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 Ca2+-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.
|Number of pages||19|
|Journal||Archives Internationales de Pharmacodynamie et de Therapie|
|Publication status||Published - 1993|
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