The present studies were performed to clarify the mechanism of action
of KRN2391 in various sizes of canine coronary artery. We used the res
ponses of isolated large and small coronary arteries and the changes i
n coronary blood flow (CBF) as indicators reflecting the responses of
conductive arteries and resistive arterioles, respectively. In isolate
d small coronary artery, the effect of KRN2391 (10(-8)-10(-5) M) was a
ntagonized by either methylene blue or glibenclamide. In isolated larg
e 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 o
f KRN2391, nicorandil os cromakalim produced an increase in CBF dose-d
ependently. Glibenclamide (5 mg/kg, i.v.) attenuated the increase in C
BF caused by KRN2391, nicorandil and cromakalim. ED(20), 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 administ
ration-of glibenclamide. These results suggest that the mechanism of a
ction of KRN2391 and nicorandil depends on the segment of coronary art
eries; 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 th
e size of the coronary artery decreases.