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 μg 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 β-blocker on endothelial vasodilation.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01395329.

Keywords: blood pressure; endothelin-1; metoprolol; nebivolol; vasoconstriction.

Figure 1

FBF responses to BQ-123 before and after 3 months of nebivolol (panel A), metoprolol (panel B) and placebo (panel C) intervention. Values are mean±SEM. *P<0.05 refers to the difference in the FBF responses to selective ET_A blockade before vs after intervention.

Figure 2

FBF responses to BQ-123 (100 nmol/min) alone and BQ-123 combined with BQ-788 (50 nmol/min) before and after 3 months of nebivolol (panel A), metoprolol (panel B) and placebo (panel C) intervention. Values are mean±SEM. *P<0.05 refers to the difference in the FBF responses to selective ET_A blockade before vs after intervention. †P<0.05 refers to the difference in the FBF response to non-selective ET_A/B blockade before vs after intervention.

Figure 3

FBF responses to acetylcholine (upper graphs) and sodium nitroprusside (lower graphs) before and after 3 months of nebivolol (panel A), metoprolol (panel B) and placebo (panel C) intervention. Values are mean±SEM. *P<0.05 vs before intervention.

Figure 4

FBF responses (upper panel) and total FBF (lower panel) to acetycholine in the absence or presence of non-selective ET_A/B blockade (BQ-123 +BQ-788) before and after nebivolol intervention. Values are mean±SEM. *P<0.05 vs saline.

Figure 5

FBF responses (upper panel) and total FBF (lower panel) to acetycholine in the absence or presence of non-selective ET_A/B blockade (BQ-123 +BQ-788) before and after metoprolol intervention. Values are mean±SEM. *P<0.05 vs saline.

Figure 6

FBF responses (upper panel) and total FBF (lower panel) to acetycholine in the absence or presence of non-selective ET_A/B blockade (BQ-123 +BQ-788) before and after placebo intervention. Values are mean+SEM. *P<0.05 vs saline.