Effect of Kil769, a novel K(+)-channel opener, on sensitivity to Ca2+ of contractile elements and inositol phosphate formation in porcine coronary artery.
To determine whether Kil769, a novel K(+)-channel opener, acts intracellularly in vasorelaxation, we compared the effects of Kil769 on force of contraction, intracellular Ca2+ concentration ([Ca2+]i) and inositol phosphate (IP1) formation with those of Ca(2+)-channel blockers in isolated porcine coronary artery. Kil769 (10 microM) and verapamil (1 microM), which produced submaximal relaxation, reduced the increase in [Ca2+]i and force of contraction induced by 25 mM KCl. Verapamil reduced [Ca2+]i and the force of contraction to a similar extent but Kil769 reduced force of contraction more strongly than it did [Ca2+]i. Kil769 also inhibited U46619 (9,11-dideoxy-9 alpha,11 alpha-methano-epoxy-PGF2 alpha)-induced IP1 formation and glibenclamide blocked its inhibitory effect. These results suggest that the opening of K+ channels induced by Kil769 reduces the Ca2+ sensitivity of contractile elements and inositol phospholipid hydrolysis which is related to the Ca2+ release from intracellular storage.
Yokoyama
T
T
Pharmaceutical Research Laboratory, Kirin Brewery Co. Ltd., Gunma, Japan.
Kasai
H
H
Okada
Y
Y
Izumi
H
H
Izawa
T
T
Ogawa
N
N
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016257:Fura-2 / Q000737:chemistry; D005905:Glyburide / Q000494:pharmacology; D006868:Hydrolysis; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis*; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D013552:Swine; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D007295:Inositol Phosphates; D015221:Potassium Channels; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C084622:Ki 1769; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D014700:Verapamil; D005905:Glyburide; D002118:Calcium; D016257:Fura-2