MECHANISMS OF VASODILATION OF CEREBRAL VESSELS INDUCED BY THE POTASSIUM CHANNEL OPENER NICORANDIL IN CANINE IN-VIVO EXPERIMENTS

Background and Purpose Nicorandil, a potent antianginal agent characte rized as a potassium channel opener, could produce cerebrovascular dil ation in in vitro studies. Our aim was to investigate the pharmacologi c response to the topical application of nicorandil on the vasomotor t one of pial vessels in vivo. To elucidate its mechanism, we also studi ed the inhibitory action of methylene blue and glibenclamide against n icorandil-induced vasodilation. Methods In 14 dogs prepared with a par ietal cranial window, we administered five different concentrations of nicorandil solution (10(-7), 10(-6), 10(-5), 10(-4), and 10(-3) mol/L ) under the window and measured pial arteriolar and venular diameters. After pretreating pial vessels with either 10(-5) mol/L methylene blu e or 10(-5) mol/L glibenclamide, we examined inhibitory action after t he application of 10(-5) mol/L nicorandil. In additional experiments w ith 9 dogs, we evaluated the effects of nitroglycerin and cromakalim o n pial vessels in the absence or presence of 10(-5) mol/L methylene bl ue and 10(-5) mol/L glibenclamide, respectively. Results Nicorandil pr oduced significant, concentration-dependent dilation of pial vessels ( P<.05). Methylene blue blocked nicorandil-induced dilation, whereas gl ibenclamide only attenuated such action of nicorandil. Nitroglycerin a nd cromakalim also produced a concentration-dependent increase in pial arteriolar and venular diameters (P<.05), and those effects were bloc ked in the presence of methylene blue or glibenclamide, respectively. Conclusions Our in vivo study demonstrates that topical application of nicorandil dilates both pial arterioles and venules in a concentratio n-dependent manner and suggests that the mechanisms of such action are most likely due to both cyclic GMP-mediated vascular smooth muscle di lation and the regulation of K+ flux.