Nitric Oxide Contributes to Vasomotor Tone in Hypertensive African Americans Treated With Nebivolol and Metoprolol.
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ABSTRACT:
SUBMITTER: Neuman RB
PROVIDER: S-EPMC4760906 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nebivolol, unlike other selective β1-receptor blockers, induces vasodilation attributable to increased NO bioavailability. The relative contribution of this mechanism to the blood pressure (BP)-lowering effects of nebivolol is unclear because it is normally masked by baroreflex buffering. Autonomic failure provides a unique model of hypertension devoid of autonomic modulation but sensitive to the hypotensive effects of NO potentiation. We tested the hypothesis that nebivolol would decrease BP in these patients through a mechanism independent of β-blockade. We randomized 20 autonomic failure patients with supine hypertension (14 men; 69±2 years) to receive a single oral dose of placebo, nebivolol 5 mg, metoprolol 50 mg (negative control), and sildenafil 25 mg (positive control) on separate nights in a double-blind, crossover study. Supine BP was monitored every 2 hours from 8:00 pm to 8:00 am. Compared with placebo, sildenafil and nebivolol decreased systolic BP during the night (P<0.001 and P=0.036, by mixed-effects model, maximal systolic BP reduction 8-hour postdrug of -20±6 and -24±9 mm Hg, respectively), whereas metoprolol had no effect. In a subanalysis, we divided patients into sildenafil responders (BP fall>20 mm Hg at 4:00 am) and nonresponders. Nebivolol significantly lowered systolic BP in sildenafil responders (-44±13 mm Hg) but not in nonresponders (1±11 mm Hg). Despite lowering nighttime BP, nebivolol did not worsen morning orthostatic tolerance compared with placebo. In conclusion, nebivolol effectively lowered supine hypertension in autonomic failure, independent of β1-blockade. These results are consistent with the hypothesis that NO potentiation contributes significantly to the antihypertensive effect of nebivolol.
| S-EPMC4230998 | biostudies-literature
Project description:In young healthy humans, sympathetic vasoconstriction is markedly blunted during exercise to optimize blood flow to the metabolically active muscle. This phenomenon known as functional sympatholysis is impaired in hypertensive humans and rats by angiotensin II-dependent mechanisms, involving oxidative stress and inactivation of nitric oxide (NO). Nebivolol is a ?1-adrenergic receptor blocker that has NO-dependent vasodilatory and antioxidant properties. We therefore asked whether nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage 1 hypertension, we measured muscle oxygenation and forearm blood flow responses to reflex increases in sympathetic nerve activity evoked by lower body negative pressure at rest, and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5-20 mg/d) or metoprolol (100-300 mg/d), using a double-blind crossover design. We found that nebivolol had no effect on lower body negative pressure-induced decreases in oxygenation and forearm blood flow in resting forearm (from -29±5% to -30±5% and from -29±3% to -29±3%, respectively; P=NS). However, nebivolol attenuated the lower body negative pressure-induced reduction in oxygenation and forearm blood flow in exercising forearm (from -14±4% to -1±5% and from -15±2% to -6±2%, respectively; both P<0.05). This effect of nebivolol on oxygenation and forearm blood flow in exercising forearm was not observed with metoprolol in the same subjects, despite a similar reduction in blood pressure. Nebivolol had no effect on sympathetic nerve activity at rest or during handgrip, suggesting a direct effect on vascular function. Thus, our data demonstrate that nebivolol restored functional sympatholysis in hypertensive humans by a mechanism that does not involve ?1-adrenergic receptors. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787.
| S-EPMC3785406 | biostudies-literature
Project description:Use of β-adrenergic receptor (AR) blocker is associated with increased risk of fatigue and exercise intolerance. Nebivolol is a newer generation β-blocker, which is thought to avoid this side effect via its vasodilating property. However, the effects of nebivolol on skeletal muscle perfusion during exercise have not been determined in hypertensive patients. Accordingly, we performed contrast-enhanced ultrasound perfusion imaging of the forearm muscles in 25 untreated stage I hypertensive patients at rest and during handgrip exercise at baseline or after 12 wk of treatment with nebivolol (5-20 mg/day) or metoprolol succinate (100-300 mg/day), with a subsequent double crossover for 12 wk. Metoprolol and nebivolol each induced a reduction in the resting blood pressure and heart rate (130.9 ± 2.6/81.7 ± 1.8 vs. 131.6 ± 2.7/80.8 ± 1.5 mmHg and 63 ± 2 vs. 64 ± 2 beats/min) compared with baseline (142.1 ± 2.0/88.7 ± 1.4 mmHg and 75 ± 2 beats/min, respectively, both P < 0.01). Metoprolol significantly attenuated the increase in microvascular blood volume (MBV) during handgrip at 12 and 20 repetitions/min by 50% compared with baseline (mixed-model P < 0.05), which was not observed with nebivolol. Neither metoprolol nor nebivolol affected microvascular flow velocity (MFV). Similarly, metoprolol and nebivolol had no effect on the increase in the conduit brachial artery flow as determined by duplex Doppler ultrasound. Thus our study demonstrated a first direct evidence for metoprolol-induced impairment in the recruitment of microvascular units during exercise in hypertensive humans, which was avoided by nebivolol. This selective reduction in MBV without alteration in MFV by metoprolol suggested impaired vasodilation at the precapillary arteriolar level.
