Vol 65, No 1 | Hypertension

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We sought to investigate the role of aldosterone as a mediator of disease and its relationship with the counter-regulatory natriuretic peptide (NP) system. We measured plasma aldosterone (n=1674; aged≥45 years old) in a random sample of the general population from Olmsted County, MN. In a multivariate logistic regression model, aldosterone analyzed as a continuous variable was associated with hypertension (odds ratio [OR]=1.75; 95% confidence interval [CI]=1.57–1.96; P<0.0001), obesity (OR=1.34; 95% CI=1.21–1.48; P<0.0001), chronic kidney disease (OR=1.39; 95% CI=1.22–1.60; P<0.0001), central obesity (OR=1.47; 95% CI=1.32–1.63; P<0.0001), metabolic syndrome (OR=1.41; 95% CI=1.26–1.58; P<0.0001), high triglycerides (OR=1.23; 95% CI=1.11–1.36; P<0.0001), concentric left ventricular hypertrophy (OR=1.22; 95% CI=1.09–1.38; P=0.0007), and atrial fibrillation (OR=1.24; 95% CI=1.01–1.53; P=0.04), after adjusting for age and sex. The associations with hypertension, central obesity, metabolic syndrome, triglycerides, and concentric left ventricular hypertrophy remained significant after further adjustment for body mass index, NPs, and renal function. Furthermore, aldosterone in the highest tertile correlated with lower NP levels and increased mortality. Importantly, most of these associations remained significant even after excluding subjects with aldosterone levels above the normal range. In conclusion, we report that aldosterone is associated with hypertension, chronic kidney disease, obesity, metabolic syndrome, concentric left ventricular hypertrophy, and lower NPs in the general community. Our data suggest that aldosterone, even within the normal range, may be a biomarker of cardiorenal and metabolic disease. Further studies are warranted to evaluate a therapeutic and preventive strategy to delay the onset and progression of disease, using mineralocorticoid antagonists or chronic NP administration in high-risk subjects identified by plasma aldosterone.

Trends in Blood Pressure Among Adults With Hypertension

United States, 2003 to 2012

Hypertension. 2015 | Volume 65, Issue 1: 54–61,

Published Online:November 16, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04012

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The aim of this study is to describe trends in the awareness, treatment, and control of hypertension; mean blood pressure; and the classification of blood pressure among US adults 2003 to 2012. Using data from the National Health and Nutrition Examination Survey 2003 to 2012, a total of 9255 adult participants aged ≥18 years were identified as having hypertension, defined as measured blood pressure ≥140/90 mm Hg or taking prescription medication for hypertension. Awareness and treatment among hypertensive adults were ascertained via an interviewer administered questionnaire. Controlled hypertension among hypertensive adults was defined as systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg. Blood pressure was categorized as optimal blood pressure, prehypertension, and stage I and stage II hypertension. Between 2003 and 2012, the percentage of adults with controlled hypertension increased (P-trend <0.01). Hypertensive adults with optimal blood pressure and with prehypertension increased from 13% to 19% and 27% to 33%, respectively (P-trend <0.01 for both groups). Among hypertensive adults who were taking antihypertensive medication, uncontrolled hypertension decreased from 38% to 30% (P-trend <0.01). Similarly, a decrease in mean systolic blood pressure was observed (P-trend <0.01); however, mean diastolic blood pressure remained unchanged. The trend in the control of blood pressure has improved among hypertensive adults resulting in a higher percentage with blood pressure at the optimal or prehypertension level and a lower percentage in stage I and stage II hypertension. Overall, mean systolic blood pressure decreased as did the prevalence of uncontrolled hypertension among the treated hypertensive population.

Blood Pressure in Relation to Environmental Lead Exposure in the National Health and Nutrition Examination Survey 2003 to 2010

Hypertension. 2015 | Volume 65, Issue 1: 62–69,

Published Online:October 6, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04023

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In view of the declining environmental lead exposure in the United States, we analyzed the National Health and Nutrition Examination Survey (2003–2010) for association of blood pressure and hypertension with blood lead. The 12 725 participants included 21.1% blacks, 20.5% Hispanics, 58.4% whites, and 48.7% women. Blacks compared with non-Blacks had higher systolic and diastolic pressures (126.5 versus 123.9 and 71.9 versus 69.6 mm Hg) and higher hypertension prevalence (44.7 versus 36.8%). Blood lead was lower in whites than in non-whites (1.46 versus 1.57 μg/dL) and in women than in men (1.25 versus 1.80 μg/dL). In multivariable analyses of all participants, blood lead doubling was associated with higher (P≤0.0007) systolic and diastolic pressure (+0.76 mm Hg; 95% confidence interval, 0.38–1.13 and +0.43 mm Hg; 0.18–0.68), but not with the odds of hypertension (0.95; 0.90–1.01; P=0.11). Associations with blood lead were nonsignificant (P≥0.09) for systolic pressure in women and for diastolic pressure in non-whites. Among men, systolic pressure increased with blood lead (P≤0.060) with effect sizes associated with blood lead doubling ranging from +0.65 mm Hg in whites to +1.61 mm Hg in blacks. For systolic pressure, interactions of ethnicity and sex with blood lead were all significant (P≤0.019). In conclusion, small and inconsistent effect sizes in the associations of blood pressure with blood lead likely exclude current environmental lead exposure as a major hypertension cause in the United States.

Periodic Limb Movements During Sleep and Prevalent Hypertension in the Multi-Ethnic Study of Atherosclerosis

Hypertension. 2015 | Volume 65, Issue 1: 70–77,

Published Online:October 6, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04193

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Periodic limb movements during sleep (PLMS) are associated with immediate increases in blood pressure. Both PLMS and hypertension have different distributions across racial/ethnic groups. We sought to determine whether PLMS is associated with hypertension among various racial/ethnic groups. A total of 1740 men and women underwent measurement of blood pressure and polysomnography with quantification of PLMS. Hypertension was defined as systolic blood pressure (SBP) ≥140, diastolic BP ≥90, or taking antihypertensive medication. For those taking antihypertensives, an estimated pretreatment SBP value was derived based on observed SBP and medication type/dose. Measures of PLMS, PLMS index, and PLMS arousal index were the main explanatory variables. Hypertension and SBP were modeled with logistic and multivariable regression adjusted for age, sex, body mass index, cardiovascular risk factors, lifestyle/habitual factors, apnea-hypopnea index, and race/ethnicity. In the overall cohort, prevalent hypertension was modestly associated with PLMS index (10 U; odds ratio, 1.05; 95% confidence interval, 1.00–1.10) and PLMS arousal index (1 U; 1.05; 1.01–1.09) after adjusting for confounders. Association in the overall cohort was influenced by large effect sizes in blacks, in whom the odds of prevalent hypertension increased by 21% (1%–45%) for 10 U PLMS index increase and 20% (2%–42%) for 1-U PLMS arousal index increase. In blacks, every 1-U PLMS arousal index increase was associated with SBP 1.01 mm Hg higher (1.01; 0.04–1.98). Associations between PLMS and blood pressure outcomes were also suggested among Chinese-Americans but not in whites or Hispanics. In a multiethnic cohort of community-dwelling men and women, prevalent hypertension and SBP are associated with PLMS frequency in blacks.

High-Sensitivity Troponin T and Cardiovascular Events in Systolic Blood Pressure Categories

Atherosclerosis Risk in Communities Study

Hypertension. 2015 | Volume 65, Issue 1: 78–84,

Published Online:October 27, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04206

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Based on observational studies, there is a linear increase in cardiovascular risk with higher systolic blood pressure (SBP), yet clinical trials have not shown benefit across all SBP categories. We assessed whether troponin T measured using high-sensitivity assay was associated with cardiovascular disease within SBP categories in 11 191 Atherosclerosis Risk in Communities study participants. Rested sitting SBP by 10-mm Hg increments and troponin categories were identified. Incident heart failure hospitalization, coronary heart disease, and stroke were ascertained for a median of 12 years after excluding individuals with corresponding disease. Approximately 53% of each type of cardiovascular event occurred in individuals with SBP<140 mm Hg and troponin T ≥3 ng/L. Higher troponin T was associated with increasing cardiovascular events across most SBP categories. The association was strongest for heart failure and least strong for stroke. There was no similar association of SBP with cardiovascular events across troponin T categories. Individuals with troponin T ≥3 ng/L and SBP <140 mm Hg had higher cardiovascular risk compared with those with troponin T <3 ng/L and SBP 140 to 159 mm Hg. Higher troponin T levels within narrow SBP categories portend increased cardiovascular risk, particularly for heart failure. Individuals with lower SBP but measurable troponin T had greater cardiovascular risk compared with those with suboptimal SBP but undetectable troponin T. Future trials of systolic hypertension may benefit by using high-sensitivity troponin T to target high-risk patients.

Resistive and Pulsatile Arterial Load as Predictors of Left Ventricular Mass and Geometry

The Multi-Ethnic Study of Atherosclerosis

Hypertension. 2015 | Volume 65, Issue 1: 85–92,

Published Online:October 6, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04333

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Arterial load is composed of resistive and various pulsatile components, but their relative contributions to left ventricular (LV) remodeling in the general population are unknown. We studied 4145 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, who underwent cardiac MRI and radial arterial tonometry. We computed systemic vascular resistance (SVR=mean arterial pressure/cardiac output) and indices of pulsatile load including total arterial compliance (TAC, approximated as stroke volume/central pulse pressure), forward wave amplitude (P_f), and reflected wave amplitude (P_b). TAC and SVR were adjusted for body surface area to allow for appropriate sex comparisons. We performed allometric adjustment of LV mass for body size and sex and computed standardized regression coefficients (β) for each measure of arterial load. In multivariable regression models that adjusted for multiple confounders, SVR (β=0.08; P<0.001), TAC (β=0.44; P<0.001), P_b (β=0.73; P<0.001), and P_f (β=−0.23; P=0.001) were significant independent predictors of LV mass. Conversely, TAC (β=−0.43; P<0.001), SVR (β=0.22; P<0.001), and P_f (β=−0.18; P=0.004) were independently associated with the LV wall/LV cavity volume ratio. Women demonstrated greater pulsatile load than men, as evidenced by a lower indexed TAC (0.89 versus 1.04 mL/mm Hg per square meter; P<0.0001), whereas men demonstrated a higher indexed SVR (34.0 versus 32.8 Wood Units×m²; P<0.0001). In conclusion, various components of arterial load differentially associate with LV hypertrophy and concentric remodeling. Women demonstrated greater pulsatile load than men. For both LV mass and the LV wall/LV cavity volume ratio, the loading sequence (ie, early load versus late load) is an important determinant of LV response to arterial load.

Blood Pressure and Risk of All-Cause Mortality in Advanced Chronic Kidney Disease and Hemodialysis

The Chronic Renal Insufficiency Cohort Study

Hypertension. 2015 | Volume 65, Issue 1: 93–100,

Published Online:October 6, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04334

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Studies of hemodialysis patients have shown a U-shaped association between systolic blood pressure (SBP) and mortality. These studies have largely relied on dialysis-unit SBP measures and have not evaluated whether this U-shape also exists in advanced chronic kidney disease, before starting hemodialysis. We determined the association between SBP and mortality at advanced chronic kidney disease and again after initiation of hemodialysis. This was a prospective study of Chronic Renal Insufficiency Cohort participants with advanced chronic kidney disease followed through initiation of hemodialysis. We studied the association between SBP and mortality when participants (1) had an estimated glomerular filtration rate <30 mL/min/1.73 m² (n=1705), (2) initiated hemodialysis and had dialysis-unit SBP measures (n=403), and (3) initiated hemodialysis and had out-of-dialysis-unit SBP measured at a Chronic Renal Insufficiency Cohort study visit (n=326). Cox models were adjusted for demographics, cardiovascular risk factors, and dialysis parameters. A quadratic term for SBP was included to test for a U-shaped association. At advanced chronic kidney disease, there was no association between SBP and mortality (hazard ratio, 1.02 [95% confidence interval, 0.98–1.07] per every 10 mm Hg increase). Among participants who started hemodialysis, a U-shaped association between dialysis-unit SBP and mortality was observed. In contrast, there was a linear association between out-of-dialysis-unit SBP and mortality (hazard ratio, 1.26 [95% confidence interval, 1.14–1.40] per every 10 mm Hg increase). In conclusion, more efforts should be made to obtain out-of-dialysis-unit SBP, which may merit more consideration as a target for clinical management and in interventional trials.

Randomized Withdrawal Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension Responsive to Droxidopa

Italo Biaggioni,
Roy Freeman,
Christopher J. Mathias,
Phillip Low,
L. Arthur Hewitt,
Horacio Kaufmann and
on behalf of Droxidopa 302 Investigators

Hypertension. 2015 | Volume 65, Issue 1: 101–107,

Published Online:October 27, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04035

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Abstract—
We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100–600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study (the primary outcome; N=101) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa (P=0.509). Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient’s self-reported ability to perform activities requiring standing a short time (P=0.033) and standing a long time (P=0.028). Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa (P=0.013). There was no significant difference between groups for standing systolic blood pressure (P=0.680). Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00633880.

Systolic and Diastolic Blood Pressure Changes in Relation With Myocardial Infarction and Stroke in Patients With Coronary Artery Disease

Hypertension. 2015 | Volume 65, Issue 1: 108–114,

Published Online:October 20, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04310

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Excessively high and low achieved blood pressure (BP) may be associated with a bad outcome in patients with coronary artery disease, the J curve phenomenon. The effect of BP changes from baseline in relation with the subsequent risk of stroke and myocardial infarction (MI) is unknown. Of the 25 620 patients randomized in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study, we selected 19 102 patients with coronary artery disease at baseline. BP at entry was 141/82 mm Hg, and its average decrease during follow-up was 7/6 mm Hg. BP entered the analysis as time-varying variable modeled with restricted cubic splines. After adjustment for several potential determinants of reverse causality, a change in BP from baseline by –34/–21 mm Hg (10th percentile) was associated with a lesser risk of stroke without any significant increase in the risk of MI. A rise in systolic/diastolic BP from baseline by 20/10 mm Hg (90th percentile) was associated with an increased risk of stroke, whereas the risk of MI increased with systolic BP and not with diastolic BP. In conclusion, in patients with coronary artery disease and initially free from congestive heart failure, a BP reduction from baseline over the examined BP range had little effect on the risk of MI and predicted a lower risk of stroke. An increase in systolic BP from baseline increased the risk of stroke and MI. The relationships of BP with risk were much steeper for stroke than for MI. A treatment-induced BP reduction over the explored range seems to be safe in patients with coronary artery disease.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153101.

Predicting the Effects of Blood Pressure–Lowering Treatment on Major Cardiovascular Events for Individual Patients With Type 2 Diabetes Mellitus

Results From Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation

Hypertension. 2015 | Volume 65, Issue 1: 115–121,

Published Online:October 13, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04421

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Blood pressure–lowering treatment reduces cardiovascular risk in patients with diabetes mellitus, but the effect varies between individuals. We sought to identify which patients benefit most from such treatment in a large clinical trial in type 2 diabetes mellitus. In Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) participants (n=11 140), we estimated the individual patient 5-year absolute risk of major adverse cardiovascular events with and without treatment by perindopril–indapamide (4/1.25 mg). The difference between treated and untreated risk is the estimated individual patient’s absolute risk reduction (ARR). Predictions were based on a Cox proportional hazards model inclusive of demographic and clinical characteristics together with the observed relative treatment effect. The group-level effect of selectively treating patients with an estimated ARR above a range of decision thresholds was compared with treating everyone or those with a blood pressure >140/90 mm Hg using net benefit analysis. In ADVANCE, there was wide variation in treatment effects across individual patients. According to the algorithm, 43% of patients had a large predicted 5-year ARR of ≥1% (number-needed-to-treat [NNT₅] ≤100) and 40% had an intermediate predicted ARR of 0.5% to 1% (NNT₅=100–`200). The proportion of patients with a small ARR of ≤0.5% (NNT₅≥200) was 17%. Provided that one is prepared to treat at most 200 patients for 5 years to prevent 1 adverse outcome, prediction-based treatment yielded the highest net benefit. In conclusion, a multivariable treatment algorithm can identify those individuals who benefit most from blood pressure–lowering therapy in terms of ARR of major adverse cardiovascular events and may be used to guide treatment decisions in individual patients with diabetes.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00145925.

Ivabradine Improves Left Ventricular Function During Chronic Hypertension in Conscious Pigs

Hypertension. 2015 | Volume 65, Issue 1: 122–129,

Published Online:October 27, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04323

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During chronic hypertension, increases in heart rate (HR) or adrenergic stimulation are associated with maladaptive left ventricular responses as isovolumic contraction and relaxation durations failed to reduce, impeding filling. We, therefore, investigated the effects of acute selective HR reduction with ivabradine on left ventricular dysfunction during chronic hypertension. Accordingly, chronically instrumented pigs received angiotensin II infusion during 4 weeks to induce chronic hypertension. Left ventricular function was investigated while angiotensin II infusion was stopped. A single intravenous dose of ivabradine was administered at days 0 and 28. Dobutamine infusion was also performed. HR was increased at day 28 versus day 0. Paradoxically, both isovolumic contraction and relaxation times failed to reduce and remained unchanged (57±3 versus 58±3 ms and 74±3 versus 70±3 at day 28 versus day 0, respectively). At day 28, ivabradine significantly reduced HR by 27%. Concomitantly, abnormal ventricular responses were corrected because both isovolumic contraction and relaxation times were significantly reduced while filling time was improved. Similarly at day 28, maladaptive responses of isovolumic contraction and relaxation to dobutamine were no longer observed during HR reduction with ivabradine. Correction of HR reduction with pacing showed that non-HR–related mechanisms also participated to these beneficial effects. In this model of chronic hypertension and left ventricular hypertrophy, acute HR reduction with ivabradine corrects the maladaptive responses of cardiac cycle phases by restoring a normal profile for isovolumic contraction and relaxation both at rest and under adrenergic stimuli, ultimately favoring filling.

Role of In Vivo Vascular Redox in Resistance Arteries

Rob H.P. Hilgers and
Kumuda C. Das

Hypertension. 2015 | Volume 65, Issue 1: 130–139,

Published Online:October 13, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04473

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Vascular thiol redox state has been shown to modulate vasodilator functions in large conductance Ca²⁺-activated K⁺ channels and other related channels. However, the role of vascular redox in small resistance arteries is unknown. To determine how in vivo modulation of thiol redox state affects small resistance arteries relaxation, we generated a transgenic mouse strain that overexpresses thioredoxin, a small redox protein (Trx-Tg), and another strain that is thioredoxin-deficient (dnTrx-Tg). The redox state of the mesenteric arteries (MAs) in Trx-Tg mice is found to be predominantly in reduced state; in contrast, MAs from dnTrx-Tg mice remain in oxidized state. Thus, we created an in vivo redox system of mice and isolated the second-order branches of the main superior MAs from wild-type, Trx-Tg, or dnTrx-Tg mice to assess endothelium-dependent relaxing responses in a wire myograph. In MAs isolated from Trx-Tg mice, we observed an enhanced intermediate-conductance Ca²⁺–activated potassium channel contribution resulting in a larger endothelium-dependent hyperpolarizing (EDH) relaxation in response to indirect (acetylcholine) and direct (NS309) opening of endothelial calcium-activated potassium channels. MAs derived from dnTrx-Tg mice showed both blunted nitric oxide–mediated and EDH-mediated relaxation compared with Trx-Tg mice. In a control study, diamide decreased EDH relaxations in MAs of wild-type mice, whereas dithiothreitol improved EDH relaxations and was able to restore the diamide-induced impairment in EDH response. Furthermore, the basal or angiotensin II–mediated systolic blood pressure remained significantly lower in Trx-Tg mice compared with wild-type or dnTrx-Tg mice, thus directly establishing redox-mediated EDH in blood pressure control.

Acute Exertion Elicits a H₂O₂-Dependent Vasodilator Mechanism in the Microvasculature of Exercise-Trained but Not Sedentary Adults

Hypertension. 2015 | Volume 65, Issue 1: 140–145,

Published Online:November 3, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04540

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Brachial artery flow–mediated vasodilation in exercise-trained (ET) individuals is maintained after a single bout of heavy resistance exercise compared with sedentary individuals. The purpose of this study was to determine whether vasodilation is also maintained in the microcirculation of ET individuals. A total of 51 sedentary and ET individuals underwent gluteal subcutaneous fat biopsy before and after performing a single bout of leg press exercise. Adipose arterioles were cannulated in an organ bath, and vasodilation to acetylcholine was assessed±the endothelial nitric oxide inhibitorl-NG-nitroarginine methyl ester, the cyclooxygenase inhibitor indomethacin, or the hydrogen peroxide scavenger polyethylene glycol catalase. Separate vessels (isolated from the same groups) were exposed to an intraluminal pressure of 150 mm Hg for 30 minutes to mimic the pressor response, which occurs with isometric exercise. Vasodilation to acetylcholine was reduced in microvessels from sedentary subjects after either a single weight lifting session or exposure to increased intraluminal pressure, whereas microvessels from ET individuals maintained acetylcholine-mediated vasodilation. Before weight lifting, vasodilation of microvessels from ET individuals was reduced in the presence of l-NG-nitroarginine methyl ester and indomethacin. After weight lifting or exposure to increased intraluminal pressure, polyethylene glycol catalase significantly reduced vasodilation, whereas l-NG-nitroarginine methyl ester and indomethacin had no effect. These results indicate that (1) endothelium-dependent vasodilation in the microvasculature is maintained after heavy resistance exercise in ET individuals but not in sedentary subjects and that (2) high pressure alone or during weight lifting may induce a mechanistic switch in the microvasculature to favor hydrogen peroxide as the vasoactive mediator of dilation.

Distensibility of the Aorta and Carotid Artery and Left Ventricular Mass From Childhood to Early Adulthood

Hypertension. 2015 | Volume 65, Issue 1: 146–152,

Published Online:October 27, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.03316

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Abstract—
In adults, arterial distensibility decreases with age and relates to changes in cardiac left ventricular mass. Longitudinal data on changes in arterial distensibility from childhood to adulthood are lacking. Our aim was to study the effect of age and sex, and low-saturated fat dietary counseling on arterial distensibility from childhood to early adulthood. In addition, we assessed the association of arterial distensibility with left ventricular mass. Distensibility of the abdominal aorta and common carotid artery was measured repeatedly at ages 11, 13, 15, 17, and 19 years (n=395–472) in an atherosclerosis prevention trial (Special Turku Coronary Risk Factor Intervention Project [STRIP]). Aortic and carotid distensibility decreased with age (both P<0.0001). In boys, distensibility values were generally lower (P<0.0001) and showed steeper decrease by age (age and sex interaction: both P<0.01). The low-saturated fat dietary counseling given in STRIP was not significantly associated with arterial distensibility. Left ventricular mass increased with age (P<0.0001), and it was greater in boys (P<0.0001). In conclusion, a marked age-related decrease in vascular distensibility was found already at this young age, and this decrease was more pronounced in boys than girls. The longitudinal progression of aortic and carotid distensibility was related with changes in left ventricular mass.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00223600.

Activation of D₄ Dopamine Receptor Decreases Angiotensin II Type 1 Receptor Expression in Rat Renal Proximal Tubule Cells

Hypertension. 2015 | Volume 65, Issue 1: 153–160,

Published Online:November 3, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04038

This article corrects the following:
- Correction
  - Volume 67Issue 6Hypertension
  - 1 June 2016

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The dopaminergic and renin–angiotensin systems interact to regulate blood pressure. Disruption of the D₄ dopamine receptor gene in mice produces hypertension that is associated with increased renal angiotensin type 1 (AT₁) receptor expression. We hypothesize that the D₄ receptor can inhibit AT₁ receptor expression and function in renal proximal tubule cells from Wistar–Kyoto (WKY) rats, but the D₄ receptor regulation of AT₁ receptor is aberrant in renal proximal tubule cells from spontaneously hypertensive rats (SHRs). The D₄ receptor agonist, PD168077, decreased AT₁ receptor protein expression in a time- and concentration-dependent manner in WKY cells. By contrast, in SHR cells, PD168077 increased AT₁ receptor protein expression. The inhibitory effect of D₄ receptor on AT₁ receptor expression in WKY cells was blocked by a calcium channel blocker, nicardipine, or calcium-free medium, indicating that calcium is involved in the D₄ receptor–mediated signaling pathway. Angiotensin II increased Na⁺-K⁺ ATPase activity in WKY cells. Pretreatment with PD168077 decreased the stimulatory effect of angiotensin II on Na⁺-K⁺ ATPase activity in WKY cells. In SHR cells, the inhibitory effect of D₄ receptor on angiotensin II–mediated stimulation of Na⁺-K⁺ ATPase activity was aberrant; pretreatment with PD168077 augmented the stimulatory effect of AT₁ receptor on Na⁺-K⁺ ATPase activity in SHR cells. This was confirmed in vivo; pretreatment with PD128077 for 1 week augmented the antihypertensive and natriuretic effect of losartan in SHRs but not in WKY rats. We suggest that an aberrant interaction between D₄ and AT₁ receptors may play a role in the abnormal regulation of sodium excretion in hypertension.

