Hypertension current issue

[In Memoriam] Juan Carlos Romero, MD: 1937-2008

Carretero, O. A., Nasjletti, A. — 2009-06-17

[Letters to the Editor] Depression and Blood Pressure Control: All Antidepressants Are not the Same

Dawood, T., Schlaich, M., Brown, A., Lambert, G. — 2009-06-17

[Letters to the Editor] Response to Depression and Blood Pressure Control: All Antidepressants Are not the Same

Licht, C. M.M., Penninx, B. W.J.H., de Geus, E. J.C. — 2009-06-17

[Brief Reviews] Vascular Aging: A Tale of EVA and ADAM in Cardiovascular Risk Assessment and Prevention

Nilsson, P. M., Boutouyrie, P., Laurent, S. — 2009-06-17

[Letters to the Editor] Is Combined L- and T-Channel Blockade Better Than L-Channel Blockade in Therapy?

Godfraind, T. — 2009-06-17

[Letters to the Editor] Response to Is Combined L- and T-Channel Blockade Better than L-Channel Blockade in Therapy?

Wilson, D. P., Ball, C. J., Turner, S. P., Saint, D. A., Beltrame, J. F. — 2009-06-17

[Letters to the Editor] Implementation of Pay for Performance Policy in England

Falaschetti, E., Campbell, N. R.C., Mohan, S., Poulter, N. — 2009-06-17

[Letters to the Editor] Meta-Analysis of the Effects of Treating Blood Pressure on Cardiovascular Outcomes of Dialysis Patients

Goldsmith, D. J.A., Covic, A. C. — 2009-06-17

[Letters to the Editor] Response to Meta-Analysis of the Effects of Treating Blood Pressure on Cardiovascular Outcomes of Dialysis Patients

Agarwal, R., Sinha, A. D. — 2009-06-17

[Letters to the Editor] Sympathetic Activity and Clinical Outcome in Dialysis Patients

Siddiqi, L., Blankestijn, P. J. — 2009-06-17

[Letters to the Editor] Response to Sympathetic Activity and Clinical Outcome in Dialysis Patients

Agarwal, R. — 2009-06-17

[Letters to the Editor] Combination Treatment to Prevent Atherosclerosis

Koh, K. K. — 2009-06-17

[Brief Reviews] Postmenopausal Hypertension: Mechanisms and Therapy

Barton, M., Meyer, M. R. — 2009-06-17

[Letters to the Editor] Response to Combination Treatment to Prevent Atherosclerosis

Kushiro, T. — 2009-06-17

[Letters to the Editor] Method of Blood Collection May Explain the Suppression of Plasma Renin Concentration in Prorenin Transgenic Mice

Campbell, D. J. — 2009-06-17

[Letters to the Editor] Response to Method of Blood Collection May Explain the Suppression of Plasma Renin Concentration in Prorenin Transgenic Mice

Reudelhuber, T. L. — 2009-06-17

[Editorial Commentaries] Triple Fixed-Dose Combination Therapy: Back to the Past

Black, H. R. — 2009-06-17

[Editorial Commentaries] Does It Matter When Drugs Are Taken?

Morgan, T. O. — 2009-06-17

[Editorial Commentaries] The Kidney: Both Culprit and Victim

Ritz, E. — 2009-06-17

[Editorial Commentaries] Hypertension: Are We {beta}ARKing Up the Right Tree?

Attramadal, H. — 2009-06-17

[Editorial Commentaries] Treatment of Chronic Proteinuric Kidney Disease: What Next?

Benigni, A., Remuzzi, G. — 2009-06-17

[Original Articles] Triple Antihypertensive Therapy With Amlodipine, Valsartan, and Hydrochlorothiazide: A Randomized Clinical Trial

Calhoun, D. A., Lacourciere, Y., Chiang, Y. T., Glazer, R. D. — 2009-06-17

Many patients with hypertension require ≥3 agents to achieve target blood pressure (BP). The efficacy/safety of the dual combinations of valsartan (Val)/hydrochlorothiazide (HCTZ) and amlodipine (Aml)/Val in hypertension are well established. This randomized, double-blind study evaluated the efficacy/safety of triple therapy with Aml/Val/HCTZ for moderate or severe hypertension (mean sitting systolic BP: ≥145 mm Hg; mean sitting diastolic BP: ≥100 mm Hg). The study included a single-blind, placebo run-in period, followed by double-blind treatment for 8 weeks; patients were randomly assigned to 1 of 4 groups titrated to Aml/Val/HCTZ 10/320/25 mg, Val/HCTZ 320/25 mg, Aml/Val 10/320 mg, or Aml/HCTZ 10/25 mg once daily. Dual-therapy recipients received half of the target doses of both agents for the first 2 weeks, titrating to target doses during week 3. Those on triple therapy received Val/HCTZ 160.0/12.5 mg during week 1, Aml/Val/HCTZ 5.0/160.0/12.5 mg during week 2, and target doses of all 3 of the agents during week 3. Of the 4285 patients enrolled, 2271 were randomly assigned to treatment, and 2060 completed the study. Triple therapy was significantly superior to all of the dual therapies in reducing mean sitting systolic BP and mean sitting diastolic BP from baseline to end point (all P<0.0001). Significantly more patients on triple therapy achieved overall BP control (<140/90 mm Hg; P<0.0001) and systolic and diastolic control (P≤0.0002) compared with each dual therapy. Aml/Val/HCTZ was well tolerated. The benefits of triple therapy over dual therapy were observed regardless of age, sex, race, ethnicity, or baseline mean sitting systolic BP. In conclusion, this study demonstrates the efficacy/safety of treating moderate and severe hypertension with Aml/Val/HCTZ 10/320/25 mg.

