereas with atrasentan, survival rate of TGR was 96%, thus, similar to 93% in Hannover Sprague–Dawley rats. From day 60 on, systolic blood pressure in atrasentan-treated TGRs was transiently lower (P<0.05) than in untreated or bosentan-treated TGRs. Glomerular podocyte injury was substantially reduced with atrasentan treatment independent of severe hypertension and strongly correlated with survival (P<0.001). Our data indicate that in homozygous TGR ET receptors play an important role also in established hypertension. Selective ET_A receptor blockade not only reduces podocyte injury and end-organ damage but also improves growth and survival independently of hypertension.

Soluble Guanylate Cyclase Stimulation on Cardiovascular Remodeling in Angiotensin II–Induced Hypertensive Rats

Hypertension. 2006 | Volume 48, Issue 5: 972–978,

Published Online:September 18, 2006,

https://doi.org/10.1161/01.HYP.0000241087.12492.47

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It is unknown whether long-term pharmacological stimulation of soluble guanylate cyclase (sGC), elevating intracellular cGMP levels, has a beneficial effect on hypertension. The purpose of this study is to investigate the effects of BAY41-2272, an orally available sGC stimulator, on cardiovascular remodeling in hypertensive rats. Eight-week-old male Wistar rats with hypertension induced by angiotensin II infused subcutaneously at 250 ng/kg per minute were treated orally with a low ([L] 2 mg/kg per day) or high ([H] 10 mg/kg per day) dose of BAY41-2272 for 14 days. BAY41-2272-H partially suppressed the rise in blood pressure and reduced the heart weight (4.20±0.34 versus 3.68±0.20 mg/g; P<0.01), whereas BAY41-2272-L had no effect. However, both doses decreased the angiotensin II–induced left ventricular accumulation of collagen in the perivascular area (L, −20%, P<0.05; H, −30%, P<0.01) and myocardial interstitium (L, −21%, P<0.05; H, −38%, P<0.01), reducing the number of activated fibroblasts surrounding coronary arteries (L, −74%; H, −79%; P<0.05). BAY41-2272 downregulated the angiotensin II–induced left ventricular gene expression of type 1 collagen (L, −41%, P<0.05; H, −49%, P<0.01) and transforming growth factor-β1 (L, −49%, P<0.05; H, −65%, P<0.01). cGMP levels were elevated by BAY41-2272 not only in the left ventricle, but also in cultured cardiac fibroblasts, resulting in reduced thymidine incorporation into the cells. Thus, stimulation of sGC by BAY41-2272 attenuates fibrosis of the left ventricle in rats with angiotensin II–induced hypertension partly in a pressure-independent manner, suggesting an important role for sGC generating cGMP in inhibiting cardiovascular remodeling.

Elastolytic Cathepsin Induction/Activation System Exists in Myocardium and Is Upregulated in Hypertensive Heart Failure

Hypertension. 2006 | Volume 48, Issue 5: 979–987,

Published Online:September 18, 2006,

https://doi.org/10.1161/01.HYP.0000242331.99369.2f

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Cathepsins are cysteine proteases that participate in various types of tissue remodeling. However, their expressions during myocardial remodeling have not been examined. In this study, we investigated their expressions in the left ventricular (LV) myocardium of rats and humans with hypertension-induced LV hypertrophy or heart failure (HF). Real-time PCR and immunoblot analysis revealed that the abundance of cathepsin S mRNA or protein in the LV tissues was greater in rats or humans with HF than in those with hypertrophy or in control subjects. Immunostaining showed that cathepsin S was localized predominantly to cardiac myocytes and coronary vascular smooth muscle cells, but also overlapped in part with macrophages. Elastic lamina fragmentations significantly increased in the LV intramyocardial coronary arteries of HF rats. The amount of elastolytic activity in the extract of the LV myocardium was markedly increased for HF rats compared with controls, and this activity was mostly because of cathepsin S. Although the amount of elastin mRNA was increased in the LV myocardium of HF rats, the area of interstitial elastin was not. The expression of interleukin 1β was increased in the LV myocardium of HF rats, and this cytokine was found to increase the expression and activity of cathepsin S in cultured neonatal cardiomyocytes. These results suggest that cathepsin S participates in pathological LV remodeling associated with hypertension-induced HF. This protease is, thus, a potential target for therapeutics aimed at preventing or reversing cardiac remodeling.

