Mechanisms of vasodilation of cerebral vessels induced by the potassium channel opener nicorandil in canine in vivo experiments.
OBJECTIVE
Nicorandil, a potent antianginal agent characterized as a potassium channel opener, could produce cerebrovascular dilation in in vitro studies. Our aim was to investigate the pharmacologic response to the topical application of nicorandil on the vasomotor tone of pial vessels in vivo. To elucidate its mechanism, we also studied the inhibitory action of methylene blue and glibenclamide against nicorandil-induced vasodilation.


METHODS
In 14 dogs prepared with a parietal 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 arterial and venular diameters. After pretreating pial vessels with either 10(-5) mol/L methylene blue or 10(-5) mol/L glibenclamide, we examined inhibitory action after the application of 10(-5) mol/L nicorandil. In additional experiments with 9 dogs, we evaluated the effects of nitroglycerin and cromakalim on pial vessels in the absence or presence of 10(-5) mol/L methylene blue and 10(-5) mol/L glibenclamide, respectively.


RESULTS
Nicorandil produced significant, concentration-dependent dilation of pial vessels (P < .05). Methylene blue blocked nicorandil-induced dilation, whereas glibenclamide only attenuated such action of nicorandil. Nitroglycerin and cromakalim also produced a concentration-dependent increase in pial arteriolar and venular diameters (P < .05), and those effects were blocked 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 concentration-dependent manner and suggests that the mechanisms of such actions are most likely due to both cyclic GMP-mediated vascular smooth muscle dilation and the regulation of K+ flux.
Ishiyama
T
T
Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Japan.
Dohi
S
S
Iida
H
H
Akamatsu
S
S
Ohta
S
S
Shimonaka
H
H
D000287:Administration, Topical; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology; D019806:Cromakalim; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004285:Dogs; D005905:Glyburide / Q000494:pharmacology; D008751:Methylene Blue / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020108:Nicorandil; D005996:Nitroglycerin / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply* / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014699:Venules / Q000187:drug effects
D001578:Benzopyrans; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; D005996:Nitroglycerin; D005905:Glyburide; D008751:Methylene Blue; D004121:Dimethyl Sulfoxide