Single dose administration of dietary inorganic nitrate acutely reduces blood pressure in normotensive healthy volunteers, via bioconversion to the vasodilator nitric oxide. We assessed whether dietary nitrate might provide sustained blood pressure lowering in hypertensive patients.We randomly assigned 68 hypertensive patients in a double-blind, placebo-controlled clinical trial to receive daily dietary supplementation for 4-weeks with either dietary nitrate (250mL daily, as beetroot juice) or a placebo (250mL daily, as nitrate-free beetroot juice) following a 2-week run-in period and followed by a 2-week wash-out. We performed stratified randomization of drug-naïve (n=34) and treated (n=34) hypertensive patients aged 18-85 years. The primary end-point was change in clinic, ambulatory and home blood pressure compared to placebo. Daily supplementation with dietary nitrate was associated with reduction in blood pressure measured by 3 different methods. Mean (95% CI) reduction in clinic blood pressure was 7.7/2.4mmHg (3.6-11-8/0.0-4.9,p<0.001 and p=0.050). 24h ambulatory blood pressure was reduced by 7.7/5.2mmHg (4.1-11.2/2.7-7.7,p<0.001 for both). Home blood pressure was reduced by 8.1/3.8mmHg (3.8-12.4/0.7-6.9,p<0.001 and p<0.01) with no evidence of tachyphylaxis over the 4-week intervention period. Endothelial function improved by ~20% (p<0.001) and arterial stiffness was reduced by 0.59m/s (0.24-0.93;p<0.01) after dietary nitrate consumption with no change after placebo. The intervention was well tolerated. This is the first evidence of durable blood pressure reduction with dietary nitrate supplementation in a relevant patient group. These findings suggest a role for dietary nitrate as an affordable, readily-available, adjunctive treatment in the management of hypertensive patients.(Funded by The British Heart Foundation, Clinicaltrials.gov: NCT01405898).
Blood pressure; Nitric Oxide; Nitrites; Nitrates; Diet
Angiotensin II (Ang II) plays a major role in the pathogenesis of end-organ injury in hypertension via its diverse hemodynamic and nonhemodynamic effects. Erythroblastosis virus E26 oncogen homolog-1 (ETS-1) is an important transcription factor recently recognized as an important mediator of cell proliferation, inflammation, and fibrosis. In the present studies, we tested the hypothesis that ETS-1 is a common mediator of the renal proinflammatory and profibrotic effects of Ang II. C57BL6 mice (n=6 per group) were infused with vehicle (control), Ang II (1.4 mg/kg per day), Ang II and an ETS-1 dominant-negative peptide (10 mg/kg per day), or Ang II and an ETS-1 mutant peptide (10 mg/kg per day) via osmotic minipump for 2 or 4 weeks. The infusion of Ang II resulted in significant increases in blood pressure and left ventricular hypertrophy, which were not modified by ETS-1 blockade. The administration of ETS-1 dominant-negative peptide significantly attenuated Ang II-induced renal injury as assessed by urinary protein excretion, mesangial matrix expansion, and cell proliferation. Furthermore, ETS-1 dominant-negative peptide but not ETS-1 mutant peptide significantly reduced Ang II-mediated upregulation of transforming growth factor-β, connective tissue growth factor, and α-smooth muscle actin. In addition, ETS-1 blockade reduced several proinflammatory effects of Ang II, including macrophage infiltration, nitrotyrosine expression, and NOX4 mRNA expression. Our studies suggest that ETS-1 is a common mediator of the proinflammatory and profibrotic effects of Ang II-induced hypertensive renal damage and may result in the development of novel strategies in the treatment and prevention of end-organ injury in hypertension.
angiotensin II; hypertension (kidney); ETS-1; extracellular matrix; physiology/pathophysiology; growth factors and cytokines; oxidative stress (kidney)
Excess pressure integral (XSPI), a new index of surplus work performed by the left ventricle, can be calculated from blood pressure (BP) waveforms and may indicate circulatory dysfunction. We investigated whether XSPI predicted future cardiovascular (CV) events and target organ damage in treated hypertensive individuals.
Radial BP waveforms were acquired by tonometry in 2069 individuals (63±8y) in the Conduit Artery Functional Evaluation sub-study of the Anglo-Scandinavian Cardiac Outcomes trial. Measurements of left ventricular mass index (LVMI; n = 862) and common carotid artery intima media thickness (cIMT; n = 923) were also performed. XSPI and the integral of reservoir pressure (PRI) were lower in people treated with amlodipine ± perindopril than atenolol ± bendroflumethiazide, although brachial systolic BP was similar. A total of 134 CV events accrued over a median 3.4 years of follow-up; XSPI was a significant predictor of CV events after adjustment for age and sex and this relationship was unaffected by adjustment for conventional CV risk factors or Framingham risk score. XSPI, central systolic BP, central augmentation pressure (AP), central pulse pressure (cPP) and PRI were correlated with LVMI, but only XSPI, AP and cPP were positively associated with cIMT. Associations between LVMI and XSPI and PRI, and cIMT and XSPI were unaffected by multivariable adjustment for other covariates. XSPI is a novel indicator of CV dysfunction and independently predicts CV events and target organ damage in a prospective clinical trial.
Blood Pressure; Cardiovascular events; Antihypertensive therapy
African American men have higher blood pressure levels and consequentially higher prevalence of hypertension compared to men from other ethnic groups in the United States. Socio-familial factors in childhood have been found to play an important role in hypertension, but few studies have examined this relationship among African American men. We investigated whether childhood family living arrangements are independently associated with mean blood pressure and hypertension in a cross-sectional sample of 515 unrelated African American male participants aged 20 years and older enrolled in the Howard University Family Study between 2001 and 2008. African American men who lived with both parents compared to the reference group of men who never lived with both parents during their lifetime had lower systolic blood pressure [−4.4 mmHg (95% Confidence Interval: −7.84, −0.96)], pulse pressure [−3.9 mmHg (95% Confidence Interval: −6.28, −1.51)] and mean arterial blood pressure [−2.0 mmHg (95% Confidence Interval: −4.44, 0.51)]. This protective effect was more pronounced among men who lived with both parents for 1 to 12 years of their lives; they had decreased systolic blood pressure [−6.5 mmHg, (95% Confidence Interval: −10.99, −1.95)], pulse pressure [−5.4 mmHg, (95% Confidence Interval: −8.48, −2.28)], mean arterial pressure [−3.3 mmHg, (95% Confidence Interval: −6.56, 0.00)], and a 46% decreased odds of developing hypertension (OR = 0.54; 95% Confidence Interval: 0.30, 0.99). No statistically significant associations were found for diastolic blood pressure. These results provide preliminary evidence that childhood family structure exerts a long-term influence on blood pressure among African American men.
Blood Pressure; Hypertension; African Americans; Family Characteristics; Social Environment
Arterial baroreflex sensitivity is attenuated in chronic heart failure (CHF) state, which is associated with cardiac arrhythmias and sudden cardiac death in the patients with CHF. Our previous study showed that CHF-induced sodium channel dysfunction in the baroreceptor neurons was involved in the blunted baroreflex sensitivity in CHF rats. Mitochondria-derived superoxide overproduction decreased expression and activation of the sodium channels in the baroreceptor neurons from CHF rats. However, the molecular mechanisms responsible for the sodium channel dysfunction in the baroreceptor neurons from CHF rats remain unknown. We tested the involvement of NFκB in the sodium channel dysfunction and evaluated the effects of in-vivo transfection of manganese superoxide dismutase gene and NFκB shRNA on the baroreflex function in CHF rats. CHF was developed at 6–8 weeks after left coronary artery ligation in adult rats. Western bolt and chromatin immunoprecipitation data showed that phosphorylated NFκB p65 and ability of NFκB p65 binding to the sodium channel promoter were increased in the nodose ganglia from CHF rats. In-vivo transfection of adenoviral manganese superoxide dismutase gene or lentiviral NFκB p65 shRNA into the nodose ganglia partially reversed CHF-reduced sodium channel expression and cell excitability in the baroreceptor neurons and improved CHF-blunted arterial baroreflex sensitivity. Additionally, transfection of adenoviral manganese superoxide dismutase also inhibited the augmentation of phosphorylated NFκB p65 in the nodose neurons from CHF rats. The present study suggests that superoxide-NFκB signaling contributes to CHF-induced baroreceptor dysfunction and resultant impairment of baroreflex function.