Insulin Resistance and Obesity in a Mouse Model of Systemic Lupus Erythematosus

Hypertension. 2006 | Volume 48, Issue 5: 988–993,

Published Online:September 18, 2006,

https://doi.org/10.1161/01.HYP.0000243612.02929.df

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Accumulating data indicate that metabolic syndrome is an inflammatory condition. Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with nephritis and cardiovascular disease. Evidence suggests that individuals with SLE are at risk for developing insulin resistance; however, this has not been directly examined. Using an established mouse strain with SLE (NZBWF1), we examined whether SLE is associated with increased body weight and fat deposition. Mean arterial pressure was significantly increased (140±4 versus 114±2 mm Hg; n≥5) in SLE mice by 36 weeks of age compared with control mice (NZW/LacJ). Body weight in SLE mice was higher at each age compared with controls by 12%, 22%, and 34% (n>30). Visceral adipose tissue weight was increased in SLE by 44%, 74%, and 117% at 8, 20, and 36 weeks, respectively (n≥12). Plasma leptin was increased in SLE mice (8.6±1.0 versus 24.7±2.2 ng/mL; n=5), and renal and adipose tissue exhibited macrophage infiltration. Fasted insulin was higher in SLE mice (0.6±0.1 versus 1.4±0.3 ng/mL; n≥10), but fasted glucose was not different (94±5 versus 80±9; n≥9). A glucose tolerance test caused a significantly greater and longer increase in blood glucose from mice with SLE compared with control mice. Food intake was not different between control and SLE mice. However, mice with SLE demonstrated lower levels of nighttime activity than controls. These data show that the NZBWF1 strain may be an important model to study the effects of obesity and insulin resistance on SLE-associated hypertension.

Medroxyprogesterone Acetate But Not Drospirenone Ablates the Protective Function of 17β-Estradiol in Aldosterone Salt-Treated Rats

Hypertension. 2006 | Volume 48, Issue 5: 994–1001,

Published Online:September 25, 2006,

https://doi.org/10.1161/01.HYP.0000242482.57186.e8

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Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17β-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17β-estradiol in ovariectomized animals after 8 weeks of continuous treatment. The beneficial role of 17β-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate. In contrast, drospirenone was either neutral or additive to 17β-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation. The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation. Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties.

Reduction of Blood Pressure Levels Study Group

Samuel J. Mann

Hypertension. 2006 | Volume 48, Issue 5: e104,

Published Online:October 2, 2006,

https://doi.org/10.1161/01.HYP.0000242423.46358.74

Response to Reduction of Blood Pressure Levels Study Group

Carlos M. Ferrario and
Ronald D. Smith

Hypertension. 2006 | Volume 48, Issue 5: e105,

Published Online:October 2, 2006,

https://doi.org/10.1161/01.HYP.0000242421.27697.81

A New Hormone Therapy With Drospirenone and NO Production in Postmenopausal Women

Kazushi Tsuda

Hypertension. 2006 | Volume 48, Issue 5: e106,

Published Online:September 25, 2006,

https://doi.org/10.1161/01.HYP.0000244900.75100.41

Response to a New Hormone Therapy With Drospirenone and NO Production in Postmenopausal Women

William B. White

Hypertension. 2006 | Volume 48, Issue 5: e107,

Published Online:September 25, 2006,

https://doi.org/10.1161/01.HYP.0000244902.46371.7e

Table of Contents

Brief Reviews

Mechanisms of Sympathetic Activation in Obesity-Related Hypertension

Caveolin-Dependent Angiotensin II Type 1 Receptor Signaling in Vascular Smooth Muscle

Vascular Gap Junctions in Hypertension

Editorial

Prehypertension Revisited

Editorial Commentaries

Acupuncture for Hypertension

Can 2500 Years Come to an End?

Antihypertensive Prescribing

Do We Have Reason to Celebrate?

Salt Reduction for Preventing Hypertension and Cardiovascular Disease

A Population Approach Should Include Children

The Adrenergic Nervous System Conversing With the Adrenal Cortex

New Implications for Salt-Sensitive Hypertension

Is There a New Treatment for Hypertensive Disease in the Horizon?

