Release of endothelial nitric oxide in coronary arteries by celiprolol, a beta(1)-adrenoceptor antagonist: possible clinical relevance.
Mechanisms underlying celiprolol-induced vasodilatation were analyzed in isolated porcine coronary arteries. Celiprolol induced dose-related relaxation of the artery rings with endothelium, an effect which was suppressed by N(G)-nitro-L-arginine methylester (L-NAME), nitric oxide (NO) scavenger, guanylate cyclase inhibitor, endothelium denudation, and removal of Ca(2+). L-NAME contracted, and superoxide dismutase relaxed, the arteries only when the endothelium was preserved. Neither superoxide dismutase nor beta-adrenoceptor antagonists changed celiprolol-induced relaxations. Celiprolol increased the cyclic GMP content in the tissue. The release of NO from endothelium, estimated by the extracellular production of cyclic GMP in arteries incubated in medium containing guanylate cyclase and GTP, was augmented by celiprolol, and L-NAME abolished this action of celiprolol. It is concluded that celiprolol elicits relaxation by acting on sites other than beta-adrenoceptors in the endothelium and by releasing NO, which activates soluble guanylate cyclase in smooth muscle and produces cyclic GMP. Scavenging of superoxide anions from the endothelium does not seem to account for the induced relaxation.
Research Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho-Monguchi-cho, isshoin, Minami-ku, 601-8550, Kyoto, Japan.
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Noda
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Oka
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Kitazawa
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Ukai
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Toda
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017272:Celiprolol / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase / Q000494:pharmacology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D017272:Celiprolol; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester