K+ channel-opening action and KRN2391-induced reduction of Ca2+ sensitivity of arterial smooth muscle
Okada, Y.; Yanagisawa, T.; Yamagishi, T.; Taira, N.
Archives Internationales de Pharmacodynamie et de Therapie 326: 33-51
1993
ISSN/ISBN: 0003-9780 PMID: 8185411 Document Number: 409342
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 Ca-2+ concentrations ((Ca-2+)-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 (Ca-2+)-i and force of contraction induced by 30 mM KCl-physiological salt solution and the effect on (Ca-2+)i was almost abolished by 10-5 M glibenclamide, although the effect on force of contraction was only partially inhibited. The (Ca-2+)-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 Ca-2+ concentration ((Ca-2+)-o). This finding indicates that these substances reduce the Ca-2+ sensitivity of contractile elements (Ca-2+ 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 K14032. These results suggest that, in addition to the nitrate-like action, the opening of the K+ channel by KRN2391 reduces not only (Ca-2+)-i but also the Ca-2+ sensitivity of contractile elements, resulting in vasodilatation.