| S-EPMC4967201 | biostudies-literature
Project description:The metal binding protein metallothionein (MT) is a target for nitric oxide (NO), causing release of bound zinc that affects myogenic reflex in systemic resistance vessels. Here, we investigate a role for NO-induced zinc release in pulmonary vasoregulation. We show that acute hypoxia causes reversible constriction of intraacinar arteries (<50 microm/L) in isolated perfused mouse lung (IPL). We further demonstrate that isolated pulmonary (but not aortic) endothelial cells constrict in hypoxia. Hypoxia also causes NO-dependent increases in labile zinc in mouse lung endothelial cells and endothelium of IPL. The latter observation is dependent on MT because it is not apparent in IPL of MT(-/-) mice. Data from NO-sensitive fluorescence resonance energy transfer-based reporters support hypoxia-induced NO production in pulmonary endothelium. Furthermore, hypoxic constriction is blunted in IPL of MT(-/-) mice and in wild-type mice, or rats, treated with the zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN), suggesting a role for chelatable zinc in modulating HPV. Finally, the NO donor DETAnonoate causes further vasoconstriction in hypoxic IPL in which NO vasodilatory pathways are inhibited. Collectively, these data suggest that zinc thiolate signaling is a component of the effects of acute hypoxia-mediated NO biosynthesis and that this pathway may contribute to constriction in the pulmonary vasculature.
| S-EPMC2735130 | biostudies-literature
Project description:BPC 157-activated endothelial nitric oxide synthase (eNOS) is associated with tissue repair and angiogenesis as reported in previous studies. However, how BPC 157 regulates the vasomotor tone and intracellular Src-Caveolin-1 (Cav-1)-eNOS signaling is not yet clear. The present study demonstrated a concentration-dependent vasodilation effect of BPC 157 in isolated rat aorta. Attenuation of this vasodilation effect in the absence of endothelium suggested an endothelium-dependent vasodilation effect of BPC 157. Although slightly increased vasorelaxation in aorta without endothelium was noticed at high concentration of BPC 157, there was no direct relaxation effect on three-dimensional model made of vascular smooth muscle cells. The vasodilation effect of BPC 157 was nitric oxide mediated because the addition of L-NAME or hemoglobin inhibited the vasodilation of aorta. Nitric oxide generation was induced by BPC 157 as detected by intracellular DFA-FM DA labeling which was capable of promoting the migration of vascular endothelial cells. BPC 157 enhanced the phosphorylation of Src, Cav-1 and eNOS which was abolished by pretreatment with Src inhibitor, confirming the upstream role of Src in this signal pathway. Activation of eNOS required the released binding with Cav-1 in advance. Co-immunoprecipitation analysis revealed that BPC 157 could reduce the binding between Cav-1 and eNOS. Together, the present study demonstrates that BPC 157 can modulate the vasomotor tone of an isolated aorta in a concentration- and nitric oxide-dependent manner. BPC 157 can induce nitric oxide generation likely through the activation of Src-Cav-1-eNOS pathway.
| S-EPMC7555539 | biostudies-literature
Project description:BackgroundHypertension is the the primary cause of diastolic heart failure. Oxidative stress plays an important role in cardiac diastolic dysfunction caused by hypertension. The occurrence of oxidative stress is related to the level of nitric oxide (NO) in the body. Tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. Nebivolol can reduce myocardial oxidative stress and increase NO activity. Therefore, we investigated the effects of monotherapy or combination therapy of different doses of BH4 and nebivolol on cardiac diastolic function in spontaneously hypertensive rats, and preliminarily expounded the related mechanisms.MethodsLeft ventricular function was evaluated by non-invasive echocardiographic assessment and invasive right carotid artery catheterization methods. ELISA was used to measure myocardial 3-nitrotyrosine content, NO production, and cyclic guanosine monophosphate (cGMP) concentration in the myocardium; quantitative real-time PCR (qRT-PCR) was used to determine endothelial nitric oxide synthase (eNOS), phospholamban and sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) mRNA expression levels; Western blot was used to detect the protein expression levels of eNOS and eNOS dimers in myocardial tissue, and immunohistochemical detection of cGMP expression in the myocardium was performed.ResultsStudies have shown that compared with those in the control group, NO generation and the expression level of myocardial eNOS mRNA, eNOS expression of dimers, phospholamban, SERCA2a and cGMP increased significantly after the combined intervention of BH4 and nebivolol, while the expression of 3-nitrotyrosine was significantly decreased.ConclusionsThe combined treatment group had a synergistic effect on reducing myocardial oxidative stress, increasing eNOS content, and increasing NO production, and had a more obvious protective effect on diastolic dysfunction through the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway.