baroreceptor; baroreflex; heart failure; NFκB; sodium channel; superoxide
Williams syndrome, is caused by the deletion of 26-28 genes, including elastin, on human chromosome 7. Elastin insufficiency leads to the cardiovascular hallmarks of this condition, namely focal stenosis and hypertension. Extrapolation from the Eln+/− mouse suggests that affected persons may also have stiff vasculature, a risk factor for stroke, myocardial infarction and cardiac death. NCF1, one of the variably deleted Williams genes, is a component of the NAD(P)H oxidase complex and is involved in the generation of oxidative stress, making it an interesting candidate modifier for vascular stiffness. Using a case-control design, vascular stiffness was evaluated by pulse wave velocity in 77 Williams cases and matched controls. Cases had stiffer conducting vessels than controls (p<0.001), with increased stiffness observed in even the youngest Williams children. Pulse wave velocity increased with age at comparable rates in cases and controls and, although the degree of vascular stiffness varied, it was seen in both hypertensive and normotensive Williams participants. Use of anti-hypertension medication and extension of the Williams deletion to include NCF1 were associated with protection from vascular stiffness. These findings demonstrate that vascular stiffness is a primary vascular phenotype in Williams syndrome and that treatment with anti-hypertensives and/or agents inhibiting oxidative stress may be important in managing patients with this condition, potentially even those who are not overtly hypertensive.
Elastin; NADPH Oxidase; Williams Syndrome; Vascular stiffness; Pulse wave velocity
Hypoxic pulmonary hypertension is characterized by increased vascular tone, altered vasoreactivity and vascular remodeling, which are associated with alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells. We have previously shown that classical transient receptor potential 1 and 6 (TRPC1 and TRPC6) are upregulated in pulmonary arteries of chronic hypoxic rats, but it is unclear whether these channels are essential for the development of pulmonary hypertension. Here we found that pulmonary hypertension was suppressed in TRPC1 and TRPC6 knockout (Trpc1−/− and Trpc6−/−) mice compared to wildtype after exposure to 10% O2 for 1 and 3 weeks. Muscularization of pulmonary microvessels was inhibited, but rarefaction was unaltered in hypoxic Trpc1−/− and Trpc6−/− mice. Small pulmonary arteries of normoxic wildtype mice exhibited vasomotor tone, which was significantly enhanced by chronic hypoxia. Similar vasomotor tone was found in normoxic Trpc1−/− pulmonary arteries, but the hypoxia-induced enhancement was blunted. In contrast, there was minimal vascular tone in normoxic Trpc6−/− pulmonary arteries, but the hypoxia-enhanced tone was preserved. Chronic hypoxia caused significant increase in serotonin-induced vasoconstriction; the enhanced vasoreactivity was attenuated in Trpc1−/− and eliminated in Trpc6−/− pulmonary arteries. Moreover, the effects of 3-week hypoxia on pulmonary arterial pressure, right ventricular hypertrophy and muscularization of microvessels were further suppressed in Trpc1−/−Trpc6−/− double-knockout mice. Our results therefore provide clear evidence that TRPC1 and TRPC6 participate differentially in various pathophysiological processes; and the presence of TRPC1 and TRPC6 are essential for the full development of hypoxic pulmonary hypertension in the mouse model.
Chronic hypoxia; pulmonary hypertension; vasoreactivity; vascular remodeling; vasomotor tone
Hypertensive disorders of pregnancy are associated with intrauterine growth restriction and preterm birth. However, the associations of patterns of blood pressure change during pregnancy with these outcomes have not been studied in detail. We studied repeat antenatal blood pressure measurements of 9,697 women in the Avon Longitudinal Study of Parents and Children (median (interquartile range) 10 (9, 11) measurements per woman). Bivariate linear spline models were used to relate blood pressure changes to perinatal outcomes.
