title: Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism.
abstract: Nebivolol, a beta 1 selective adrenergic receptor antagonist with additional properties, is a racemic mixture of (S,R,R,R)- and (R,S,S,S)-enantiomers. We investigated its effects on human forearm vasculature. Blood flow was measured using venous occlusion plethysmography during brachial artery infusion of drugs. Interaction between nebivolol and the L-arginine/nitric oxide pathway was investigated via comparison with carbachol (an endothelium-dependent agonist) and nitroprusside, and by coinfusion of a competitive inhibitor of nitric oxide synthase, NG-monomethyl L-arginine (LNMMA) +/- L-arginine. Nebivolol (354 micrograms/min) increased blood flow by 91 +/- 18% (mean +/- SEM, n = 8, P < .01) whereas an equimolar dose of atenolol had no significant effect. L-NMMA (1 mg/min) inhibited vasodilation to nebivolol (by 65 +/- 10%) and carbachol (by 49 +/- 8%) to a significantly greater extent than it reduced responses to nitroprusside. Inhibition of nebivolol response by L-NMMA was abolished by L-arginine (62 +/- 11% inhibition by L-NMMA, 15 +/- 17% inhibition by L-NMMA with L-arginine, 10 mg/min, n = 8). Vasodilation caused by the (S,R,R,R)- and (R,S,S,S)-enantiomers was similar. We conclude that nebivolol vasodilates human forearm vasculature via the L-arginine/nitric oxide pathway.
authors.affiliation: Department of Clinical Pharmacology, United Medical School, Guy's Hospital, London, England.
authors.forename: J R
authors.initials: JR
authors.lastname: Cockcroft
authors.forename: P J
authors.initials: PJ
authors.lastname: Chowienczyk
authors.forename: S E
authors.initials: SE
authors.lastname: Brett
authors.forename: C P
authors.initials: CP
authors.lastname: Chen
authors.forename: A G
authors.initials: AG
authors.lastname: Dupont
authors.forename: L
authors.initials: L
authors.lastname: Van Nueten
authors.forename: S J
authors.initials: SJ
authors.lastname: Wooding
authors.forename: J M
authors.initials: JM
authors.lastname: Ritter
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D001578:Benzopyrans / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001916:Brachial Artery / Q000187:drug effects* / Q000502:physiology; D004983:Ethanolamines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D000068577:Nebivolol; D009569:Nitric Oxide / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D019323:omega-N-Methylarginine
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D014665:Vasodilator Agents; D000068577:Nebivolol; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine