Possible involvement of nitric oxide-cGMP pathway in the negative chronotropic effect of CD-832, a novel dihydropyridine derivative.
Effects of zaprinast, an inhibitor of guanosine 3', 5'-cyclic monophosphate (cGMP)-specific phosphodiesterase, and methylene blue, an inhibitor of soluble guanylate cyclase, on the negative chronotropic response to CD-832, a novel dihydropyridine derivative with a nitrate moiety, and nifedipine were examined with isolated guinea-pig right atria in the presence and absence of isoproterenol. CD-832 and nifedipine produced concentration-dependent negative chronotropic effects both in the absence and presence of isoproterenol. In the absence of isoproterenol, the concentration-response curves for CD-832 and nifedipine were neither potentiated by zaprinast nor inhibited by methylene blue. In the presence of isoproterenol (10[-8] M), zaprinast produced a three-fold leftward shift of the concentration-response curve for CD-832, while methylene blue produced a three-fold rightward shift. The concentration-response curve for nifedipine was not affected by these agents. SIN-1, a nitric oxide (NO) donor, had no chronotropic effect in the absence of isoproterenol, but had a concentration-dependent negative chronotropic effect in the presence of isoproterenol: the beating rate decreased to values close to that in the absence of isoproterenol. These findings suggest that NO-cGMP mediated pathway is involved in the negative chronotropic actions of CD-832 under beta-adrenergic stimulation.
Noguchi
K
K
Pharmaceutical Research Laboratories, Taisho Pharmaceutical Co., Ltd., Ohmiya, Saitama, Japan. s15922@ccm.taisho.co.jp
Shijuku
T
T
Nakasone
C
C
Takahashi
K
K
Higuchi
S
S
Tanaka
Y
Y
Tanaka
H
H
Shigenobu
K
K
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*
C082828:CD 832; D002121:Calcium Channel Blockers; D009536:Niacinamide; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D006152:Cyclic GMP; D009543:Nifedipine; D007545:Isoproterenol