K+ channel-opening action and KRN2391-induced reduction of Ca2+ sensitivity of arterial smooth muscle.
To clarify the vasodilating mechanism of KRN2391, a novel vasodilator having a combined nitrate-like and K+ channel-opening action, we investigated its effects on membrane potentials, intracellular Ca2+ concentrations ([Ca2+]i) and force of contraction in canine coronary artery. KRN2391 hyperpolarized the membrane of arterial smooth muscle cells in 5 and 30 mM KCl-physiological salt solutions. KRN2391 reduced the increases in [Ca2+]i and force of contraction induced by 30 mM KCl-physiological salt solution and the effect on [Ca2+]i was almost abolished by 10(-5) M glibenclamide, although the effect on force of contraction was only partially inhibited. The [Ca2+]i-force curves in the presence of KRN2391 or the selective K+ channel openers Ki4032 and cromakalim were shifted to the right, as compared to the control curve determined by varying the extracellular Ca2+ concentration ([Ca2+]o). This finding indicates that these substances reduce the Ca2+ sensitivity of contractile elements (Ca2+ desensitization). The Ca(2+)-desensitizing action of KRN2391 was partly antagonized by 10(-5) M glibenclamide. There was no interaction between nitroglycerin and cromakalim or Ki4032. These results suggest that, in addition to the nitrate-like action, the opening of the K+ channel by KRN2391 reduces not only [Ca2+]i but also the Ca2+ sensitivity of contractile elements, resulting in vasodilatation.
Okada
Y
Y
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Yanagisawa
T
T
Yamagishi
T
T
Taira
N
N
D000818:Animals; D001158:Arteries / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D005260:Female; D005453:Fluorescence; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D005996:Nitroglycerin / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D015221:Potassium Channels; D011725:Pyridines; D014665:Vasodilator Agents; C070492:N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate; C074246:KI 4032; D011189:Potassium Chloride; D005996:Nitroglycerin; D005905:Glyburide; D002118:Calcium