title: Nebivolol, but not metoprolol, lowers blood pressure in nitric oxide-sensitive human hypertension.
abstract: 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.
authors.affiliation: From the Vanderbilt Autonomic Dysfunction Center and Division of Clinical Pharmacology, Department of Medicine (L.E.O., A.G., C.A.S., A.C.A., B.K.B., S.R.R., D.R., I.B.), and Departments of Pharmacology (S.R.R., D.R., I.B.), Neurology (D.R.), and Biostatistics (L.C.), Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Okamoto
authors.affiliation: From the Vanderbilt Autonomic Dysfunction Center and Division of Clinical Pharmacology, Department of Medicine (L.E.O., A.G., C.A.S., A.C.A., B.K.B., S.R.R., D.R., I.B.), and Departments of Pharmacology (S.R.R., D.R., I.B.), Neurology (D.R.), and Biostatistics (L.C.), Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Gamboa
authors.affiliation: From the Vanderbilt Autonomic Dysfunction Center and Division of Clinical Pharmacology, Department of Medicine (L.E.O., A.G., C.A.S., A.C.A., B.K.B., S.R.R., D.R., I.B.), and Departments of Pharmacology (S.R.R., D.R., I.B.), Neurology (D.R.), and Biostatistics (L.C.), Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Cyndya A
authors.initials: CA
authors.lastname: Shibao
authors.affiliation: From the Vanderbilt Autonomic Dysfunction Center and Division of Clinical Pharmacology, Department of Medicine (L.E.O., A.G., C.A.S., A.C.A., B.K.B., S.R.R., D.R., I.B.), and Departments of Pharmacology (S.R.R., D.R., I.B.), Neurology (D.R.), and Biostatistics (L.C.), Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Arnold
authors.affiliation: From the Vanderbilt Autonomic Dysfunction Center and Division of Clinical Pharmacology, Department of Medicine (L.E.O., A.G., C.A.S., A.C.A., B.K.B., S.R.R., D.R., I.B.), and Departments of Pharmacology (S.R.R., D.R., I.B.), Neurology (D.R.), and Biostatistics (L.C.), Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Leena
authors.initials: L
authors.lastname: Choi
authors.affiliation: From the Vanderbilt Autonomic Dysfunction Center and Division of Clinical Pharmacology, Department of Medicine (L.E.O., A.G., C.A.S., A.C.A., B.K.B., S.R.R., D.R., I.B.), and Departments of Pharmacology (S.R.R., D.R., I.B.), Neurology (D.R.), and Biostatistics (L.C.), Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Black
authors.affiliation: From the Vanderbilt Autonomic Dysfunction Center and Division of Clinical Pharmacology, Department of Medicine (L.E.O., A.G., C.A.S., A.C.A., B.K.B., S.R.R., D.R., I.B.), and Departments of Pharmacology (S.R.R., D.R., I.B.), Neurology (D.R.), and Biostatistics (L.C.), Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: Satish R
authors.initials: SR
authors.lastname: Raj
authors.affiliation: From the Vanderbilt Autonomic Dysfunction Center and Division of Clinical Pharmacology, Department of Medicine (L.E.O., A.G., C.A.S., A.C.A., B.K.B., S.R.R., D.R., I.B.), and Departments of Pharmacology (S.R.R., D.R., I.B.), Neurology (D.R.), and Biostatistics (L.C.), Vanderbilt University School of Medicine, Nashville, TN.
authors.forename: David
authors.initials: D
authors.lastname: Robertson
authors.affiliation: From the Vanderbilt Autonomic Dysfunction Center and Division of Clinical Pharmacology, Department of Medicine (L.E.O., A.G., C.A.S., A.C.A., B.K.B., S.R.R., D.R., I.B.), and Departments of Pharmacology (S.R.R., D.R., I.B.), Neurology (D.R.), and Biostatistics (L.C.), Vanderbilt University School of Medicine, Nashville, TN. Italo.biaggioni@vanderbilt.edu.
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage; D000368:Aged; D001578:Benzopyrans / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage*; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism*; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D000068577:Nebivolol; D009569:Nitric Oxide; D008790:Metoprolol
keywords: autonomic nervous system; hypertension; nebivolol; nitric oxide