Hypertension On-line First

[Editorial Commentary] Cardiac Benefits of Mineralocorticoid Receptor Inhibition in Renal Failure

Graf, K., Hucko, T., Stawowy, P. — 2008-06-30

[Scientific Contribution] Physiological Interaction Between {alpha}-Adducin and WNK1-NEDD4L Pathways on Sodium-Related Blood Pressure Regulation

2008-06-30

Abstract—The kidney plays an important role in salt and blood pressure (BP) homeostasis. In previous studies, variants in the genes for -adducin (ADD1), WNK1, and NEDD4L, which all regulate renal sodium absorption, have been associated with increased BP. However, findings have been inconsistent. We tested whether this is because of physiological interactions between the effects of variants in these genes. We assessed the single and combined effects of the ADD1 (Gly460Trp), WNK1 (rs880054 A/G), and NEDD4L (rs4149601 G/A) polymorphisms on renal and BP response to an acute Na load (n=344 subjects), BP decrease after 1 month of treatment with 12.5 mg of hydrochlorothiazide (n=193), and ambulatory 24-hour BP (n=690). Individually, the variants showed modest effects on some of the studied phenotypes. We found the ADD1 Trp allele to be permissive for the effects of variants of the other genes. In combination, the same variants (ADD1 Trp/WNK1 GG/Nedd4L GA+AA) showed a consistent effect on renal Na handling (P=0.009) and acute BP response to a saline infusion (P=0.021), BP lowering after thiazide treatment (P=0.008), and nocturnal systolic BP (P=0.044). Physiological interaction between the ADD1 and WNK1-NEDD4L pathways influences the effects of variants in these genes on sodium-related BP regulation. Relatively common alleles in the ADD1, WNK1, and NEDD4L genes when present in combination may have significant effects on renal sodium handling, BP, and antihypertensive response to thiazides.

[Editorial Commentary] Antihypertensive Therapy in Children. Implications for Future Studies

Sinaiko, A. R. — 2008-06-30

[Scientific Contribution] Efficacy and Safety of the Angiotensin Receptor Blocker Valsartan in Children With Hypertension Aged 1 to 5 Years

2008-06-30

Abstract—The efficacy and safety of valsartan were studied in 90 children (mean age: 3.2 years; 60% male; 30% black) with systolic blood pressure (SBP) ≥95th percentile. Nineteen percent received valsartan in addition to previous antihypertensive therapy. Subjects were randomly assigned to low-, medium-, or high-dose valsartan for 2 weeks (phase 1) and then reassigned randomly to placebo or to remain on the same valsartan dose for 2 additional weeks (phase 2). After this, subjects were enrolled into a 52-week, open-label phase during which valsartan was dosed to achieve SBP <95th percentile. Statistically significant reductions in SBP and diastolic blood pressure of 8.5 mm Hg and 5.7 mm Hg, respectively, were observed at the end of phase 1 in all of the valsartan dose groups. SBP and diastolic blood pressure were also significantly lower during phase 2 in valsartan recipients compared with placebo recipients. SBP <95th percentile was achieved in 77.3% of subjects during the open-label phase. Adverse events were minor and occurred at similar frequencies in each of the 3 dose groups in phase 1 and at equal frequencies in the valsartan and placebo arms in phase 2. Serious adverse events and drug-related adverse events occurred infrequently during both the double-blind (2.2% and 5.6%, respectively) and open-label (14.8% and 6.8%, respectively) portions of the study. Valsartan treatment had no demonstrable negative effects on growth and development. In this study, the first trial of an antihypertensive agent conducted in children <6 years of age, valsartan effectively lowered SBP and diastolic blood pressure compared with placebo.

[Scientific Contribution] Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Prevents Oxidative Stress in Uremic Rats

2008-06-30

Abstract—Chronic renal failure causes left ventricular hypertrophy, but the molecular mechanisms involved remain unknown. We, therefore, investigated whether the mineralocorticoid receptor is implicated in the cardiac hypertrophy observed in uremic rats and whether mineralocorticoid receptor blockade could be protective in chronic renal failure. Experimental groups were: control rats, uremic rats (NPX) with 5/6 nephrectomy (5 weeks), and NPX rats fed with spironolactone for 5 weeks. Systolic blood pressure was increased in both NPX rats and NPX rats fed with spironolactone for 5 weeks. Echocardiography revealed concentric left ventricular hypertrophy in uremia, which was attenuated by spironolactone. Enlarged cardiomyocyte size was observed in both left and right ventricles of NPX rats, an effect that was prevented by spironolactone. Mineralocorticoid receptor antagonism attenuated the increase of ventricular brain natriuretic peptide mRNA levels induced by nephrectomy. Left ventricular gene expressions of aldosterone synthase, mineralocorticoid receptor, and hydroxysteroid dehydrogenase type 2 were the same in the 3 groups, whereas gene expression of the glucocorticoid receptor was significantly diminished in chronic renal failure rats. No significant differences in cardiac aldosterone were observed between control rats and NPX rats, although NPX rats fed with spironolactone for 5 weeks showed increased plasma aldosterone levels. However, a significant increase in serum and glucocorticoid-inducible kinase-1 mRNA expression and protein was present in the NPX group; spironolactone treatment significantly reduced serum and glucocorticoid-inducible kinase-1 mRNA and protein in the left ventricle. Uremic rats exhibited a significant increase of superoxide production and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits expression (NOX-2, NOX-4, and p47^phox) in the left ventricle, which was prevented by the mineralocorticoid receptor antagonist. Our findings provide evidence of the beneficial effects of spironolactone in cardiac hypertrophy and cardiac oxidative stress in chronic renal failure.

[Scientific Contribution] Increased Myeloperoxidase in the Placenta and Circulation of Women With Preeclampsia

2008-06-30

Abstract—Myeloperoxidase (MPO) is a hemoprotein normally released from activated monocytes and neutrophils. Traditionally viewed as a microbicidal enzyme, MPO also induces low-density lipoprotein oxidation, activates metalloproteinases, and oxidatively consumes endothelium-derived NO. The elevated plasma MPO level is a risk factor for myocardial events in patients with coronary artery disease. Patients with preeclampsia display evidence of the inflammation and endothelial dysfunction associated with oxidative stress in the circulation, vasculature, and placenta. We hypothesized that MPO levels in the circulation and placental extracts from women with preeclampsia would be greater than levels in women with normal pregnancies. Placental extracts were prepared from placental villous biopsies from preeclamptic (n=27) and control (n=43) placentas. EDTA plasma samples were obtained from gestationally age-matched preeclamptic and control normal pregnancies. MPO concentrations were measured by ELISA. Immunohistochemistry was used to determine MPO localization in the placenta. MPO levels in placental extracts from women with preeclampsia were significantly higher than the levels in normal control subjects (546±62 versus 347±32 ng/mL; P=0.025). MPO was found in the floating villi and basal plate of placentas with a greater staining in the basal plates from preeclampsia placentas compared with normal pregnancies. Plasma MPO levels were 3-fold higher in patients with preeclampsia compared with normal control subjects (36.6±7.6 versus 11.0±3.1 ng/mL; P=0.003). In conclusion, MPO levels are significantly increased in the circulation and placenta of women with preeclampsia. We speculate that MPO may contribute to the oxidative damage reported in the endothelium and placenta of women with preeclampsia.

[Scientific Contribution] Serotonin 5-HT2B Receptor Blockade Prevents Reactive Oxygen Species-Induced Cardiac Hypertrophy in Mice

2008-06-30

Abstract—We established previously that 5-HT_2B receptors are involved in cardiac hypertrophy through the regulation of hypertrophic cytokines in cardiac fibroblasts. Moreover, the generation of reactive oxygen species and tumor necrosis factor- through the activation of reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase has been implicated in cardiac hypertrophy. In this study, we investigated whether 5-HT_2B receptors could be involved in the development of cardiac hypertrophy associated with superoxide anion production. Therefore, we measured the effects of serotonergic 5-HT_2B receptor blockade on left-ventricular superoxide anion generation in 2 established pharmacological models of cardiac hypertrophy, ie, angiotensin II and isoproterenol infusions in mice. Angiotensin II infusion for 14 days increased superoxide anion concentration (+32%), NAD(P)H oxidase maximal activity (+84%), and p47^phox NAD(P)H oxidase subunit expression in the left ventricle together with hypertension (+37 mm Hg) and cardiac hypertrophy (+17% for heart weight:body weight). The 5-HT_2B receptor blockade by a selective antagonist (SB215505) prevented the increase in cardiac superoxide generation and hypertrophy. Similarly, infusion for 5 days of isoproterenol increased left-ventricular NAD(P)H oxidase activity (+48%) and cardiac hypertrophy (+31%) that were prevented by the 5-HT_2B receptor blockade. Finally, in the primary culture of left-ventricular cardiac fibroblasts, angiotensin II and isoproterenol stimulated NAD(P)H oxidase activity. This activation was prevented by SB215505. These findings suggest that the 5-HT_2B receptor may represent a new target to reduce cardiac hypertrophy and oxidative stress. Its blockade affects both angiotensin II and β-adrenergic trophic responses without significant hemodynamic alteration.