NADPH Oxidase in the Renal Microvasculature Is a Primary Target for Blood Pressure–Lowering Effects by Inorganic Nitrate and Nitrite

Hypertension. 2015 | Volume 65, Issue 1: 161–170,

Published Online:October 13, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04222

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Renal oxidative stress and nitric oxide (NO) deficiency are key events in hypertension. Stimulation of a nitrate–nitrite–NO pathway with dietary nitrate reduces blood pressure, but the mechanisms or target organ are not clear. We investigated the hypothesis that inorganic nitrate and nitrite attenuate reactivity of renal microcirculation and blood pressure responses to angiotensin II (ANG II) by modulating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NO bioavailability. Nitrite in the physiological range (10⁻⁷–10⁻⁵ mol/L) dilated isolated perfused renal afferent arterioles, which were associated with increased NO. Contractions to ANG II (34%) and simultaneous NO synthase inhibition (56%) were attenuated by nitrite (18% and 26%). In a model of oxidative stress (superoxide dismutase-1 knockouts), abnormal ANG II–mediated arteriolar contractions (90%) were normalized by nitrite (44%). Mechanistically, effects of nitrite were abolished by NO scavenger and xanthine oxidase inhibitor, but only partially attenuated by inhibiting soluble guanylyl cyclase. Inhibition of NADPH oxidase with apocynin attenuated ANG II–induced contractility (35%) similar to that of nitrite. In the presence of nitrite, no further effect of apocynin was observed, suggesting NADPH oxidase as a possible target. In preglomerular vascular smooth muscle cells and kidney cortex, nitrite reduced both basal and ANG II–induced NADPH oxidase activity. These effects of nitrite were also abolished by xanthine oxidase inhibition. Moreover, supplementation with dietary nitrate (10⁻² mol/L) reduced renal NADPH oxidase activity and attenuated ANG II–mediated arteriolar contractions and hypertension (99±2–146±2 mm Hg) compared with placebo (100±3–168±3 mm Hg). In conclusion, these novel findings position NADPH oxidase in the renal microvasculature as a prime target for blood pressure–lowering effects of inorganic nitrate and nitrite.

Chronic Central Nervous System MC3/4R Blockade Attenuates Hypertension Induced by Nitric Oxide Synthase Inhibition but Not by Angiotensin II Infusion

Hypertension. 2015 | Volume 65, Issue 1: 171–177,

Published Online:October 6, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.03999

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We examined whether central melanocortin 3 and 4 receptor (MC3/4R) blockade attenuates the blood pressure (BP) responses to chronic L-NAME or angiotensin II (Ang II) infusion in Sprague–Dawley rats implanted with telemetry transmitters, venous catheters, and intracerebroventricular cannula into the lateral ventricle. After 5 days of control measurements, L-NAME (10 μg/kg/min IV, groups 1 and 2) or Ang II (10 ng/kg/min IV, groups 3 and 4) were infused for 24 days, and starting on day 7 of L-NAME or Ang II infusion, the MC3/4R antagonist SHU-9119 (24 nmol/d, n=6/group; groups 1 and 3) or vehicle (saline 0.5 μL/h, n=6/group; groups 2 and 4) was infused intracerebroventricularly for 10 days. A control normotensive group also received SHU-9119 for 10 days (n=5). L-NAME and Ang II increased BP by 40±3 and 56±5 mm Hg, respectively, although heart rate was slightly reduced. MC3/4R blockade doubled food intake and reduced heart rate (≈40 to ≈50 bpm) in all groups. MC3/4R blockade caused only a small reduction in BP in normotensive group (4 mm Hg) and no change in rats receiving Ang II, although markedly reducing BP by 21±4 mm Hg in L-NAME–treated rats. After SHU-9119 infusion was stopped, food intake, heart rate, and BP gradually returned to values observed before SHU-9119 infusion was started. Ganglionic blockade at the end of L-NAME or Ang II infusion caused similar BP reduction in both groups. These results suggest that the brain MC3/4R contributes, at least in part, to the hypertension induced by chronic L-NAME infusion but not by Ang II.

Gαi₂-Protein–Mediated Signal Transduction

Central Nervous System Molecular Mechanism Countering the Development of Sodium-Dependent Hypertension

Hypertension. 2015 | Volume 65, Issue 1: 178–186,

Published Online:October 13, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04463

Abstract Export Citations PDF/EPUB
Excess dietary salt intake is an established cause of hypertension. At present, our understanding of the neuropathophysiology of salt-sensitive hypertension is limited by a lack of identification of the central nervous system mechanisms that modulate sympathetic outflow and blood pressure in response to dietary salt intake. We hypothesized that impairment of brain Gαi₂-protein–gated signal transduction pathways would result in increased sympathetically mediated renal sodium retention, thus promoting the development of salt-sensitive hypertension. To test this hypothesis, naive or renal denervated Dahl salt-resistant and Dahl salt-sensitive (DSS) rats were assigned to receive a continuous intracerebroventricular control scrambled or a targeted Gαi₂-oligodeoxynucleotide infusion, and naive Brown Norway and 8-congenic DSS rats were fed a 21-day normal or high-salt diet. High salt intake did not alter blood pressure, suppressed plasma norepinephrine, and evoked a site-specific increase in hypothalamic paraventricular nucleus Gαi₂-protein levels in naive Brown Norway, Dahl salt-resistant, and scrambled oligodeoxynucleotide-infused Dahl salt-resistant but not DSS rats. In Dahl salt-resistant rats, Gαi₂ downregulation evoked rapid renal nerve-dependent hypertension, sodium retention, and sympathoexcitation. In DSS rats, Gαi₂ downregulation exacerbated salt-sensitive hypertension via a renal nerve-dependent mechanism. Congenic-8 DSS rats exhibited sodium-evoked paraventricular nucleus-specific Gαi₂-protein upregulation and attenuated hypertension, sodium retention, and global sympathoexcitation compared with DSS rats. These data demonstrate that paraventricular nucleus Gαi₂-protein–gated pathways represent a conserved central molecular pathway mediating sympathoinhibitory renal nerve-dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. Impairment of this mechanism contributes to the development of salt-sensitive hypertension.

