The group at C2 of N-ethylnicotinamide determines the vasodilator potencies and mechanisms of action of nicorandil and its congeners in canine coronary arteries.
The relaxant mechanisms of action of nicorandil and its congeners (SG-86, SG-103, SG-209 and SG-212) on large coronary arteries were investigated in isolated canine circumflex arteries contracted with 25 mmol/l KCl or 10(-7) mol/l U46619, a thromboxane A2 analogue. SG-212, SG-86, SG-209 and SG-103 were obtained by replacement of the nitroxy group of nicorandil by bromine, the hydroxy, acetoxy and nicotinoyloxy groups, respectively. Nicorandil (10(-6)-10(-3) mol/l), SG-212 (3 x 10(-4)-10(-2) mol/l), SG-209 (10(-4)-10(-2) mol/l), SG-103 (3 x 10(-4)-10(-2) mol/l), and SG-86 (10(-3)-10(-2) mol/l) all produced a concentration-dependent relaxation in KCl- or U46619-contracted arteries. The order of relaxant potency was as follows: Nicorandil much greater than SG-209 greater than SG-212 = SG-103 greater than SG-86. The relaxant effect of nicorandil was not affected by glibenclamide but antagonized by methylene blue. In the presence of glibenclamide, the concentration-relaxation curves for SG-209 underwent rightward parallel shifts. The relaxant effect of SG-209, however, was not affected by methylene blue. The concentration-relaxation curves for SG-212 underwent rightward parallel shifts only to a limited extent in the presence of glibenclamide, but they were not affected by methylene blue. The relaxant effect of SG-103 was affected by neither glibenclamide or methylene blue. The relaxant effect of SG-86 was not affected by glibenclamide. The relaxant effect of nicorandil accompanied an increase in cyclic-GMP levels but that of SG-209 did not.(ABSTRACT TRUNCATED AT 250 WORDS)
Satoh
K
K
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Yamada
H
H
Yoneyama
F
F
Taira
N
N
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D005260:Female; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D011189:Potassium Chloride / Q000037:antagonists & inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D011450:Prostaglandin Endoperoxides, Synthetic; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; C013524:N-ethylnicotinamide; D011189:Potassium Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid