Dissociation of cyclic AMP and contractile responses to isoprenaline: effects of a dihydropyridine derivative, nicardipine (YC-93), on canine ventricular muscle

Abstract

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.