[Original Articles] Chronotherapy With the Angiotensin-Converting Enzyme Inhibitor Ramipril in Essential Hypertension: Improved Blood Pressure Control With Bedtime Dosing

Hermida, R. C., Ayala, D. E. — 2009-06-17

Clinical studies have demonstrated a different effect on blood pressure of some angiotensin-converting enzyme inhibitors when administered in the morning versus the evening. Their administration at bedtime resulted in a higher effect on nighttime blood pressure as compared with morning dosing. This study investigated the administration time-dependent effects of ramipril on ambulatory blood pressure. We studied 115 untreated hypertensive patients, 46.7±11.2 years of age, randomly assigned to receive ramipril (5 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured for 48 hours before and after 6 weeks of treatment. The blood pressure reduction during diurnal activity was similar for both treatment times. Bedtime administration of ramipril, however, was significantly more efficient than morning administration in reducing asleep blood pressure. The awake:asleep blood pressure ratio was decreased after ramipril on awakening but significantly increased toward a more dipping pattern after bedtime dosing. The proportion of patients with controlled ambulatory blood pressure increased from 43% to 65% (P=0.019) with bedtime treatment. Nocturnal blood pressure regulation is significantly better achieved at bedtime as compared with morning administration of ramipril, without any loss in efficacy during diurnal active hours. This might be clinically important, because nighttime blood pressure has been shown to be a more relevant marker of cardiovascular risk than diurnal mean values. The change in the dose-response curve, increased proportion of controlled patients, and improved efficacy on nighttime blood pressure with administration of ramipril at bedtime should be taken into account when prescribing this angiotensin-converting enzyme inhibitor for treatment of essential hypertension.

[Original Articles] Blood Pressure Control Among Persons Without and With Chronic Kidney Disease: US Trends and Risk Factors 1999-2006

2009-06-17

Recent guidelines recommending more aggressive blood pressure control in patients with chronic kidney disease have unknown impact. We assessed trends in and predictors of blood pressure control in 8829 adult National Health and Nutrition Examination Survey 1999–2006 participants with hypertension (self-report, measured blood pressure, or use of antihypertensive medications), without (n=7178) and with (n=1651) chronic kidney disease. Uncontrolled blood pressure was defined as follows: general definition, systolic blood pressure ≥140 mm Hg and diastolic blood pressure ≥90 mm Hg, and disease-specific definition, systolic blood pressure ≥130 mm Hg and diastolic blood pressure ≥85 mm Hg (1999–2002) and systolic blood pressure ≥130 mm Hg and diastolic blood pressure ≥80 mm Hg (2003–2006) for those with chronic kidney disease (estimated glomerular filtration rate: <60 mL/min per 1.73 m²) or diabetes mellitus (self-report). Proportions with uncontrolled blood pressure in 1999–2006 were greater in those with chronic kidney disease versus those without chronic kidney disease (51.5% versus 48.7% [general definition: P=0.122] and 68.8% versus 51.7% [disease-specific definition: P<0.001]). In those with chronic kidney disease, there were significant decreases in uncontrolled blood pressure over time (55.9% to 47.8% [general definition: P=0.011]). With adjustment for demographic, socioeconomic, and clinical variables, older age (P<0.001) and lack of antihypertensive treatment (P<0.001) were associated with uncontrolled blood pressure, regardless of chronic kidney disease status; nonwhite race (P=0.002) was associated in those without chronic kidney disease, whereas female sex (P=0.030) was associated in those with chronic kidney disease. Multiple medications (P<0.001) and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (P=0.001) were associated with less uncontrolled blood pressure. Although some improvement has occurred over time, uncontrolled blood pressure remains highly prevalent, especially in subjects with chronic kidney disease and in nonwhites, older persons, and women. Therapy appears suboptimal.