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Project description:Skin tone is a significant marker used by others to evaluate and rank the social position of minorities. While skin color represents a particularly salient dimension of race, its consequences for health remains unclear. This study uses four waves of panel data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study and random intercept multilevel models to address three research questions critical to understanding the skin color-health relationship among African American adults (N=1,680): what is the relationship between skin color and two global measures of health (cumulative biological risk and self-rated health)? To what extent are these relationships gendered? Do socioeconomic resources, stressors, and discrimination help explain the skin color-health relationship? Findings indicate that dark-skinned women have more physiological deterioration and self-report worse health than lighter-skinned women. These associations are not evident among men, and socioeconomic factors, stressors, and discrimination do not explain the light-dark disparity in physiological deterioration among women. Differences in self-ratings of health among women are partially explained by education and income. Results of this study highlight heterogeneity in determinants of health among African Americans, and provide a more nuanced understanding of health inequality by identifying particularly disadvantaged members of racial groups that are often assumed to have monolithic experiences.
| S-EPMC7051017 | biostudies-literature
Project description:Significance: Cytoglobin (Cygb) was discovered as a new addition to the globin superfamily and subsequently identified to have potent nitric oxide (NO) dioxygenase function. Cygb plays a critical role in the oxygen-dependent regulation of NO levels and vascular tone. Recent Advances: In recent years, the mechanism of the Cygb-mediated NO dioxygenation has been studied in isolated protein, smooth muscle cell, isolated blood vessel, and in vivo animal model systems. Studies in Cygb-/- mice have demonstrated that Cygb plays a critical role in regulating blood pressure and vascular tone. This review summarizes advances in the knowledge of NO dioxygenation/metabolism regulated by Cygb. Advances in measurement of NO diffusion dynamics across blood vessels and kinetic modeling of Cygb-mediated NO dioxygenation are summarized. The oxygen-dependent regulation of NO degradation by Cygb is also reviewed along with how Cygb paradoxically generates NO from nitrite under anaerobic conditions. The important role of Cygb in the regulation of vascular function and disease is reviewed. Critical Issues: Cygb is a more potent NO dioxygenase (NOD) than previously known globins with structural differences in heme coordination and environment, conferring it with a higher rate of reduction and more rapid process of NO dioxygenation with unique oxygen dependence. Various cellular reducing systems regenerate the catalytic oxyferrous Cygb species, supporting a high rate of NO dioxygenation. Future Directions: There remains a critical need to further characterize the factors and processes that modulate Cygb-mediated NOD function, and to develop pharmacological or other approaches to modulate Cygb function and expression.
| S-EPMC7196366 | biostudies-literature
Project description:Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure (BP). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4-week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP: -9.6 ± 8.0 vs -5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP: -18.7 ± 13.8 vs -13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (-17.0 ± 13.2/-9.6 ± 7.5 vs -7.0 ± 18.6/-6.7 ± 9.3 mm Hg, adjusted P<.0001/.008). Therefore, age should be considered when selecting antihypertensive therapy in European and African American populations with hypertension.
| S-EPMC5722670 | biostudies-literature
Project description:BackgroundTraumatic brain injury (TBI) has been reported to increase the concentration of nitric oxide (NO) in the brain and can lead to loss of cerebrovascular tone; however, the sources, amounts, and consequences of excess NO on the cerebral vasculature are unknown. Our objective was to elucidate the mechanism of decreased cerebral artery tone after TBI.Methods and resultsCerebral arteries were isolated from rats 24 hours after moderate fluid?percussion TBI. Pressure?induced increases in vasoconstriction (myogenic tone) and smooth muscle Ca2+ were severely blunted in cerebral arteries after TBI. However, myogenic tone and smooth muscle Ca2+ were restored by inhibition of NO synthesis or endothelium removal, suggesting that TBI increased endothelial NO levels. Live native cell NO, indexed by 4,5?diaminofluorescein (DAF?2 DA) fluorescence, was increased in endothelium and smooth muscle of cerebral arteries after TBI. Clamped concentrations of 20 to 30 nmol/L NO were required to simulate the loss of myogenic tone and increased (DAF?2T) fluorescence observed following TBI. In comparison, basal NO in control arteries was estimated as 0.4 nmol/L. Consistent with TBI causing enhanced NO?mediated vasodilation, inhibitors of guanylyl cyclase, protein kinase G, and large?conductance Ca2+?activated potassium (BK) channel restored function of arteries from animals with TBI. Expression of the inducible isoform of NO synthase was upregulated in cerebral arteries isolated from animals with TBI, and the inducible isoform of NO synthase inhibitor 1400W restored myogenic responses following TBI.ConclusionsThe mechanism of profound cerebral artery vasodilation after TBI is a gain of function in vascular NO production by 60?fold over controls, resulting from upregulation of the inducible isoform of NO synthase in the endothelium.
| S-EPMC4338739 | biostudies-literature