Bilateral or Unilateral Stimulation for Baroreflex Activation Therapy

Hypertension. 2015 | Volume 65, Issue 1: 187–192,

Published Online:October 20, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04492

Abstract Export Citations PDF/EPUB

Abstract—
Previous trials have shown that in patients with resistant hypertension device-based baroreflex activation therapy (BAT) can substantially reduce blood pressure. However, the fact that electrodes had to be implanted bilaterally may be a drawback for further development of the technique. In this study, we explored whether unilateral stimulation would produce comparable results as bilateral stimulation. In the Pivotal trial, treatment-resistant hypertensive patients were randomized to receive either immediate BAT or deferred BAT, that is, 6 months after implantation. We adjusted stimulation parameters individually so as to provide optimal baroreflex activation. Unilateral stimulation was applied unless bilateral stimulation resulted in a greater blood pressure reduction. When we pooled the 6-month data for the group with immediate BAT and the 12-month data for the group with deferred BAT, a total of 215 patients had been stimulated on one side only (127 at the right side and 88 at the left side), whereas 80 patients had been stimulated bilaterally. Although blood pressure and heart rate did not differ between the 2 groups at baseline, all these variables were significantly lower in the unilateral than in the bilateral group after the 6-month period. When we compared the effect of right-sided stimulation with those of either left-sided or bilateral stimulation, we found right-sided stimulation to be the most effective. We conclude that unilateral and in particular right-sided BAT has a more profound effect on blood pressure than bilateral or left-sided BAT.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00442286.

Reduced Effect of Percutaneous Renal Denervation on Blood Pressure in Patients With Isolated Systolic Hypertension

Hypertension. 2015 | Volume 65, Issue 1: 193–199,

Published Online:October 20, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04336

Abstract Export Citations PDF/EPUB
Renal denervation can reduce blood pressure in certain patients with resistant hypertension. The effect in patients with isolated systolic hypertension (ISH, ≥140/<90 mm Hg) is unknown. This study investigated the effects of renal denervation in 126 patients divided into 63 patients with ISH and 63 patients with combined hypertension (CH, ≥140/≥90 mm Hg) defined as baseline office systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 antihypertensive agents. Renal denervation significantly reduced office SBP and diastolic blood pressure (DBP) at 3, 6, and 12 months by 17/18/17 and 5/4/4 mm Hg in ISH and by 28/27/30 and 13/16/18 mm Hg in CH, respectively. The reduction in SBP and DBP in ISH was lower compared with patients with CH at all observed time points (P<0.05 for SBP/DBP intergroup comparison). The nonresponder rate (change in office SBP <10 mm Hg) after 6 months was 37% in ISH and 21% in CH (P<0.001). Mean 24-hour ambulatory SBP and DBP after 3, 6, and 12 months were significantly reduced by 10/13/15 and 6/6/9 mm Hg in CH, respectively. In patients with ISH the reduction in systolic ambulatory blood pressure was 4/8/7 mm Hg (P=0.032/P<0.001/P=0.009) and 3/4/2 mm Hg (P=0.08/P<0.001/P=0.130) in diastolic ambulatory blood pressure after 3, 6, and 12 months, respectively. The ambulatory blood pressure reduction was significantly lower after 3 and 12 months in SBP and after 12 months in ambulatory DBP, respectively. In conclusion, renal denervation reduces office and ambulatory blood pressure in patients with ISH. However, this reduction is less pronounced compared with patients with CH.

Genome-Wide Identification of Long Noncoding RNAs in Rat Models of Cardiovascular and Renal Disease

Hypertension. 2015 | Volume 65, Issue 1: 200–210,

Published Online:November 10, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04498

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Long noncoding RNAs (lncRNAs) are an emerging class of genomic regulatory molecules reported in various species. In the rat, which is one of the major mammalian model organisms, discovery of lncRNAs on a genome-wide scale is lagging. Renal lncRNA sequencing and lncRNA transcriptome analysis were conducted in 3 rat strains that are widely used in cardiovascular and renal research: the Dahl salt-sensitive rat, the spontaneously hypertensive rat, and the Dahl salt-resistant rat. Through the RNA sequencing approach, 3273 transcripts were identified as rat lncRNAs. A majority of lncRNAs were without predicted target genes. Differential expression of 273 and 749 lncRNAs was detected between Dahl salt-sensitive versus Dahl salt-resistant and Dahl salt-sensitive versus spontaneously hypertensive rat comparisons, respectively. To couple the observed differential expression of lncRNAs with the status of mRNAs, an mRNA transcriptome analysis was conducted. Several cis mRNA genes were coregulated with lncRNAs. Of these, the protein expression status of 4 target genes, Asb3, Chac2, Pex11b, and Sp5, were differentially expressed between the relevant strain comparisons, thereby suggesting that the differentially expressed lncRNAs associated with these genes are candidate genetic determinants of blood pressure. This study serves as a first-generation catalog of rat lncRNAs and illustrates the prioritization of lncRNAs as candidates for complex polygenic traits.

Variants in Striatin Gene Are Associated With Salt-Sensitive Blood Pressure in Mice and Humans

Hypertension. 2015 | Volume 65, Issue 1: 211–217,

Published Online:November 3, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04233

Abstract Export Citations PDF/EPUB
Striatin is a novel protein that interacts with steroid receptors and modifies rapid, nongenomic activity in vitro. We tested the hypothesis that striatin would in turn affect mineralocorticoid receptor function and consequently sodium, water, and blood pressure homeostasis in an animal model. We evaluated salt sensitivity of blood pressure in novel striatin heterozygote knockout mice. Compared with wild type, striatin heterozygote exhibited a significant increase in blood pressure when sodium intake was increased from restricted (0.03%) to liberal (1.6%) sodium. Furthermore, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocorticoid-regulated kinase 1, and epithelial sodium channel was increased in striatin heterozygote versus wild-type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocorticoid receptor’s rapid, nongenomic pathway, was reduced. To determine the potential clinical relevance of these findings, we tested the association between single nucleotide polymorphic variants of striatin gene and salt sensitivity of blood pressure in 366 white hypertensive subjects. HapMap-derived tagging single nucleotide polymorphisms identified an association of rs2540923 with salt sensitivity of blood pressure (odds ratio, 6.25; 95% confidence interval, 1.7–20; P=0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocorticoid receptor activity. The data also support the hypothesis that the rapid, nongenomic mineralocorticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure.