[Original Articles] Blood Pressure Components and Changes in Relation to White Matter Lesions: A 32-Year Prospective Population Study

2009-06-17

This study aimed to examine the long-term effect of high blood pressure (systolic blood pressure, diastolic blood pressure, pulse pressure, and mean arterial pressure) on white matter lesions and to study changes in different blood pressure components in relation to white matter lesions. A representative population of women was examined in 1968 and re-examined in 1974, 1980, 1992, and 2000. The presence and severity of white matter lesions on computed tomography were rated by a visual rating scale in 1992 and 2000 in 539 women. Systolic and diastolic blood pressures were measured at all of the examinations. We found that presence and severity of white matter lesions in 1992/2000 were associated with higher diastolic blood pressure and mean arterial pressure at each examination but not with systolic blood pressure and pulse pressure. Odds ratios (95% CIs) for the presence of white matter lesions per 10-mm Hg increase in diastolic pressure were 1.4 (1.0 to 1.9) in 1968, 1.3 (1.0 to 1.8) in 1974, 1.4 (1.1 to 1.9) in 1980, and 1.3 (1.0 to 1.6) in 1992 after adjustment for confounders. The presence of white matter lesions was also associated with a 24-year increase in diastolic pressure (>10 mm Hg), systolic pressure (>40 mm Hg), pulse pressure (>24 mm Hg), and mean arterial pressure (>6 mm Hg; odds ratios [95% CIs]: 2.6 [1.3 to 5.1] for diastolic pressure; 2.0 [1.2 to 3.4] for systolic pressure; 1.8 [1.1 to 2.7] for pulse pressure; and 2.2 [1.4 to 3.4] for mean arterial pressure). Our findings suggest that lowering high diastolic blood pressure and preventing large increases in systolic and diastolic blood pressures may have a protective effect on white matter lesions.

[Original Articles] Antihypertensive Medication Use During Pregnancy and the Risk of Cardiovascular Malformations

2009-06-17

We used data from the National Birth Defects Prevention Study, a population-based, case-control study, to examine whether previously reported associations between antihypertensive medications and cardiovascular malformations could be confirmed and to explore whether new associations might be identified. Cases (n=5021) were ascertained through birth defects surveillance systems from 1997 through 2003 in 10 US states. Controls (n=4796) were live births without birth defects selected randomly from birth certificates or hospital discharge listings in the same geographic regions. Logistic regression was used to examine the relationship between antihypertensive medication treatment and the occurrence of cardiovascular malformations while controlling for confounding variables. First-trimester treatment with antihypertensive medication was associated with pulmonary valve stenosis (odds ratio [OR]: 2.6; 95% CI: 1.3 to 5.4), Ebstein malformation (crude OR: 11.4; exact 95% CI: 2.8 to 34.1), coarctation of the aorta (OR: 3.0; 95% CI: 1.3 to 6.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Treatment initiated after the first trimester was associated with pulmonary valve stenosis (OR: 2.4; 95% CI: 1.1 to 5.4), perimembranous ventricular septal defects (OR: 2.3; 95% CI: 1.2 to 4.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Untreated hypertension was associated with Ebstein malformation (OR: 2.1; 95% CI: 1.0 to 4.3) and secundum atrial septal defects (OR: 1.3; 95% CI: 1.0 to 1.6). Antihypertensive medication use and/or the underlying hypertension might increase the risk of having an infant with specific left and right obstructive and septal defects. Additional studies with adequate power will be needed to confirm these findings.

[Original Articles] G Protein-Coupled Receptor Kinase 2 Expression and Activity Are Associated With Blood Pressure in Black Americans

2009-06-17

Hypertension occurs with higher prevalence and morbidity in black Americans compared with other groups. Alterations in the signal transduction pathways of 7-transmembrane spanning receptors are found in hypertensive patients. G protein–coupled receptor kinases (GRKs) play an important role in regulating this receptor signaling. The 2 most abundantly expressed GRKs in the cardiovascular system are GRK2 and GRK5, and each has unique substrates. Understanding changes in expression may give us insight into activated receptors in the pathophysiological progression of hypertension. In heart failure and white hypertensives, increased GRK2 expression arises because of neurohormonal stimulation of particular receptors. GRK2 subsequently desensitizes specific receptors, including β-adrenergic receptors. In blood pressure control, β-adrenergic receptor desensitization could lead to increased blood pressure. GRK2 and GRK5 mRNA were evaluated in lymphocytes of black Americans via quantitative real-time PCR. GRK2 mRNA expression directly correlated with systolic blood pressure and norepinephrine levels. GRK2 was elevated >30% among those with systolic blood pressure ≥130 mm Hg. No significant correlation between GRK5 mRNA expression and blood pressure or catecholamines was observed. Diabetic status, age, sex, and body mass index were also compared with GRK2 expression using univariate and multivariate analyses. GRK2 protein expression was elevated 2-fold in subjects with higher blood pressure, and GRK activity was increased >40%. Our data suggest that GRK2, but not GRK5, is correlated with increasing blood pressure in black Americans. Understanding the receptors stimulated by increased neurohormonal activation may give insight into the pathophysiology of hypertension in this at-risk population.