[Scientific Contribution] Genomic Association Analysis Suggests Chromosome 12 Locus Influencing Antihypertensive Response to Thiazide Diuretic

2008-06-30

Abstract—We conducted a genome-wide association study to identify novel genes influencing diastolic blood pressure (BP) response to hydrochlorothiazide, a commonly prescribed thiazide diuretic preferred for the treatment of high BP. Affymetrix GeneChip Human Mapping 100K Arrays were used to measure single nucleotide polymorphisms across the 22 autosomes in 194 non-Hispanic black subjects and 195 non-Hispanic white subjects with essential hypertension selected from opposite tertiles of the race- and sex-specific distributions of age-adjusted diastolic BP response to hydrochlorothiazide (25 mg daily, PO, for 4 weeks). The black sample consisted of 97 "good" responders (diastolic BP response [mean±SD]=-18.3±4.2 mm Hg; age=47.1±6.1 years; 51.5% women) and 97 "poor" responders (diastolic BP response=-0.18±4.3; age=47.4±6.5 years; 51.5% women). Haplotype trend regression identified a region of chromosome 12q15 in which haplotypes constructed from 3 successive single nucleotide polymorphisms (rs317689, rs315135, and rs7297610) in proximity to lysozyme (LYZ), YEATS domain containing 4 (YEATS4), and fibroblast growth receptor substrate 2 (FRS2) were significantly associated with diastolic BP response (nominal P=2.39x10^-7; Bonferroni corrected P=0.024; simulated experiment-wise P=0.040). Genotyping of 35 additional single nucleotide polymorphisms selected to "tag" linkage disequilibrium blocks in these genes provided corroboration that variation in LYZ and YEATS4 was associated with diastolic BP response in a statistically independent data set of 291 black subjects and in the sample of 294 white subjects. These results support the use of genome-wide association analyses to identify novel genes influencing antihypertensive drug responses.

[Letters to the Editor] The Interarm Blood Pressure Difference

Clark, C. E., Campbell, J. L. — 2008-06-23

[Letters to the Editor] Response to Prognostic Significance of Between-Arm Blood Pressure Differences: Between-Arm Blood Pressure Difference and Mortality and the Interarm Blood Pressure Difference: Between-Arm Blood Pressure Differences Are Important

Agarwal, R. — 2008-06-23

[Letters to the Editor] Response to Combination Therapy for Treatment or Prevention of Atherosclerosis

Kim-Mitsuyama, S., Nakamura, T., Yamamoto, E., Ogawa, H. — 2008-06-23

[Letters to the Editor] Combination Therapy for Treatment or Prevention of Atherosclerosis

Koh, K. K., Quon, M. J. — 2008-06-23

[Letters to the Editor] Prognostic Significance of Between-Arm Blood Pressure Differences: Between-Arm Blood Pressure Difference and Mortality

Kleefstra, N., Houweling, S. T., Logtenberg, S. J.J., Bilo, H. J.G. — 2008-06-23

[Editorial Commentary] Psychophysiological Stress Reactivity and Hypertension

Steptoe, A. — 2008-06-23

[Scientific Contribution] Nitric Oxide Formation Is Inversely Related to Serum Levels of Antiangiogenic Factors Soluble Fms-Like Tyrosine Kinase-1 and Soluble Endogline in Preeclampsia

2008-06-23

Abstract—Deficient NO formation has been implicated in hypertensive disorders of pregnancy. However, no previous study has compared the circulating nitrite concentrations in healthy pregnant women with those found in hypertensive disorders of pregnancy. Moreover, 2 antiangiogenic factors produced in the placenta (soluble fms-like tyrosine kinase-1 and soluble endogline) may affect NO formation during pregnancy. Here, we hypothesized that lower concentrations of markers of NO formation exist in hypertensive disorders of pregnancy and that inverse relationships exist between these markers and soluble fms-like tyrosine kinase-1 or soluble endogline. In this cross-sectional study, we compared 58 healthy pregnant women with 56 gestational hypertensive subjects and 45 preeclamptic patients. We measured plasma and whole blood nitrite concentrations using an ozone-based chemiluminescence assay and serum soluble fms-like tyrosine kinase-1 and soluble endogline concentrations using enzyme immunoassays. Whole blood nitrite levels were significantly lower in gestational hypertensive subjects and preeclamptic patients (-36% and -58%, respectively; both P<0.05) compared with healthy pregnant women. The plasma nitrite levels were 37% lower in both groups with hypertensive disorders of pregnancy compared with the group with normotensive pregnancies (both P<0.05). As expected, we found higher circulating soluble fms-like tyrosine kinase-1 and soluble endogline concentrations in preeclampsia compared with gestational hypertensive subjects or with healthy pregnancies (both P<0.05). We found negative correlations between antiangiogenic factors and plasma or whole blood nitrite concentrations (Spearman's r from -0.175 to -0.226; all P<0.05). Our results show clinical evidence for impaired NO formation in preeclampsia or gestational hypertension. The negative correlations between markers of NO formation and antiangiogenic factors in preeclamptic patients suggest an inhibitory effect for these factors on NO formation.

[Editorial Commentary] Endothelium and Fibrinolysis in Hypertension. Important Facets of a Prothrombotic State?

Lip, G. Y.H., Blann, A. D. — 2008-06-23

[Scientific Contribution] The V433M Variant of the CYP4F2 Is Associated With Ischemic Stroke in Male Swedes Beyond Its Effect on Blood Pressure

2008-06-23

Abstract—Cytochrome (CYP) 4A11 and CYP4F2 are responsible for renal production of 20-hydroxyeicosatetraenoic acid, a vasoconstrictor and natriuretic substance. The CYP4A11 F434S and CYP4F2 V433M polymorphisms reduce 20-hydroxyeicosatetraenoic acid production in vitro. The aim of the present study was to evaluate the effect of these polymorphisms on blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes. The polymorphisms were genotyped in the cardiovascular cohort of the Malmö Diet and Cancer Study. The incidence of cardiovascular events (coronary events, n=276; ischemic stroke, n=199) was monitored over 10 years of follow-up. The analysis of BP levels was performed twice: either excluding or including subjects under antihypertensive treatment. In the whole population, CYP4A11 S434S homozygotes had higher systolic BP, both crude and adjusted for the number of antihypertensive drugs, and higher prevalence of hypertension with respect to F434 carriers. Male, but not female, CYP4F2 M433 carriers had significantly higher crude and adjusted systolic and diastolic BPs and a trend toward higher hypertension prevalence (P=0.06) with respect to V433V homozygotes. After adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke in male CYP4F2 M433 carriers was significantly higher with respect to V433V homozygotes (hazard ratio: 1.69; 95% CI: 1.10 to 2.60) even when baseline BP levels and hypertension prevalence were included in the Cox proportional hazard model. A common CYP4F2 V433M polymorphism might increase the risk of incident ischemic stroke in male subjects only partially through its elevating effect on BP. Additional studies are needed to confirm these data.

[Scientific Contribution] Association of Parental Hypertension With Concentrations of Select Biomarkers in Nonhypertensive Offspring

