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



URL: http://www.clinicaltrials.gov. Unique identifier: NCT01395329.
From the Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder (K.J.D., B.L.S., C.A.D., T.D.B., D.L.B., J.J.G., C.A.D.); Department of Medicine, University of Colorado, Denver (B.L.S., C.A.D.); and Department of Medicine, Denver Health Medical Center, CO (B.L.S.).
Kyle J
KJ
Diehl
From the Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder (K.J.D., B.L.S., C.A.D., T.D.B., D.L.B., J.J.G., C.A.D.); Department of Medicine, University of Colorado, Denver (B.L.S., C.A.D.); and Department of Medicine, Denver Health Medical Center, CO (B.L.S.).
Brian L
BL
Stauffer
From the Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder (K.J.D., B.L.S., C.A.D., T.D.B., D.L.B., J.J.G., C.A.D.); Department of Medicine, University of Colorado, Denver (B.L.S., C.A.D.); and Department of Medicine, Denver Health Medical Center, CO (B.L.S.).
Caitlin A
CA
Dow
From the Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder (K.J.D., B.L.S., C.A.D., T.D.B., D.L.B., J.J.G., C.A.D.); Department of Medicine, University of Colorado, Denver (B.L.S., C.A.D.); and Department of Medicine, Denver Health Medical Center, CO (B.L.S.).
Tyler D
TD
Bammert
From the Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder (K.J.D., B.L.S., C.A.D., T.D.B., D.L.B., J.J.G., C.A.D.); Department of Medicine, University of Colorado, Denver (B.L.S., C.A.D.); and Department of Medicine, Denver Health Medical Center, CO (B.L.S.).
Danielle L
DL
Brunjes
From the Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder (K.J.D., B.L.S., C.A.D., T.D.B., D.L.B., J.J.G., C.A.D.); Department of Medicine, University of Colorado, Denver (B.L.S., C.A.D.); and Department of Medicine, Denver Health Medical Center, CO (B.L.S.).
Jared J
JJ
Greiner
From the Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder (K.J.D., B.L.S., C.A.D., T.D.B., D.L.B., J.J.G., C.A.D.); Department of Medicine, University of Colorado, Denver (B.L.S., C.A.D.); and Department of Medicine, Denver Health Medical Center, CO (B.L.S.). desouzac@colorado.edu.
Christopher A
CA
DeSouza
D000704:Analysis of Variance; D001795:Blood Pressure Determination; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D019332:Endothelin-1 / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000068577:Nebivolol / Q000627:therapeutic use*; D012016:Reference Values; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D019332:Endothelin-1; D014665:Vasodilator Agents; D000068577:Nebivolol
blood pressure; endothelin-1; metoprolol; nebivolol; vasoconstriction