[Original Articles] Hypertension Prevalence, Awareness, Treatment, and Control in Mozambique: Urban/Rural Gap During Epidemiological Transition

Damasceno, A., Azevedo, A., Silva-Matos, C., Prista, A., Diogo, D., Lunet, N. — 2009-06-17

The prediction of cardiovascular risk profile trends in low-income countries and timely action to modulate their transitions are among the greatest global health challenges. In 2005 we evaluated a nationally representative sample of the Mozambican population (n=3323; 25 to 64 years old) following the Stepwise Approach to Chronic Disease Risk Factor Surveillance. Prevalence of hypertension (systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg and/or antihypertensive drug therapy), awareness (having been informed of the hypertensive status by a health professional in the previous year), treatment among the aware (use of antihypertensive medication in the previous fortnight), and control among those treated (blood pressure <140/90 mm Hg) were 33.1% (women: 31.2%; men: 35.7%), 14.8% (women: 18.4%; men: 10.6%), 51.9% (women: 61.1%; men: 33.3%), and 39.9% (women: 42.9%; men: 28.7%), respectively. Urban/rural comparisons are presented as age- and education-adjusted odds ratios (ORs) and 95% CIs. Among women, hypertension (OR: 2.0; 95% CI: 1.2 to 3.0) and awareness (OR: 4.3; 95% CI: 1.9 to 9.5) were more frequent in urban areas. No urban/rural differences were observed in men (hypertension: OR: 1.3, 95% CI: 0.9 to 2.0; awareness: OR: 1.5, 95% CI: 0.5 to 4.7). Treatment prevalence was not significantly different across urban/rural settings (women: OR: 1.4, 95% CI: 0.5 to 4.4; men: OR: 0.3, 95% CI: 0.1 to 1.4). Control was less frequent in urban women (OR: 0.2; 95% CI: 0.0 to 1.0) and more frequent in urban men (OR: 78.1; 95% CI: 2.2 to 2716.6). Our results illustrate the changing paradigms of "diseases of affluence" and the dynamic character of epidemiological transition. The urban/rural differences across sexes support a trend toward smaller differences, emphasizing the need for strategies to improve prevention, correct diagnosis, and access to effective treatment.

[Original Articles] Does Greater Adiposity Increase Blood Pressure and Hypertension Risk?: Mendelian Randomization Using the FTO/MC4R Genotype

2009-06-17

Elevated blood pressure increases the risk of experiencing cardiovascular events like myocardial infarction and stroke. Current observational data suggest that body mass index may have a causal role in the etiology of hypertension, but this may be influenced by confounding and reverse causation. Through the use of instrumental variable methods, we aim to estimate the strength of the unconfounded and unbiased association between body mass index/adiposity and blood pressure. We explore these issues in the Copenhagen General Population Study. We used instrumental variable methods to obtain estimates of the causal association between body mass index and blood pressure. This was performed using both rs9939609 (FTO) and rs17782313 (MC4R) genotypes as instruments for body mass index. Avoiding the epidemiological problems of confounding, bias, and reverse causation, we confirmed observational associations between body mass index and blood pressure. In analyses including those taking antihypertensive drugs, but for whom appropriate adjustment had been made, systolic blood pressure was seen to increase by 3.85 mm Hg (95% CI: 1.88 to 5.83 mm Hg) for each 10% increase in body mass index (P=0.0002), with diastolic blood pressure showing an increase of 1.79 mm Hg (95% CI: 0.68 to 2.90 mm Hg) for each 10% increase in body mass index (P=0.002). Observed associations are large and illustrate the considerable benefits in terms of reductions in blood pressure–related morbidity that could be achieved through a reduction in body mass index.

[Original Articles] Low Cardiorespiratory Fitness Levels and Elevated Blood Pressure: What Is the Contribution of Visceral Adiposity?

2009-06-17

Individuals with poor cardiorespiratory fitness have higher blood pressure than fit individuals. Individuals with low fitness levels also tend to be characterized by higher visceral adiposity compared with physically fit individuals. We tested the hypothesis that the relationship between low fitness and elevated blood pressure could be related, at least in part, to the higher level of visceral adipose tissue often found among unfit individuals. This study included 407 asymptomatic, nondiabetic participants. Visceral adipose tissue was assessed by computed tomography, and fitness was measured by a progressive submaximal physical working capacity test. Participants in the highest visceral adipose tissue tertile showed the highest systolic and diastolic blood pressures, whereas participants in the highest fitness tertile had the lowest blood pressure values (P<0.001). When participants were classified into fitness tertiles and then subdivided on the basis of visceral adipose tissue (high versus low), participants with a high visceral adipose tissue had higher systolic and diastolic blood pressure values (P=0.01), independent of their fitness category. Linear regression analyses showed that age and visceral adipose tissue, but not fitness, predicted systolic blood pressure (r²=0.11 [P<0.001], 0.12 [P<0.001], and 0.01 [P value nonsignificant], for age, visceral adipose tissue, and fitness, respectively) and diastolic blood pressure (r²=0.17 [P<0.001], 0.14 [P<0.001], and 0.01 [P value nonsignificant], for age, visceral adipose tissue, and fitness, respectively). Individuals with high visceral adipose tissue levels have higher blood pressure, independent of their fitness. Visceral adipose tissue may represent an important clinical target in the management of elevated blood pressure.