2008-06-23

Abstract—Children of parents with hypertension are at increased risk of developing high blood pressure. We hypothesize that circulating concentrations of putative biomarkers (that may play a role in development of high blood pressure) are higher in nonhypertensive offspring of parents with hypertension. We compared concentrations of 4 different biomarkers (urinary albumin:creatinine ratio, circulating C-reactive protein, aldosterone:renin ratio, and plasminogen activator inhibitor-1) in nonhypertensive Framingham offspring study participants with none (n=233), 1 (n=474), or both (n=322) parents with hypertension. Parental hypertension was defined as onset before age 60 years, based on longitudinal observations of the original Framingham cohort. Serum C-reactive protein concentrations were higher in nonhypertensive offspring with 1 (median: 1.7; Q1 to Q3: 0.8 to 3.6 mg/L) or both parents with hypertension (median: 1.8; Q1 to Q3: 0.7 to 3.6 mg/L) compared with offspring without parental hypertension (median: 1.4; Q1 to Q3: 0.7 to 3.2 mg/L). In multivariable analyses, parental hypertension was associated with higher serum C-reactive protein concentration in offspring (15% increase per parent with hypertension; P=0.004). Prospectively, the relation of parental hypertension to longitudinal changes in blood pressure in the nonhypertensive offspring was attenuated on adjustment for C-reactive protein (P=0.04 for attenuation). The levels of the other biomarkers evaluated did not significantly differ in offspring according to parental hypertension status. In conclusion, serum C-reactive protein concentrations are higher in nonhypertensive offspring of parents with hypertension. These data suggest that inflammation may partly mediate the familial influences on hypertension risk.

[Scientific Contribution] A Relationship Between Insulin Sensitivity and Vasodilatation in Women With a History of Preeclamptic Pregnancy

Lampinen, K. H., Ronnback, M., Groop, P.-H., Kaaja, R. J. — 2008-06-23

Abstract—Women with a history of preeclampsia are characterized by vascular dysfunction and an increased risk of cardiovascular disease. In the present study we investigated whether insulin sensitivity is decreased in women with previous preeclampsia and whether it is associated with endothelium-dependent and/or -independent vasodilatation and/or features of metabolic syndrome. Twenty-eight nonobese women with previous severe preeclampsia and 20 women with a previous normotensive pregnancy were studied 5 to 6 years after the index pregnancy. Vasodilatation was measured by venous occlusion plethysmography after intra-arterial infusions of sodium nitroprusside and acetylcholine and insulin sensitivity by the intravenous glucose tolerance test using the minimal model technique. The women were tested for lipid profile, inflammatory status and endothelial activation. Insulin sensitivity did not differ between the groups (P=0.24). Insulin sensitivity correlated positively to endothelium-dependent vasodilatation only in the patient group in both low (β=0.59; P=0.04) and high (β=0.53; P=0.04) concentrations of acetylcholine and in a high concentration of sodium nitroprusside (β=0.0007; P=0.006). In multivariate analysis, the waist/hip ratio (P=0.04) and serum triglycerides (P=0.04) had the most effect on insulin sensitivity in the patient group. Gestational weeks at the onset of preeclamptic hypertension (P=0.02) and proteinuria (P=0.02) associated positively with insulin sensitivity together with first-trimester body mass index (P=0.008) and maximum diastolic blood pressure during preeclampsia (P=0.005). The present study indicates a relation between insulin sensitivity with vascular dilatory function in women with previous preeclampsia. Furthermore, early onset preeclampsia correlates with impaired insulin sensitivity later in life.

[Scientific Contribution] Prognostic Value of Ambulatory Heart Rate Revisited in 6928 Subjects From 6 Populations

2008-06-23

Abstract—The evidence relating mortality and morbidity to heart rate remains inconsistent. We performed 24-hour ambulatory blood pressure monitoring in 6928 subjects (not on β-blockers; mean age: 56.2 years; 46.5% women) enrolled in prospective population studies in Denmark, Belgium, Japan, Sweden, Uruguay, and China. We computed standardized hazard ratios for heart rate, while stratifying for cohort, and adjusting for blood pressure and other cardiovascular risk factors. Over 9.6 years (median), 850, 325, and 493 deaths accrued for total, cardiovascular, and noncardiovascular mortality, respectively. The incidence of fatal combined with nonfatal end points was 805, 363, 439, and 324 for cardiovascular, stroke, cardiac, and coronary events, respectively. Twenty-four-hour heart rate predicted total (hazard ratio: 1.15) and noncardiovascular (hazard ratio: 1.18) mortality but not cardiovascular mortality (hazard ratio: 1.11) or any of the fatal combined with nonfatal events (hazard ratio: ≤1.02). Daytime heart rate did not predict mortality (hazard ratio: ≤1.11) or any fatal combined with nonfatal event (hazard ratio: ≤0.96). Nighttime heart rate predicted all of the mortality outcomes (hazard ratio: ≥1.15) but none of the fatal combined with nonfatal events (hazard ratio: ≤1.11). The night:day heart rate ratio predicted total (hazard ratio: 1.14) and noncardiovascular mortality (hazard ratio: 1.12) and all of the fatal combined with nonfatal events (hazard ratio: ≥1.15) with the exception of stroke (hazard ratio: 1.06). Sensitivity analyses, in which we stratified by risk factors or from which we excluded 1 cohort at a time or the events occurring within 2 years of enrollment, showed consistent results. In the general population, heart rate predicts total and noncardiovascular mortality. With the exception of the night:day heart rate ratio, heart rate did not add to the risk stratification for fatal combined with nonfatal cardiovascular events. Thus, heart rate adds little to the prediction of cardiovascular risk.

