Mechanism of action of KRN2391, a novel vasodilator, in canine mesenteric artery.

The present study was performed to clarify the mechanism of vasodilation of KRN2391 in canine mesenteric artery compared with those of nicorandil and cromakalim. We used the responses of isolated cranial mesenteric artery in vitro and changes in mesenteric blood flow in vivo as indicators reflecting the responses of a conductive artery and resistive arterioles, respectively. In isolated cranial mesenteric artery, KRN2391 (10(-8)-10(-5) M), nicorandil (10(-7)-10(-4) M) and cromakalim (10(-7)-10(-5) M) relaxed contractions caused by 25 mM KCl in a concentration-dependent manner. The concentration-relaxation curve for KRN2391 was shifted to the right by either methylene blue (10(-5) M) or glibenclamide (10(-6) M), but the inhibitory effect of methylene blue was more potent than that of glibenclamide. The concentration-relaxation curve for nicorandil was shifted to the right by methylene blue, but not by glibenclamide. In addition, the curve for cromakalim was shifted to the right by glibenclamide, but not by methylene blue. In in vivo experiments, the injections of KRN2391 (0.3-3 micrograms/kg), nicorandil (10-100 micrograms/kg) or cromakalim (1-10 micrograms/kg) into the mesenteric artery increased mesenteric blood flow in a dose-dependent manner. Glibenclamide (5 mg/kg, i.v.) attenuated the increase in mesenteric blood flow caused by KRN2391, nicorandil and cromakalim, but had no effect on that caused by nifedipine (1 microgram/kg). The ED20 value increased about 4.7-fold for KRN2391, 3.7-fold for nicorandil and 11.5-fold for cromakalim after administration of glibenclamide, as estimated from the % change to the absolute increase in mesenteric blood flow induced by nifedipine (1 microgram/kg).(ABSTRACT TRUNCATED AT 250 WORDS)