[Original Articles] Prolactin and Preclinical Atherosclerosis in Menopausal Women With Cardiovascular Risk Factors

2009-06-17

Hyperprolactinemia has been associated with endothelial dysfunction and an adverse cardiovascular risk profile, possibly as a result of the vasoconstrictive properties of prolactin. In this cross-sectional study, we examined the hypothesis that prolactin contributes to the increased cardiovascular risk occurring in early menopause by studying apparently healthy women without hyperprolactinemia. Prolactin serum levels were measured by immunoassay in 76 women aged 54.4±4.9 years in menopause for 4.9±2.8 years, and possible correlations with traditional cardiovascular risk factors and surrogate markers of preclinical atherosclerosis, arterial stiffening, and endothelial and microcirculatory function were examined. Positive correlations between prolactin serum levels and arterial blood pressure, but no other traditional risk factors, were found. Prolactin also correlated with central aortic systolic (r=0.337; P=0.002) and diastolic (r=0.272; P=0.012) blood pressures and pulse wave velocity (r=0.264; P=0.02), a marker of aortic stiffness, but not with endothelial or microcirculatory function or carotid intima-media thickness. By multivariate regression analysis, prolactin levels determined, independent of traditional risk factors, both blood pressures and aortic stiffness. Notably, prolactin correlated with European Society of Cardiology HeartScore (r=0.364; P=0.002), a composite index that predicts 10-year cardiovascular mortality. Prolactin levels >8.0 ng/mL had 100% sensitivity to predict a high peripheral blood pressure. Prolactin may play a role in accelerated arteriosclerosis in early menopause by affecting central/peripheral blood pressure and arterial stiffness. In contrast, no correlation was observed with other risk factors or surrogate markers of atherosclerosis. Prospective studies to assess whether prolactin is an additional hormone increasing cardiovascular risk are warranted.

[Original Articles] Circulating and Placental Growth-Differentiation Factor 15 in Preeclampsia and in Pregnancy Complicated by Diabetes Mellitus

2009-06-17

Growth-differentiation factor 15 (GDF-15), a stress-responsive transforming growth factor-β–related cytokine, is emerging as a new risk marker in patients with cardiovascular disease. We explored GDF-15 in preeclampsia and in diabetic pregnancies, because these conditions are associated with augmented risk for cardiovascular disease, both in mother and in offspring. Plasma from pregnant women (n=267; controls: n=59, preeclampsia: n=85, diabetes mellitus: n=112, and superimposed preeclampsia in diabetes mellitus: n=11), fetal plasma (n=72), and amniotic fluid (n=99) were analyzed by immunoassay for GDF-15. Placental GDF-15 mRNA and protein expression levels were analyzed by quantitative real-time PCR and immunoblots in 78 and 18 pregnancies, respectively. Conditioned media from preeclamptic (n=6) and control (n=6) villous placenta explants were analyzed by immunoassay for GDF-15. Median maternal GDF-15 concentration was elevated in those with diabetes mellitus, as compared with controls (91 549 versus 79 875 ng/L; P=0.02). Median GDF-15 concentration was higher in patients with preeclampsia than in controls in term maternal blood samples (127 061 versus 80 319 ng/L; P<0.001). In the fetal circulation and amniotic fluid, GDF-15 was elevated in preeclampsia and superimposed preeclampsia in diabetes mellitus, as compared with controls. GDF-15 placental mRNA expression was elevated in preeclampsia, as compared with controls (P=0.002). Placenta immunoblots confirmed a single GDF-15 protein band, and a time-dependent increase in GDF-15 protein was detected in the conditioned media. Our study is the first to show that GDF-15 is dysregulated, both in preeclampsia and in diabetic pregnancies. The mechanisms and diagnostic implications of these findings remain to be explored.

[Original Articles] Blood Pressure-Independent Reduction in Proteinuria and Arterial Stiffness After Acute Endothelin-A Receptor Antagonism in Chronic Kidney Disease

2009-06-17

Endothelin 1 is implicated in the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism with BQ-123 on key independent surrogate markers of cardiovascular risk (blood pressure, proteinuria and renal hemodynamics, arterial stiffness, and endothelial function) in patients with nondiabetic chronic kidney disease. In a double-blind, randomized crossover study, 22 subjects with proteinuric chronic kidney disease received, on 2 separate occasions, placebo or BQ-123. Ten of these subjects also received nifedipine (10 mg) as an active control for the antihypertensive effect of BQ-123. Blood pressure, pulse wave velocity, flow-mediated dilation, renal blood flow, and glomerular filtration rate were monitored after drug dosing. BQ-123 reduced blood pressure (mean arterial pressure: –7±1%; P<0.001 versus placebo) and increased renal blood flow (17±4%; P<0.01 versus placebo). Glomerular filtration rate remained unchanged. Proteinuria (–26±4%; P<0.01 versus placebo) and pulse wave velocity (–5±1%; P<0.001 versus placebo) fell after BQ-123, but flow-mediated dilation did not change. Nifedipine matched the blood pressure and renal blood flow changes seen with BQ-123. Nevertheless, BQ-123 reduced proteinuria (–38±3% versus 26±11%; P<0.001) and pulse wave velocity (–9±1% versus –3±1%; P<0.001) to a greater extent than nifedipine. Selective endothelin-A receptor antagonism reduced blood pressure, proteinuria, and arterial stiffness on top of standard treatment in renal patients. Furthermore, these studies suggest that the reduction in proteinuria and arterial stiffness is partly independent of blood pressure. If maintained longer term, selective endothelin-A receptor antagonism may confer cardiovascular and renal benefits in patients with chronic kidney disease.