Higher systolic, but not diastolic, blood pressure at baseline (8 weeks gestation) and a greater increase in systolic and diastolic blood pressure between 18 and 36 weeks gestation were associated with lower offspring birthweight and being smaller for gestational age in confounder-adjusted models. For example, the mean difference (95% CI) in birthweight per 1 mmHg/week greater increase in systolic blood pressure between 18-30 weeks was −71g (−134, −14) and between 30-36 weeks was −175g (−208, −145). A smaller decrease in systolic and diastolic blood pressure prior to 18 weeks and a greater increase between 18 and 36 weeks was associated with a shorter gestation (percentage difference in gestational duration per 1 mmHg/week greater increase in systolic blood pressure between 18-30 weeks: −0.60% (−1.01, −0.18) and 30-36 weeks: −1.01% (−1.36, −0.74)). Associations remained strong when restricting to normotensive women. We conclude that greater increases in blood pressure, from the 18-week nadir, are related to reduced fetal growth and shorter gestation even in women whose blood pressure does not cross the threshold for hypertensive disorders of pregnancy.
ALSPAC; Birthweight; Blood pressure; Gestational age; Pregnancy
Pretreatment with a phytoestrogen genistein has been shown to attenuate the development of pulmonary hypertension (PH). Because PH is not always diagnosed early, we examined whether genistein could also reverse preexisting established PH and prevent associated right heart failure (RHF). PH was induced in male rats by 60 mg/kg of monocrotaline. After 21 days, when PH was well established, rats received daily injection of genistein (1 mg/kg per day) for 10 days or were left untreated to develop RHF by day 30. Effects of genistein on human pulmonary artery smooth muscle cell and endothelial cell proliferation and neonatal rat ventricular myocyte hypertrophy were assessed in vitro. Severe PH was evident 21 days after monocrotaline, as peak systolic right ventricular pressure increased to 66.35±1.03 mm Hg and right ventricular ejection fraction reduced to 41.99±1.27%. PH progressed to RHF by day 30 (right ventricular pressure, 72.41 ± 1.87 mm Hg; RV ejection fraction, 29.25 ± 0.88%), and mortality was ≈75% in RHF rats. Genistein therapy resulted in significant improvement in lung and heart function as right ventricular pressure was significantly reduced to 43.34±4.08 mm Hg and right ventricular ejection fraction was fully restored to 65.67 ± 1.08% similar to control. Genistein reversed PH-induced pulmonary vascular remodeling in vivo and inhibited human pulmonary artery smooth muscle cell proliferation by ≈50% in vitro likely through estrogen receptor-β. Genistein also reversed right ventricular hypertrophy (right ventricular hypertrophy index, 0.35±0.029 versus 0.70±0.080 in RHF), inhibited neonatal rat ventricular myocyte hypertrophy, and restored PH-induced loss of capillaries in the right ventricle. These improvements in cardiopulmonary function and structure resulted in 100% survival by day 30. Genistein restored PH-induced downregulation of estrogen receptor-β expression in the right ventricle and lung. In conclusion, genistein therapy not only rescues preexisting severe PH but also prevents the progression of severe PH to RHF.
pulmonary hypertension; right heart failure; genistein; angiogenesis; estrogen receptor-β
Connecting tubule glomerular feedback (CTGF) is a mechanism in which Na reabsorption in the connecting tubule (CNT) causes afferent arteriole (Af-Art) dilation. CTGF is mediated by eicosanoids, including prostaglandins and epoxyeicosatrienoic acids (EETs), however their exact nature and source remain unknown. We hypothesized that during CTGF, the CNT releases prostaglandin E2 (PGE2), which binds EP4 receptors and dilates the Af-Art. Rabbit Af-Arts with the adherent CNT intact were microdissected, perfused, and preconstricted with norepinephrine. CTGF was elicited by increasing luminal NaCl in the CNT from 10 to 80 mmol/L. We induced CTGF with or without the EP4 receptor blocker ONO-AE3-208 added to the bath in the presence of the EET synthesis inhibitor MS-PPOH. ONO-AE3-208 abolished CTGF (control: 9.4±0.5, MS-PPOH+ONOAE3-208: −0.6±0.2 μm, p<0.001, n=6). To confirm these results we used a different, specific EP4 blocker, L161982 (10−5 mol/L) which also abolished CTGF (control: 8.5±0.9, MS-PPOH+L161982: 0.8±0.4μm, p<0.001, n=6). To confirm that the eicosanoids that mediate CTGF are released from the CNT rather than the Af-Art, we first disrupted the Af-Art endothelium with an antibody and complement. Endothelial disruption did not affect CTGF (7.9±0.9 vs. 8.6±0.6 μm, p=NS, n=7). We then added arachidonic acid (AA) to the lumen of the CNT while maintaining zero NaCl in the perfusate. AA caused dose-dependent dilation of the attached Af-Art (from 8.6±1.2 to 15.3±0.7 μm, p<0.001, n=6), and this effect was blocked by ONO-AE3-208 (10−7 mol/L). We conclude that during CTGF, the CNT releases prostaglandin E2, which acts on EP4 on the Af-Art inducing endothelium-independent dilation.