Hypertension Accelerates the Progression of Alzheimer-Like Pathology in a Mouse Model of the Disease

Hypertension. 2015 | Volume 65, Issue 1: 218–224,

Published Online:October 20, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04139

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Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm²; P<0.05) and a 2-fold increase in soluble amyloid levels in the brain and in plasma. Hypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were reduced in hypertensive APPPS1 mice (by 49%, 34%, and 33%, respectively, compared with wild-type mice; P<0.05). Our results indicate that hypertension accelerates the development of Alzheimer disease–related structural and functional alterations, partially through cerebral vasculature impairment and reduced nitric oxide production.

17-Hydroxyprogesterone Caproate Significantly Improves Clinical Characteristics of Preeclampsia in the Reduced Uterine Perfusion Pressure Rat Model

Hypertension. 2015 | Volume 65, Issue 1: 225–231,

Published Online:November 3, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04484

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Preeclampsia is characterized by increased uterine artery resistance index, chronic immune activation, and decreased circulating nitric oxide levels. 17-α-Hydroxyprogesterone caproate (17-OHPC) is a synthetic metabolite of progesterone used for the prevention of recurrent preterm birth. We hypothesized that 17-OHPC could reduce mean arterial pressure by decreasing inflammation, whereas improving vasodilation by increasing nitric oxide bioavailability and uterine artery resistance index during late gestation in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. 17-OHPC (3.32 mg/kg) was intraperitoneally administered on gestation day 18 into RUPP rats, carotid catheters inserted, and mean arterial pressure, blood, and tissues were collected on day 19. Mean arterial pressure in normal pregnant (NP; n=13) was 92±2.0 and increased to123±2.0 in RUPP (n=18; P<0.0001), which was improved to 116±1.5 mm Hg in RUPP+17-OHPC (n=10; P<0.05). Circulating CD4+ T cells were 1.19%±1.0% of gated cells in NP (n=7), which increased to 8.52%±2.4% in RUPP rats (n=10; P<0.05) but was reduced to 2.72%±0.87% (n=14; P<0.05) in RUPP+17-OHPC. Circulating nitrate/nitrite was 26.34±3.5 µmol/L in NP (n=12) but was reduced to14.58±3.1 in RUPP rats (n=8; P=0.03) and increased to 22.69±1.62 in RUPP+17-OHPC (n=7; P=0.05). Endothelial nitric oxide synthase expression was 0.65±0.11 AU in NP (n=4), which decreased to 0.33±0.01 in RUPP rats (n=4; P=0.05) but increased to 0.57±0.01 in RUPP+17-OHPC (n=5; P=0.03). Uterine artery resistance index was 0.54±0.02 in NP (n=3), 0.78±0.03 in RUPP (n=4), and 0.63±0.038 in RUPP+17-OHPC (n=8; both P<0.05). Our findings demonstrate that even though modest, lowering blood pressure with 17-OHPC could be a viable treatment option for suppressing inflammation, uterine artery vasoconstriction while improving litter size.

Maternal Treatment of Spontaneously Hypertensive Rats With Pentaerythritol Tetranitrate Reduces Blood Pressure in Female Offspring

Hypertension. 2015 | Volume 65, Issue 1: 232–237,

Published Online:November 10, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04416

Abstract Export Citations PDF/EPUB
Pentaerythritol tetranitrate is devoid of nitrate tolerance and shows no reproductive or developmental toxicity in animal studies. Recently, pentaerythritol tetranitrate has been demonstrated to reduce the risk of intrauterine growth restriction and the risk of preterm birth in women with abnormal placental perfusion. This study was conducted to test the perinatal programming effect of pentaerythritol tetranitrate in spontaneously hypertensive rats, a rat model of genetic hypertension. Parental spontaneously hypertensive rats were treated with pentaerythritol tetranitrate (50 mg/kg per day) during pregnancy and lactation periods; the offspring received standard chow without pentaerythritol tetranitrate after weaning. Maternal treatment with pentaerythritol tetranitrate had no effect on blood pressure in male offspring. In the female offspring, however, a persistent reduction in blood pressure was observed at 6 and 8 months. This long-lasting effect was accompanied by an upregulation of endothelial nitric oxide synthase, mitochondrial superoxide dismutase, glutathione peroxidase 1, and heme oxygenase 1 in the aorta of 8-month-old female offspring, which was likely to result from epigenetic changes (enhanced histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation) and transcriptional activation (enhanced binding of DNA-directed RNA polymerase II to the transcription start site of the genes). In organ chamber experiments, the endothelium-dependent, nitric oxide–mediated vasodilation to acetylcholine was enhanced in aorta from female offspring of the pentaerythritol tetranitrate–treated parental spontaneously hypertensive rats. In conclusion, maternal pentaerythritol tetranitrate treatment leads to epigenetic modifications, gene expression changes, an improvement of endothelial function and a persistent blood pressure reduction in the female offspring.

Effect of Dipeptidyl Peptidase 4 Inhibition on Arterial Blood Pressure Is Context Dependent

Hypertension. 2015 | Volume 65, Issue 1: 238–249,

Published Online:November 3, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04631

This article corrects the following:
- Correction
  - Volume 65Issue 4Hypertension
  - 1 April 2015

Abstract Export Citations PDF/EPUB
Because the effects of dipeptidyl peptidase 4 (DPP4) inhibitors on blood pressure are controversial, we examined the long-term effects of sitagliptin (80 mg/kg per day) on blood pressure (radiotelemetry) in spontaneously hypertensive rats (SHR), Wistar–Kyoto rats, and Zucker Diabetic-Sprague Dawley rats (metabolic syndrome model). In SHR, chronic (3 weeks) sitagliptin significantly increased systolic, mean, and diastolic blood pressures by 10.3, 9.2, and 7.9 mm Hg, respectively, a response abolished by coadministration of BIBP3226 (2 mg/kg per day; selective Y₁-receptor antagonist). Sitagliptin also significantly increased blood pressure in SHR treated with hydralazine (vasodilator; 25 mg/kg per day) or enalapril (angiotensin-converting enzyme inhibitor; 10 mg/kg per day). In Wistar–Kyoto rats, chronic sitagliptin slightly decreased systolic, mean, and diastolic blood pressures (−1.8, −1.1, and −0.4 mm Hg, respectively). In Zucker Diabetic-Sprague Dawley rats, chronic sitagliptin decreased systolic, mean, and diastolic blood pressures by −7.7, −5.8, and −4.3 mm Hg, respectively, and did not alter the antihypertensive effects of chronic enalapril. Because DPP4 inhibitors impair the metabolism of neuropeptide Y_1–36 (NPY_1–36; Y₁-receptor agonist) and glucagon-like peptide (GLP)-1(7–36)NH₂ (GLP-1 receptor agonist), we examined renovascular responses to NPY_1–36 and GLP-1(7–36)NH₂ in isolated perfused SHR and Zucker Diabetic-Sprague Dawley kidneys pretreated with norepinephrine (to induce basal tone). In Zucker Diabetic-Sprague Dawley kidneys, NPY_1–36 and GLP-1(7–36)NH₂ exerted little, if any, effect on renovascular tone. In contrast, in SHR kidneys, both NPY_1–36 and GLP-1(7–36)NH₂ elicited potent and efficacious vasoconstriction. In conclusion: (1) The effects of DPP4 inhibitors on blood pressure are context dependent; (2) The context-dependent effects of DPP4 inhibitors are due in part to differential renovascular responses to DPP4’s most important substrates (NPY_1–36 and GLP-1(7–36)NH₂); (3) Y₁ receptor antagonists may prevent the prohypertensive and possibly augment the antihypertensive effects of DPP4 inhibitors.