[Original Articles] Enhanced Distal Nephron Sodium Reabsorption in Chronic Angiotensin II-Infused Mice

Zhao, D., Seth, D. M., Navar, L. G. — 2009-06-17

Chronic angiotensin II (Ang II) infusions enhance urinary excretion of angiotensinogen, suggesting augmentation of distal nephron sodium reabsorption. To assess whether chronic Ang II infusions (15 ng/min for 2 weeks) enhance distal nephron sodium reabsorption, we compared sodium excretion before and after blockade of the 2 main distal nephron sodium transporters by IV amiloride (5 mg/kg of body weight) plus bendroflumethiazide (12 mg/kg of body weight) in male C57/BL6 anesthetized control mice (n=10) and in chronic Ang II–infused mice (n=8). Chronic Ang II infusions increased systolic blood pressure to 141±6 mm Hg compared with 106±4 mm Hg in control mice. After anesthesia, mean arterial pressure averaged 97±4 mm Hg in chronic Ang II–infused mice compared with 94±3 mm Hg in control mice, allowing comparison of renal function at similar arterial pressures. Ang II–infused mice had lower urinary sodium excretion (0.16±0.04 versus 0.30±0.05 µEq/min; P<0.05), higher distal sodium reabsorption (1.74±0.18 versus 1.12±0.18 µEq/min; P<0.05), and higher fractional reabsorption of distal sodium delivery (91.1±1.8% versus 77.9±4.3%; P<0.05) than control mice. Urinary Ang II concentrations, measured during distal blockade, were greater in Ang II–infused mice (1235.0±277.2 versus 468.9±146.9 fmol/mL; P<0.05). In chronic Ang II–infused mice treated with spironolactone (n=5), fractional reabsorption of distal sodium delivery was similarly augmented as in chronic Ang II–infused mice (94.6±1.7%; P<0.01). These data provide in vivo evidence that there is enhanced distal sodium reabsorption dependent on sodium channel and Na⁺-Cl^– cotransporter activity and increased urinary Ang II concentrations in mice infused chronically with Ang II.

[Original Articles] Age-Related Differences in the Sympathetic-Hemodynamic Balance in Men

2009-06-17

As humans age, the tonic level of activity in sympathetic vasoconstrictor nerves increases and may contribute to age-related increases in blood pressure. In previous studies in normotensive young men with varying levels of resting sympathetic nerve activity, we observed a balance among factors contributing to blood pressure regulation, such that higher sympathetic activity was associated with lower cardiac output and lesser vascular responsiveness to -adrenergic agonists, which limited the impact of high sympathetic activity on blood pressure. In the present study, we tested the hypothesis that older normotensive men would exhibit a similar balance among these variables (sympathetic nerve activity, cardiac output, and -adrenergic responsiveness) but that this balance would be shifted toward higher sympathetic nerve activity values. We measured muscle sympathetic nerve activity, cardiac output, arterial pressure, and forearm vasoconstrictor responses in 17 older men and compared these with previous data collected in 14 younger men. Muscle sympathetic activity (burst incidence) was positively related to diastolic blood pressure in the older men (r=0.49; P=0.05); this relationship was not observed in young men. In addition, there was no relationship between cardiac output and muscle sympathetic activity (r=0.29; P>0.05) or between muscle sympathetic activity and vasoconstrictor responses in the older men (eg, norepinephrine: r=–0.21; P>0.05). Although our older subjects were normotensive, the relationship between muscle sympathetic nerve activity and diastolic blood pressure and the lack of "balance" among the other variables suggest that these changes with aging may contribute to the risk of sympathetically mediated hypertension in older humans.