arterioles; endothelium; prostaglandin E2; arachidonic acid PGE Receptor (EP4 Subtype); microcirculation; 11,12-epoxy-5,8,14-eicosatrienoic acid
The inability of mineralocorticoid receptor (MR) blockade to reduce hypertension associated with high Angiotensin (Ang) II suggests direct actions of Ang II to regulate tubular sodium reabsorption via the epithelial Na+ channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN). We used freshly isolated ASDN from mice to delineate the synergism and primacy between aldosterone and Ang II in controlling functional ENaC activity. Inhibition of MR specifically prevented the increased number of functionally active ENaC but not ENaC open probability elicited by a low sodium diet. In contrast, we found no functional role of glucocorticoid receptors (GR) in the regulation of ENaC activity by dietary salt intake. Simultaneous inhibition of MR and Ang II type 1 receptors (AT1R) ameliorated the enhanced ENaC activity caused by low dietary salt intake and produced significantly greater natriuresis than either inhibitor alone. Chronic systemic Ang II infusion induced more than two times greater increase in ENaC activity than observed during dietary sodium restriction. Importantly, ENaC activity remained greatly above control levels during maximal MR inhibition. We conclude that during variations in dietary salt intake both aldosterone and Ang II contribute complementarily to the regulation of ENaC activity in the ASDN. In contrast, in the setting of Ang II-dependent hypertension, ENaC activity is up-regulated well above the physiological range and is not effectively suppressed by inhibition of the aldosterone-MR axis. This provides a mechanistic explanation for the resistance to MR inhibition that occurs in hypertensive subjects having elevated intrarenal Ang II levels.
collecting duct; connecting tubule; distal nephron; renal sodium handling; hypertension
Pre-eclampsia (PE), new onset hypertension with proteinuria during pregnancy, is associated with chronic inflammation and placental oxidative stress (ROS). Chronic IL-17 increases blood pressure (MAP), autoantibodies (AT1-AA) and ROS during pregnancy. The objective of this study was to determine if TH17 suppression via IL-17RC (recombinant receptor C) decreases pathophysiology associated with placental ischemia (RUPP). On gestation day 14, mini-osmotic pumps infusing 100 pg/day of IL-17RC were implanted into pregnant rats undergoing RUPP (Reduced Uterine Perfusion Pressure), gestation day18 carotid catheters were inserted, day 19 MAP was recorded, TH17 cells, oxidative stress and AT1-AA were measured and analyzed via one-way ANOVA. MAP increased from 101 ±2 mmHg in normal pregnant, NP (n=19), to 120 ±1 mmHg in RUPP (n=17),but decreased to 110±2 mmHg in RUPP+IL-17RC rats (n=22). Pup weight decreased from 2.28 ± 0.2 g in NP to 1.96 ± 0.3 g in RUPP rats, but was significantly increased to 2.01 ± 0.1 in RUPP+IL-17RC rats. TH17 cells were 1.77% in RUPP but decreased to 0.65% in RUPP+IL-17RC rats. Urinary isoprostanes normalized in RUPP +IL-17RC rats (52 pg/μg) compared to 89 pg/μg in RUPP controls. Placental ROS was 652 RLU in RUPP, but decreased to 337 RLU in RUPP+IL-17RC rats. AT1-AA was 17.27 ± 0.7 bpm in RUPP but decreased to 5.00 ± 0.5 bpm in RUPP+IL-17RC rats. With this study, we show that infusion of IL-17RC blunts TH17s, oxidative stress, AT1-AA, and hypertension in the RUPP model of PE indicating that TH17 cells may play an important role in disease pathophysiology.
hypertension; pregnancy; inflammation; oxidative stress