[Scientific Contribution] Sympathoadrenal Stress Reactivity Is a Predictor of Future Blood Pressure. An 18-Year Follow-Up Study

Flaa, A., Eide, I. K., Kjeldsen, S. E., Rostrup, M. — 2008-06-23

Abstract—In the present study we hypothesized that arterial catecholamine concentrations during rest and 2 laboratory stress tests were independent predictors of blood pressure at an 18-year follow-up. At entry, blood pressure, heart rate, and arterial plasma epinephrine and norepinephrine concentrations were measured in 99 healthy men (age: 19.3±0.4 years, mean±SD) at rest, during a mental arithmetic test, and during a cold pressor test. After 18.0±0.9 years of follow-up, resting blood pressure was measured. The norepinephrine and epinephrine concentrations during the mental arithmetic explained 12.7% of the variation of future systolic blood pressure after adjusting for initial resting blood pressure, family history, body mass index, and systolic blood pressure during the stress test in a multiple regression analysis (adjusted R²=0.651; P<0.001). To conclude, the present study shows that sympathetic nervous activity during mental arithmetic predicts future blood pressure, indicating a possible causal factor in the development of essential hypertension independent of the initial blood pressure.

[Scientific Contribution] Tissue-Type Plasminogen Activator Release in Healthy Subjects and Hypertensive Patients. Relationship With {beta}-Adrenergic Receptors and the Nitric Oxide Pathway

2008-06-23

Abstract—The relationship between adrenergic stimuli and NO in modulating tissue-type plasminogen activator (t-PA) release from endothelial cells was investigated in normotensive subjects and essential hypertensive patients. Sympathetic activation, a well-known stimulus for endogenous fibrinolysis, is also involved in the determination of cardiovascular risk in essential hypertension. However, the existence of cross-talk between adrenergic stimuli and NO availability in modulating t-PA release is not well established yet. We assessed the release of t-PA in the forearm microcirculation of 58 normotensive subjects (mean age: 47±9 years) and 44 essential hypertensive patients (mean age: 48±11 years) under specific intra-arterial adrenergic stimuli. Intrabrachial infusion of epinephrine (0.1 to 0.3 µg/100 mL per minute) induced greater t-PA release in normotensive subjects as compared with essential hypertensive patients (P<0.05). However, inhibition of NO synthase with N^G-monomethyl-L-arginine (100 µg/100 mL per minute) infusion blunted epinephrine-induced t-PA release in normotensive subjects (P<0.05) but not in essential hypertensive patients. In normotensive subjects, t-PA release by epinephrine was not affected by phentolamine (8 µg/100 mL per minute) coinfusion and was abolished in the presence of propanolol (10 µg/100 mL per minute). Intrabrachial isoproterenol (0.03 µg/100 mL per minute) induced a significant increase in t-PA release (P<0.01), an effect blunted by N^G-monomethyl-L-arginine (P<0.05). In essential hypertensive patients, the response to isoproterenol was impaired as compared with normotensive subjects and was unaffected by N^G-monomethyl-L-arginine coinfusion. In conclusion, the results of the present study demonstrate that adrenergic-induced t-PA release is mediated by β-adrenoreceptors via a mechanism involving the NO pathway. Our results show an impaired adrenergic-stimulated t-PA release among essential hypertensive patients, probably mediated via a reduced NO availability. This impaired fibrinolytic activity might contribute to the increased cardiovascular risk associated with hypertension.