Role of Soluble Guanylate Cyclase

Role of Angiotensin Type 2 Receptors in Vasodilation of Resistance and Capacitance Vessels

Editorial Commentary

Heme Oxygenase-1 Inhibition of Nox Oxidase Activation Is a Microvascular Endothelial Antioxidant Effect of NO

Editorial Commentaries

Dissecting the Causes of Oxidative Stress in an In Vivo Model of Hypertension

Editorial Commentary

Digesting the Remodeled Heart

Role of Lysosomal Cysteine Proteases in Heart Failure

Editorial Commentaries

Predictors of the Evolution of Microalbuminuria

Role of Endothelin Receptors for Renal Protection and Survival in Hypertension

Waiting for Clinical Trials

Acupuncture

Stop Hypertension With the Acupuncture Research Program (SHARP)

Results of a Randomized, Controlled Clinical Trial

Antihypertensive Drug Prescribing

Changes in Antihypertensive Prescribing During US Outpatient Visits for Uncomplicated Hypertension Between 1993 and 2004

Canadian Hypertension Control Program

Large Increases in Hypertension Diagnosis and Treatment in Canada After a Healthcare Professional Education Program

Salt Reduction and Blood Pressure

Importance of Salt in Determining Blood Pressure in Children

Meta-Analysis of Controlled Trials

ACE Inhibition and Albumin Excretion

Predictors of Angiotensin-Converting Enzyme Inhibitor–Induced Reduction of Urinary Albumin Excretion in Nondiabetic Patients

Ambulatory Blood Pressure and Stroke

Predicting Stroke Using 4 Ambulatory Blood Pressure Monitoring-Derived Blood Pressure Indices

The Ohasama Study

Genetics

Implication of Chromosome 18 in Hypertension by Sibling Pair and Association Analyses

Putative Involvement of the RKHD2 Gene

β-2 Adrenergic Receptor Diplotype Defines a Subset of Salt-Sensitive Hypertension

Extensive Genetic Analysis of 10 Candidate Genes for Hypertension in Japanese

Genome-Wide Scan for Premature Hypertension Supports Linkage to Chromosome 2 in a Large Kyrgyz Family

Circulating Activities of Angiotensin-Converting Enzyme, Its Homolog, Angiotensin-Converting Enzyme 2, and Neprilysin in a Family Study

Genetic Determinants of Systolic and Pulse Pressure in an Intercross Between Normotensive Inbred Rats

Renin-Angiotensin System

Chronic Low-Dose Angiotensin II Infusion Increases Venomotor Tone by Neurogenic Mechanisms

Role of Extracellular Superoxide Dismutase in the Mouse Angiotensin Slow Pressor Response

Angiotensin II Type 2 Receptor Expression After Vascular Injury

Differing Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin Receptor Blockade

Heme Oxygenase and Nitric Oxide

NO Modulates NADPH Oxidase Function Via Heme Oxygenase-1 in Human Endothelial Cells

Angiotensin II Stimulates Endothelial NO Synthase Phosphorylation in Thoracic Aorta of Mice With Abdominal Aortic Banding Via Type 2 Receptor

Endothelin and Renal Injury

Late-Onset Endothelin-A Receptor Blockade Reduces Podocyte Injury in Homozygous Ren-2 Rats Despite Severe Hypertension

Cardiac Remodeling

Soluble Guanylate Cyclase Stimulation on Cardiovascular Remodeling in Angiotensin II–Induced Hypertensive Rats

Elastolytic Cathepsin Induction/Activation System Exists in Myocardium and Is Upregulated in Hypertensive Heart Failure

Insulin Resistance and Obesity in Lupus

Insulin Resistance and Obesity in a Mouse Model of Systemic Lupus Erythematosus

Estrogen, Progesterone, and Aldosterone Interactions

Medroxyprogesterone Acetate But Not Drospirenone Ablates the Protective Function of 17β-Estradiol in Aldosterone Salt-Treated Rats

Letters to the Editor

Reduction of Blood Pressure Levels Study Group

Response to Reduction of Blood Pressure Levels Study Group

A New Hormone Therapy With Drospirenone and NO Production in Postmenopausal Women

Response to a New Hormone Therapy With Drospirenone and NO Production in Postmenopausal Women

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