Dissociation of cyclic AMP and contractile responses to isoprenaline: effects of a dihydropyridine derivative, nicardipine (YC-93), on canine ventricular muscle.
Nicardipine (YC-93), a 1,4-dihydropyridine derivative, inhibited the cyclic AMP phosphodiesterase (PDE) activity of purified PDE in a cell-free preparation. Its inhibitory action on the purified PDE was about seven times that of papaverine. On the other hand, YC-93 did not affect the intracellular cyclic AMP level and the accumulation of cyclic AMP caused by isoprenaline in the isolated canine right ventricular myocardium. YC-93 caused a prominent negative inotropic action which developed gradually to reach a steady level 1 h after its administration. The potency of YC-93 to depress the force of contraction was one tenth that of D600. The dose-response curve for isoprenaline was shifted to the right and downward in the presence of YC-93 in a concentration-dependent manner, and the positive inotropic action of calcium was also inhibited markedly by YC-93. The depressant action of YC-93 on the positive inotropic actions of isoprenaline and calcium was more prominent than that of D600. Although YC-93 is a potent PDE inhibitor in the cell-free preparation, the PDE in the intact cell system may be not accessible to the drug. Thus, it is considered that YC-93 acted as a calcium antagonistic drug on the isolated canine ventricular myocardium, and thereby inhibited the positive inotropic action of isoprenaline without affecting the intracellular accumulation of cyclic AMP caused by isoprenaline.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005711:Gallopamil / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009529:Nicardipine; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology*; D010208:Papaverine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D013806:Theophylline / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D011725:Pyridines; D014665:Vasodilator Agents; D005711:Gallopamil; D013806:Theophylline; D009529:Nicardipine; D010208:Papaverine; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D009543:Nifedipine; D007545:Isoproterenol; D002118:Calcium