[Scientific Contribution] Angiotensin II-Triggered p44/42 Mitogen-Activated Protein Kinase Mediates Sympathetic Excitation in Heart Failure Rats

Wei, S.-G., Yu, Y., Zhang, Z.-H., Weiss, R. M., Felder, R. B. — 2008-06-23

Abstract—Angiotensin II (Ang II), acting via angiotensin type 1 receptors in the brain, activates the sympathetic nervous system in heart failure (HF). We reported recently that Ang II stimulates mitogen-activated protein kinase (MAPK) to upregulate brain angiotensin type 1 receptors in HF rats. In this study we tested the hypothesis that Ang II–activated MAPK signaling pathways contribute to sympathetic excitation in HF. Intracerebroventricular administration of PD98059 and UO126, 2 selective p44/42 MAPK inhibitors, induced significant decreases in mean arterial pressure, heart rate, and renal sympathetic nerve activity in HF rats, but had no effect on these variables in sham-operated rats. Pretreatment with losartan attenuated the effects of PD98059. Intracerebroventricular administration of the p38 MAPK inhibitor SB203580 and the c-Jun N-terminal kinase inhibitor SP600125 had no effect on mean arterial pressure, heart rate, or renal sympathetic nerve activity in HF. The phosphatidylinositol 3-kinase inhibitor LY294002 induced a small decrease in mean arterial pressure and heart rate but no change in renal sympathetic nerve activity. Immunofluorescent staining demonstrated increased p44/42 MAPK activity in neurons of the paraventricular nucleus of the hypothalamus of HF rats, colocalized with Fra-like activity (indicating chronic neuronal excitation). Intracerebroventricular PD98059 and UO126 reduced Fra-like activity in the paraventricular nucleus of the hypothalamus neurons in HF rats. In confirmatory acute studies, intracerebroventricular Ang II increased mean arterial pressure, heart rate, and renal sympathetic nerve activity in baroreceptor-denervated rats and Fra-like immunoreactivity in the paraventricular nucleus of the hypothalamus of neurally intact rats. Central administration of PD98059 markedly reduced these responses. These data demonstrate that intracellular p44/42 MAPK activity contributes to Ang II–induced neuronal excitation in the paraventricular nucleus of the hypothalamus and augmented sympathetic nerve activity in rats with HF.

[Brief Review] Adaptation and Maladaptation of the Heart in Obesity

Harmancey, R., Wilson, C. R., Taegtmeyer, H. — 2008-06-23

[Letters to the Editor] Response to Thyrotropin-Releasing Hormone Precursor Gene Knocking Down Impedes Melanocortin-Induced Hypertension in Rats

2008-06-16

[Letters to the Editor] Thyrotropin-Releasing Hormone Precursor Gene Knocking Down Impedes Melanocortin-Induced Hypertension in Rats

2008-06-16

[Scientific Contribution] Aortic Stiffness in Untreated Adult Patients With Human Immunodeficiency Virus Infection

2008-06-16

Abstract—HIV infection is associated with chronic immune activation, subclinical inflammation, and an atherogenic metabolic profile. It remains controversial whether HIV infection is a risk factor for accelerated arteriosclerosis independent from the effects of antiretroviral drugs. We investigated whether aortic stiffness, an early marker of arteriosclerosis, is increased in HIV patients who were not under antiretroviral treatment. In 39 untreated HIV-infected patients and 78 individually matched age-, sex-, and blood pressure–matched HIV-uninfected control subjects, we determined aortic pulse wave velocity (PWV), a direct noninvasive measure of aortic stiffness, by tonometric method. Subjects with overt cardiovascular disease or major cardiovascular risk factors were excluded from the study. Prevalence of the metabolic syndrome was higher in HIV patients (18% versus 5%; P=0.025). HIV patients had a higher aortic PWV (7.5±1.4 versus 6.7±1.1 m · s^-1; P=0.001) than control subjects. Age, mean arterial pressure as a measure of distending pressure, and HIV infection (all P<0.05) independently predicted aortic PWV when a consistent number of cardiovascular risk factors was simultaneously controlled for. Among HIV-infected subjects, serum -glutamyl transpeptidase concentration (β=0.46; P=0.003) and mean arterial pressure (β=0.32; P=0.03) were independent determinants of aortic PWV. In conclusion, aortic stiffness is increased in HIV-infected individuals who have never received antiretroviral therapy. PWV increases with increasing serum -glutamyl transpeptidase concentration. Our data support the hypothesis that HIV infection is a risk factor for arteriosclerosis.

[Editorial Commentary] Aldosterone, Hypertension, and Cardiovascular Disease. An Endless Story

Ruilope, L. M. — 2008-06-16

[Scientific Contribution] History of Hypertension and Eplerenone in Patients With Acute Myocardial Infarction Complicated by Heart Failure

2008-06-16

Abstract—In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (n=6632), eplerenone-associated reduction in all-cause mortality was significantly greater in those with a history of hypertension (Hx-HTN). There were 4007 patients with Hx-HTN (eplerenone: n=1983) and 2625 patients without Hx-HTN (eplerenone: n=1336). Propensity scores for eplerenone use, separately calculated for patients with and without Hx-HTN, were used to assemble matched cohorts of 1838 and 1176 pairs of patients. In patients with Hx-HTN, all-cause mortality occurred in 18% of patients treated with placebo (rate, 1430/10 000 person-years) and 14% of patients treated with eplerenone (rate, 1058/10 000 person-years) during 2350 and 2457 years of follow-up, respectively (hazard ratio [HR]: 0.71; 95% CI: 0.59 to 0.85; P<0.0001). Composite end point of cardiovascular hospitalization or cardiovascular mortality occurred in 33% of placebo-treated patients (3029/10 000 person-years) and 28% of eplerenone-treated patients (2438/10 000 person-years) with Hx-HTN (HR: 0.82; 95% CI: 0.72 to 0.94; P=0.003). In patients without Hx-HTN, eplerenone reduced heart failure hospitalization (HR: 73; 95% CI: 0.55 to 0.97; P=0.028) but had no effect on mortality (HR: 0.91; 95% CI: 0.72 to 1.15; P=0.435) or on the composite end point (HR: 0.91; 95% CI: 0.76 to 1.10; P=0.331). Eplerenone should, therefore, be prescribed to all of the post–acute myocardial infarction patients with reduced left ventricular ejection fraction and heart failure regardless of Hx-HTN.

[Editorial Commentary] The Flame That Lights the Fire. Oxidative Stress, Inflammation, and Renal Damage in Angiotensin II-Induced Hypertension

Schiffrin, E. L. — 2008-06-09

[Letters to the Editor] Response to Cardiotrophin-1 in Adolescents: Impact of Obesity and Blood Pressure

2008-06-09

[Letters to the Editor] Cardiotrophin-1 in Adolescents: Impact of Obesity and Blood Pressure

Jung, C., Fritzenwanger, M., Figulla, H. R. — 2008-06-09

[Scientific Contribution] Role of Inflammation in the Development of Renal Damage and Dysfunction in Angiotensin II-Induced Hypertension

2008-06-09

Abstract—Angiotensin II (Ang II)–induced hypertension is associated with an inflammatory response that may contribute to the development of target organ damage. We tested the hypothesis that, in Ang II–induced hypertension, CC chemokine receptor 2 (CCR2) activation plays an important role in the development of renal fibrosis, damage, and dysfunction by causing oxidative stress, macrophage infiltration, and cell proliferation. To test this hypothesis, we used CCR2 knockout mice (CCR2^-/-). The natural ligand of CCR2 is monocyte chemoattractant protein-1, a chemokine important for macrophage recruitment and activation. CCR2^-/- and age-matched wild-type (CCR2^+/+) C57BL/6J mice were infused continuously with either Ang II (5.2 ng/10 g per minute) or vehicle via osmotic minipumps for 2 or 4 weeks. Ang II infusion caused similar increases in systolic blood pressure and left ventricular hypertrophy in both strains of mice. However, in CCR2^-/- mice with Ang II–induced hypertension, oxidative stress, macrophage infiltration, albuminuria, and renal damage were significantly decreased, and glomerular filtration rate was significantly higher than in CCR2^+/+ mice. We concluded that, in Ang II–induced hypertension, CCR2 activation plays an important role in the development of hypertensive nephropathy via increased oxidative stress and inflammation.

[Editorial Commentary] Metalloproteinases Damage the Insulin Receptor to Cause Insulin Resistance in Spontaneously Hypertensive Rats

Bohlen, H. G. — 2008-06-09

[Brief Review] Mechanisms of Arterial Remodeling in Hypertension. Coupled Roles of Wall Shear and Intramural Stress

Humphrey, J. D. — 2008-06-09

[Letters to the Editor] Segmental Renal Sodium Handling in Relation to the Human SAH Gene

2008-06-02

[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.