Dataset Information

Chronic Nebivolol Treatment Suppresses Endothelin-1-Mediated Vasoconstrictor Tone in Adults With Elevated Blood Pressure.

ABSTRACT: Endothelin-1 (ET-1) plays a major role in the pathophysiology of hypertension and its associated cardiovascular risk. We tested the hypothesis that chronic nebivolol treatment reduces ET-1-mediated vasoconstrictor tone in adult humans with elevated blood pressure (BP). Furthermore, reducing ET-1 vasoconstrictor activity contributes to the improvement in endothelial vasodilator function associated with nebivolol treatment. Forty-two middle-aged adults with elevated BP (systolic BP ?130 mm Hg or diastolic BP ?85 mm Hg) completed a 3-month, double-blind, randomized, placebo controlled trial: 14 received nebivolol (8 men/6 women; 5 mg per day); 14 received metoprolol succinate (9 men/5 women; 100 mg per day); and 14 received placebo (9 men/5 women). Forearm blood flow (plethysmography) responses to selective (BQ-123: 100 nmol/min; 60 minutes) and nonselective (BQ-123+BQ-788 [50 nmol/min]; 60 minutes) ET-1 receptor blockade, as well as acetylcholine (4.0, 8.0, and 16.0 ?g per 100 mL of tissue per minute) in the absence and presence of nonselective ET-1 receptor blockade were determined before and after each treatment intervention. Forearm blood flow responses to BQ-123 and BQ-123+BQ-788 were similarly and significantly elevated (?30% and 60%, respectively) from baseline in all 3 groups. Nebivolol, but not metoprolol or placebo, therapy resulted in a marked (?25% and 45%; P<0.05) reduction in forearm blood flow response to BQ-123 and BQ-123+BQ-788. Moreover, after nebivolol therapy only, vasodilator response to acetylcholine was not significantly increased by ET-1 receptor blockade. These results demonstrate that nebivolol, but not metoprolol, treatment reduces ET-1-mediated vasoconstrictor tone in adult humans with elevated BP. In addition, nebivolol-induced reduction in ET-1-mediated vasoconstrictor tone underlies the favorable effects of this ?-blocker on endothelial vasodilation.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01395329.

SUBMITTER: Diehl KJ

PROVIDER: S-EPMC4871319 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Chronic Nebivolol Treatment Suppresses Endothelin-1-Mediated Vasoconstrictor Tone in Adults With Elevated Blood Pressure.

Diehl Kyle J KJ Stauffer Brian L BL Dow Caitlin A CA Bammert Tyler D TD Brunjes Danielle L DL Greiner Jared J JJ DeSouza Christopher A CA

Hypertension (Dallas, Tex. : 1979) 20160425 6

<h4>Unlabelled</h4>Endothelin-1 (ET-1) plays a major role in the pathophysiology of hypertension and its associated cardiovascular risk. We tested the hypothesis that chronic nebivolol treatment reduces ET-1-mediated vasoconstrictor tone in adult humans with elevated blood pressure (BP). Furthermore, reducing ET-1 vasoconstrictor activity contributes to the improvement in endothelial vasodilator function associated with nebivolol treatment. Forty-two middle-aged adults with elevated BP (systolic ...[more]

PMID: 27113048

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Project description:The human brain requires adequate cerebral blood flow to meet the high demand for nutrients and to clear waste products. With age, there is a chronic reduction in cerebral blood flow in small resistance arteries that can eventually limit proper brain function. The endothelin system is a key mediator in the regulation of cerebral blood flow, but the contributions of its constituent receptors in the endothelial and vascular smooth muscle layers of cerebral arteries have not been well defined in the context of aging. We isolated posterior cerebral arteries from young and aged Fischer 344 rats, as well as ETB receptor knock-out rats and mounted the vessels in plexiglass pressure myograph chambers to measure myogenic tone in response to increasing pressure and targeted pharmacological treatments. We used an ETA receptor antagonist (BQ-123), an ETB receptor antagonist (BQ-788), endothelin-1, an endothelin-1 synthesis inhibitor (phosphoramidon), and vessel denudation to dissect the roles of each receptor in aging vasculature. Aged rats exhibited a higher myogenic tone than young rats, and the tone was sensitive to the ETA antagonist, BQ-123, but insensitive to the ETB antagonist, BQ-788. By contrast, the tone in the vessels from young rats was raised by BQ-788 but unaffected by BQ-123. When the endothelial layer that is normally enriched with ETB1 receptors was removed from young vessels, myogenic tone increased. However, denudation of the endothelial layer did not influence vessels from aged animals. This indicated that endothelial ETB1 receptors were not functional in the vessels from aged rats. There was also an increase in ETA receptor expression with age, whereas ETB receptor expression remained constant between young and aged animals. These results demonstrate that in young vessels, ETB1 receptors maintain a lower myogenic tone, but in aged vessels, a loss of ETB receptor activity allows ETA receptors in vascular smooth muscle cells to raise myogenic tone. Our findings have potentially important clinical implications for treatments to improve cerebral perfusion in older adults with diseases characterized by reduced cerebral blood flow.

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Dataset Information

Chronic Nebivolol Treatment Suppresses Endothelin-1-Mediated Vasoconstrictor Tone in Adults With Elevated Blood Pressure.

Publications

Chronic Nebivolol Treatment Suppresses Endothelin-1-Mediated Vasoconstrictor Tone in Adults With Elevated Blood Pressure.

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