title: Hyperpolarization induced by K+ channel openers inhibits Ca2+ influx and Ca2+ release in coronary artery.
abstract: The vasodilating mechanisms of the K+ channel openers--cromakalim, pinacidil, nicorandil, KRN2391, and Ki4032--were examined by measurement of the cytoplasmic Ca2+ concentration ([Ca2+]i) using the fura-2 method in canine or porcine coronary arterial smooth muscle. The five K+ channel openers all produced a reduction of [Ca2+]i in 5 and 30 mM KCl physiological salt solution (PSS), the effects of which were antagonized by tetrabutylammonium (TBA) or glibenclamide, but failed to affect [Ca2+]i in 45 and 90 mM MCl-PSS. Cromakalim and Ki4032 only partially inhibited the 30 mM KCl-induced contractures, whereas pinacidil, nicorandil, and KRN2391 nearly abolished contractions produced by high KCl-PSS. The increased [Ca2+]i and force produced by a thromboxane A2 analogue, U46619, were inhibited by K+ channel openers and verapamil. In the absence of extracellular Ca2+, U46619 induced a transient increase in [Ca2+]i with a contraction, which is effectively inhibited by cromakalim and Ki4032. Their inhibitory effects were blocked by TBA and counteracted by 20 mM KCl-induced depolarization. Cromakalim and Ki4032 did not affect caffeine-induced Ca2+ release. Cromakalim reduced U46619-induced IP3 production and TBA blocked this inhibitory effect. Thus, cromakalim and Ki4032 are more specific K+ channel openers than pinacidil, nicorandil, and KRN2391. The vasodilation related with a reduction of [Ca2+]i produced by K+ channel openers is due to the hyperpolarization of the plasma membrane resulting in not only the closure of voltage-dependent Ca2+ channels but also inhibition of the production of IP3 and Ca2+ release from intracellular stores related to stimulation of the thromboxane A2 receptor.
authors.affiliation: Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yanagisawa
authors.forename: T
authors.initials: T
authors.lastname: Yamagishi
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism*; D004285:Dogs; D005260:Female; D005453:Fluorescence; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020108:Nicorandil; D015221:Potassium Channels / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D015221:Potassium Channels; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C070492:N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate; D009536:Niacinamide; D020108:Nicorandil; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D002118:Calcium