K+ channel-opening action contributes to the preventive effects of nicorandil on U46619-induced vasoconstriction of canine large coronary arteries in vivo.
The antispasmogenic effects of nicorandil on epicardial coronary artery vasoconstriction were compared with those of a K+ channel opener, cromakalim, and a nitrovasodilator, nitroglycerin, in open-chest dogs. Intracoronary administration of U46619 (0.5-1.0 micrograms), a stable thromboxane A2 analogue, reduced the external diameter of the left circumflex coronary artery with no marked alternations in systemic hemodynamics. This U46619-induced vasoconstriction of large epicardial coronary arteries was dose-dependently prevented by the intracoronary infusion of nicorandil (1-10 micrograms/kg/min), cromakalim (0.03 micrograms/kg/min) and nitroglycerin (1 micrograms/kg/min). After pretreatment with glibenclamide (3 mg/kg, i.v.), and ATP-sensitive K+ channel blocker, these effects of nicorandil and cromakalim were inhibited significantly, whereas the response to nitroglycerin remained unchanged. Nicorandil (3 micrograms/kg/min), cromakalim (0.03 micrograms/kg/min) and nitroglycerin (1 micrograms/kg/min) increased coronary blood flow. However, the inhibitory effects of each drug on the U46619-induced vasoconstriction were not influenced by the partial occlusion of the left circumflex coronary artery, which kept coronary blood flow constant. This indicates a direct antispasmogenic effect of K+ channel openers, which is independent of that mediated by the response to flow. Furthermore, our results suggest that, by this effect, nicorandil protects large coronary arteries from U46619-induced vasoconstriction.
Kamijo
T
T
Toxicology Research Laboratories, Chugai Pharmaceutical Co., Ltd., Nagano, Japan.
Iwai
T
T
Haruta
K
K
Takeda
K
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D019806:Cromakalim; D004285:Dogs; D005260:Female; D005905:Glyburide; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D015221:Potassium Channels / Q000819:agonists*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000008:administration & dosage; D011758:Pyrroles / Q000494:pharmacology; D013928:Thromboxane A2 / Q000008:administration & dosage / Q000031:analogs & derivatives; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D015221:Potassium Channels; D011450:Prostaglandin Endoperoxides, Synthetic; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D005905:Glyburide