[Original Articles] Eutrophic Remodeling of Small Arteries in Type 1 Diabetes Mellitus Is Enabled by Metabolic Control: A 10-Year Follow-Up Study

2009-06-17

Type 2 diabetes mellitus profoundly changes small artery remodeling in response to hypertension. Abnormal increases of both wall thickness and lumen diameter are associated with an increased mortality. Changes to small artery structure in response to blood pressure (BP) in patients with type 1 diabetes mellitus have never been examined. In 1997, 17 patients with type 1 diabetes mellitus and 9 control subjects underwent in vitro assessment of gluteal-fat small arteries using pressure myography. Patients with BP <140/90 mm Hg (systolic BP: 119±3 mm Hg; n=12) had normal-resistance artery structure. However, patients with BP >140/90 mm Hg (systolic BP: 152±5 mm Hg; n=5) demonstrated vascular hypertrophic remodeling with a significant increase in the medial cross-sectional area and wall thickness. In 2008, 8 of the original 17 diabetic patients returned for a repeat assessment. All 8 of the patients had significantly improved cholesterol (2008: 154±9 mg/dL versus 1997: 191±9 mg/dL; P=0.01) and low-density lipoprotein cholesterol (2008: 79±8 mg/dL versus 1997: 122±9 mg/dL; P=0.003) but higher BPs (systolic BP: 2008: 136±3 mm Hg versus 1997: 119±6 mm Hg; P=0.03). Glycemia was improved (2008: 7.9±0.3% versus 1997: 8.9±0.6%; P=0.17), but not significantly so. In the small arteries studied, there were significant increases in medial wall thickness and wall:lumen ratio, but cross-sectional area was unchanged, indicating eutrophic remodeling. Collectively, these findings suggest that, with poor metabolic control, small arteries from patients with type 1 diabetes mellitus show hypertrophic growth in response to elevated BP, similar to that seen in type 2 diabetes mellitus. However, metabolic improvements enable eutrophic remodeling to occur in response to an increase in BP. This has only been observed previously in patients without diabetes mellitus.

[Original Articles] Atorvastatin Prevents Angiotensin II-Induced Vascular Remodeling and Oxidative Stress

2009-06-17

Angiotensin II (Ang II) modulates vasomotor tone, cell growth, and extracellular matrix deposition. This study analyzed the effect of atorvastatin in the possible alterations induced by Ang II on structure and mechanics of mesenteric resistance arteries and the signaling mechanisms involved. Wistar rats were infused with Ang II (100 ng/kg per day, SC minipumps, 2 weeks) with or without atorvastatin (5 mg/kg per day). Ang II increased blood pressure and plasmatic malondialdehyde levels. Compared with controls, mesenteric resistance arteries from Ang II–treated rats showed the following: (1) decreased lumen diameter; (2) increased wall/lumen; (3) decreased number of adventitial, smooth muscle, and endothelial cells; (4) increased stiffness; (5) increased collagen deposition; and (6) diminished fenestrae area and number in the internal elastic lamina. Atorvastatin did not alter blood pressure but reversed all of the structural and mechanical alterations of mesenteric arteries, including collagen and elastin alterations. In mesenteric resistance arteries, Ang II increased vascular O₂^·– production and diminished endothelial NO synthase and CuZn/superoxide dismutase but did not modify extracellular-superoxide dismutase expression. Atorvastatin improved plasmatic and vascular oxidative stress, normalized endothelial NO synthase and CuZn/superoxide dismutase expression, and increased extracellular-superoxide dismutase expression, showing antioxidant properties. Atorvastatin also diminished extracellular signal–regulated kinase 1/2 activation caused by Ang II in these vessels, indicating an interaction with Ang II–induced intracellular responses. In vascular smooth muscle cells, collagen type I release mediated by Ang II was reduced by different antioxidants and statins. Moreover, atorvastatin downregulated the Ang II–induced NADPH oxidase subunit, Nox1, expression. Our results suggest that statins might exert beneficial effects on hypertension-induced vascular remodeling by improving vascular structure, extracellular matrix alterations, and vascular stiffness. These effects might be mediated by their antioxidant properties.

[Original Articles] Tumor Necrosis Factor-{alpha} Mediates Hemolysis-Induced Vasoconstriction and the Cerebral Vasospasm Evoked by Subarachnoid Hemorrhage

2009-06-17

Hypertension can lead to subarachnoid hemorrhage and eventually to cerebral vasospasm. It has been suggested that the latter could be the result of oxidative stress and an inflammatory response evoked by subarachnoid hemorrhage. Because an unavoidable consequence of hemorrhage is lysis of red blood cells, we first tested the hypothesis on carotid arteries that the proinflammatory cytokine tumor necrosis factor- contributes to vascular oxidative stress evoked by hemolysis. We observed that hemolysis induces a significant increase in tumor necrosis factor- both in blood and in vascular tissues, where it provokes Rac-1/NADPH oxidase–mediated oxidative stress and vasoconstriction. Furthermore, we extended our observations to cerebral vessels, demonstrating that tumor necrosis factor- triggered this mechanism on the basilar artery. Finally, in an in vivo model of subarachnoid hemorrhage obtained by the administration of hemolyzed blood in the cisterna magna, we demonstrated, by high-resolution ultrasound analysis, that tumor necrosis factor- inhibition prevented and resolved acute cerebral vasoconstriction. Moreover, tumor necrosis factor- inhibition rescued the hemolysis-induced brain injury, evaluated with the method of 2,3,5-triphenyltetrazolium chloride and by the histological analysis of pyknotic nuclei. In conclusion, our results demonstrate that tumor necrosis factor- plays a crucial role in the onset of hemolysis-induced vascular injury and can be used as a novel target of the therapeutic strategy against cerebral vasospasm.

