Mechanism of Action of KRN2391 in Canine Coronary Vascular Bed

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Abstract
The present studies were performed to clarify the mechanism of action of KRN2391 in various sizes of canine coronary artery. We used the responses of isolated large and small coronary arteries and the changes in coronary blood flow (CBF) as indicators reflecting the responses of conductive arteries and resistive arterioles, respectively. In isolated small coronary artery, the effect of KRN2391 (10(-8)-10(-5) M) was antagonized by either methylene blue or glibenclamide. In isolated large coronary artery, the vasorelaxant effect of KRN2391 (10(-8)-10(-5) M) and nicorandil (10(-7)-10(-4) M) were antagonized by methylene blue (10(-5) M) but not by glibenclamide (10(-6) M). The relaxant effect of cromakalim was antagonized by glibenclamide but not by methylene blue in isolated large coronary artery. Intracoronary arterial injection of KRN2391, nicorandil or cromakalim produced an increase in CBF dose-dependently. Glibenclamide (5 mg/kg, i.v.) attenuated the increase in CBF caused by KRN2391, nicorandil and cromakalim. ED20, the dose that produced an increase in CBF by 20 ml/min, increased about 5-fold for KRN2391 and nicorandil and about 12-fold for cromakalim after administration of glibenclamide. These results suggest that the mechanism of action of KRN2391 and nicorandil depends on the segment of coronary arteries; i.e., they show a nitrate action alone in large coronary artery, and a K-channel opening action in addition to a nitrate action as the size of the coronary artery decreases.