Potentiating effect of nicorandil, an antianginal agent, on relaxation induced by isoproterenol in isolated rat aorta: involvement of cyclic GMP-inhibitable cyclic AMP phosphodiesterase.
In rat aortic rings, isoproterenol (ISO) 10(-9)-3 x 10(-6)M relaxed the contraction induced by phenylephrine (PE) 3 x 10(-7)M. Pretreatment with nicorandil 3 x 10(-7) and 3 x 10(-6) M potentiated the relaxation induced by ISO. Nicorandil 3 x 10(-6) M also potentiated the relaxations induced by forskolin 3 x 10(-9) - 10(-6) M and dibutylyl-cyclic AMP 3 x 10(-6) - 3 x 10(-4) M. Nitroglycerin (NTG) 10(-8) M, but not cromakalim 3 x 10(-8) M, also potentiated the ISO relaxation. Pretreatment with glyburide 10(-6) M or apamin 10(-6) M did not affect the potentiating action of nicorandil 3 x 10(-6) M. Pretreatment with methylene blue (MB) 10(-6) M, but not with NG-monomethyl-L-arginine (NMMA), however, markedly inhibited the potentiating effect of nicorandil. Removal of endothelium impaired the relaxation induced by ISO but did not inhibit the potentiating effect of nicorandil. In addition, in the presence of MCl-154 (10(-7) M), which itself potentiated ISO-induced relaxation, nicorandil 3 x 10(-6) M did not further potentiate the relaxing response to ISO. Furthermore, nicorandil 3 x 10(-6) M potentiated the increase in the tissue level of cyclic AMP caused by ISO 3 x 10(-7) M, whereas the nicorandil-induced increase in cyclic GMP levels were not affected by ISO. These results suggest that the potentiating effect of nicorandil on the relaxation induced by ISO is most likely due to inhibition of phosphodiesterase III (PDE III) by increased cyclic GMP levels.
Satake
N
N
Department of Pharmacology, University of Hawaii, School of Medicine, Honolulu 96822, USA.
Zhou
Q
Q
Morikawa
M
M
Inoue
M
M
Shibata
S
S
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000787:Angina Pectoris / Q000503:physiopathology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004357:Drug Synergism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D006152:Cyclic GMP; D007545:Isoproterenol