Correction

Hypertension. 2015 | Volume 65, Issue 1: e1–e6,

Published Online:January 1, 2015,

https://doi.org/10.1161/HYP.0000000000000016

Correction(s) for this article
- Ambient Air Pollution and Pregnancy-Induced Hypertensive Disorders
  - Marie Pedersen
  - Leslie Stayner
  - Rémy Slama
  - Mette Sørensen
  - Francesc Figueras
  - Mark J. Nieuwenhuijsen
  - Ole Raaschou-Nielsen
  - Payam Dadvand
  - Volume 64Issue 3Hypertension
  - 16 June 2014

Table of Contents

Editorial Board

Hypertension

Clinical Implications

Clinical Implications

Editorial

Hypertension: Update 2015

Brief Review

Design Considerations for Clinical Trials of Autonomic Modulation Therapies Targeting Hypertension and Heart Failure

Recent Advances in Hypertension

Masked Hypertension

A Phenomenon of Measurement

Clinical–Pathological Conference

Rare Cause of Severe Hypertension in a Young Woman

Editorial Commentaries

Control of Hypertension

Is the Goal Reached?

Blood Pressure in Chronic Kidney Disease

Does the Emperor Have New Clothes?

The Arterial Load and Its Role on the Heart

Nitrate, Nitrite, and Nitric Oxide Find a Home in the Kidney by Offsetting Angiotensin II–Mediated Hypertension

Prospects for Droxidopa in Neurogenic Orthostatic Hypotension

Hypertension and Alzheimer Disease

Another Brick in the Wall of Awareness

Systolic Blood Pressure Target Levels

Evidence for Benefits in Stroke

Mineralocorticoid Receptor Antagonists for the Treatment of Hypertension and the Metabolic Syndrome

NO for the Pregnant Mother

No Hypertension for the Daughter?

Original Articles

Epidemiology/Population

Circulating Aldosterone and Natriuretic Peptides in the General Community

Relationship to Cardiorenal and Metabolic Disease

Trends in Blood Pressure Among Adults With Hypertension

United States, 2003 to 2012

Blood Pressure in Relation to Environmental Lead Exposure in the National Health and Nutrition Examination Survey 2003 to 2010

Periodic Limb Movements During Sleep and Prevalent Hypertension in the Multi-Ethnic Study of Atherosclerosis

High-Sensitivity Troponin T and Cardiovascular Events in Systolic Blood Pressure Categories

Atherosclerosis Risk in Communities Study

Resistive and Pulsatile Arterial Load as Predictors of Left Ventricular Mass and Geometry

The Multi-Ethnic Study of Atherosclerosis

Blood Pressure and Risk of All-Cause Mortality in Advanced Chronic Kidney Disease and Hemodialysis

The Chronic Renal Insufficiency Cohort Study

Clinical Trials

Randomized Withdrawal Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension Responsive to Droxidopa

Abstract—

Clinical Trial Registration—

Systolic and Diastolic Blood Pressure Changes in Relation With Myocardial Infarction and Stroke in Patients With Coronary Artery Disease

Abstract—

Clinical Trial Registration—

Predicting the Effects of Blood Pressure–Lowering Treatment on Major Cardiovascular Events for Individual Patients With Type 2 Diabetes Mellitus

Results From Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation

Abstract—

Clinical Trial Registration—

Heart

Ivabradine Improves Left Ventricular Function During Chronic Hypertension in Conscious Pigs

Vascular Redox

Role of In Vivo Vascular Redox in Resistance Arteries

Acute Exertion Elicits a H2O2-Dependent Vasodilator Mechanism in the Microvasculature of Exercise-Trained but Not Sedentary Adults

Hemodynamics

Distensibility of the Aorta and Carotid Artery and Left Ventricular Mass From Childhood to Early Adulthood

Abstract—

Clinical Trial Registration—

Kidney

Activation of D4 Dopamine Receptor Decreases Angiotensin II Type 1 Receptor Expression in Rat Renal Proximal Tubule Cells

Correction

NADPH Oxidase in the Renal Microvasculature Is a Primary Target for Blood Pressure–Lowering Effects by Inorganic Nitrate and Nitrite

Nervous System

Chronic Central Nervous System MC3/4R Blockade Attenuates Hypertension Induced by Nitric Oxide Synthase Inhibition but Not by Angiotensin II Infusion

Gαi2-Protein–Mediated Signal Transduction

Central Nervous System Molecular Mechanism Countering the Development of Sodium-Dependent Hypertension

Bilateral or Unilateral Stimulation for Baroreflex Activation Therapy

Abstract—

Clinical Trial Registration—

Renal Denervation

Reduced Effect of Percutaneous Renal Denervation on Blood Pressure in Patients With Isolated Systolic Hypertension

Long Non-Coding RNAs

Genome-Wide Identification of Long Noncoding RNAs in Rat Models of Cardiovascular and Renal Disease

Salt Sensitivity

Variants in Striatin Gene Are Associated With Salt-Sensitive Blood Pressure in Mice and Humans

Acute Exertion Elicits a H₂O₂-Dependent Vasodilator Mechanism in the Microvasculature of Exercise-Trained but Not Sedentary Adults

Activation of D₄ Dopamine Receptor Decreases Angiotensin II Type 1 Receptor Expression in Rat Renal Proximal Tubule Cells

Gαi₂-Protein–Mediated Signal Transduction