[Original Articles] {beta}2-Adrenoceptor Antagonist ICI 118,551 Decreases Pulmonary Vascular Tone in Mice via a Gi/o Protein/Nitric Oxide-Coupled Pathway

2009-06-17

β₂-Adrenoceptors are important modulators of vascular tone, particularly in the pulmonary circulation. Because neurohormonal activation occurs in pulmonary arterial hypertension, we have investigated the effect of different adrenergic vasoactive substances on tone regulation in large and small pulmonary arteries, as well as in systemic vessels of mice. We found that the β₂-adrenoceptor antagonist ICI 118,551 (ICI) evoked a decrease of vascular tone in large pulmonary arteries and reduced the sensitivity of pulmonary arteries toward different contracting agents, eg, norepinephrine, serotonin, or endothelin. ICI proved to act specifically on pulmonary vessels, because it shifted the dose-response curve of norepinephrine to the right in pulmonary arteries, whereas there was no effect in the aorta. Pharmacological experiments proved that the right shift of the norepinephrine dose-response curve by ICI was mediated via a β₂-adrenoceptor/G_i/o protein-dependent pathway enhancing NO production in the endothelium; these results were corroborated in β-adrenoceptor and endothelial NO synthase knockout mice where ICI had no effect. ICI increased vascular lumen diameter in lung sections and reduced pulmonary arterial pressure under normoxia and under hypoxia in the isolated perfused lung model. These effects were found to be physiologically relevant, because ICI specifically decreased pulmonary but not systemic blood pressure in vivo. Thus, the β₂-adrenoceptor antagonist ICI is a pulmonary arterial-specific vasorelaxant and, therefore, a potentially interesting novel therapeutic agent for the treatment of pulmonary arterial hypertension.

[Original Articles] Chymase Plays an Important Role in Left Ventricular Remodeling Induced by Intermittent Hypoxia in Mice

2009-06-17

Intermittent hypoxia caused by sleep apnea is associated with cardiovascular disease. Chymase has been reported to play an important role in the development of cardiovascular disease, but it is unclear whether chymase is involved in the pathogenesis of left ventricular remodeling induced by intermittent hypoxia. The aim of this study was to evaluate the effect of a novel chymase inhibitor (NK3201) on hypoxia-induced left ventricular remodeling in mice. Male C57BL/6J mice (9 weeks old) were exposed to intermittent hypoxia or normoxia and were treated with NK3201 (10 mg/kg per day) or the vehicle for 10 days. Left ventricular systolic pressure showed no significant differences among all of the experimental groups. Exposure to intermittent hypoxia increased left ventricular chymase activity and angiotensin II expression, which were both suppressed by treatment with NK3201. Intermittent hypoxia also increased the mean cardiomyocyte diameter, perivascular fibrosis, expression of inflammatory cytokines, oxidative stress, and NADPH-dependent superoxide production in the left ventricular myocardium. These changes were all suppressed by NK3201 treatment. Therefore, chymase might play an important role in intermittent hypoxia-induced left ventricular remodeling, which is independent of the systemic blood pressure.

[Original Articles] Cooperative Activation of Npr1 Gene Transcription and Expression by Interaction of Ets-1 and p300

Kumar, P., Pandey, K. N. — 2009-06-17

The objective of the present study was to gain insight into the cooperative roles of Ets-1 and p300 in transcriptional regulation and expression of the Npr1 gene (coding for guanylyl cyclase-A/natriuretic peptide receptor-A). Overexpression of Ets-1 and p300 in mouse mesangial cells increased Npr1 promoter activity by 12-fold, natriuretic peptide receptor-A mRNA levels by 5-fold, and ANP-dependent intracellular accumulation of cGMP by 26-fold. Knockdown of Ets-1 and p300 expression by small interfering RNA inhibited Npr1 gene transcription by 90%. Sequential chromatin immunoprecipitation assay demonstrated a direct physical association between p300 and Ets-1 on binding to the Npr1 promoter, suggesting that a physical interaction between Ets-1 and p300 is important to enhance Npr1 gene transcription. Mutant p300 lacking histone acetyltransferase activity did not show a functional effect with Ets-1, suggesting that histone acetyltransferase activity of p300 is required for the cooperative interaction in modulating Npr1 gene transcription. Overexpression of wild-type adenovirus E1A significantly decreased the Npr1 promoter activity by 40%, whereas mutant E1A, which is incapable of binding to p300, did not show any effect. The results indicate that Npr1 gene transcription is critically controlled by histone acetyltransferase p300 and Ets-1. The present findings should yield important insights into the molecular signaling governing Npr1 gene transcription, an important regulator in the control of hypertension and cardiovascular events.