Comparison of the Effects of Several Calcium Antagonistic Drugs (Slow-Channel Blockers) on the Electrical and Mechanical Activities of Guinea Pig Papillary Muscle

Abstract

The effects of mesudipine (an analog of nifedipine), in comparison with those of verapamil and nifedipine, were studied on the normal fast action potentials (AP), the slow AP and the contractions of guinea pig papillary muscles. In papillary muscles perfused with normal Tyrode solution, mesudipine depressed (10-7 and 10-6 M) and abolished (10-5 M) contractions within 10-12 min. The maximal upstroke velocity (+.ovrhdot.Vmax) and overshoot of the fast AP were not affected, whereas the AP duration (at 50 and 90% repolarization, APD50, ADP90) was shortened: APD90 by 30% and APD50 by 36% at 10-5 M. In order to determine the effect of mesudipine on the slow AP, the fast Na+ channels were inactivated by partial depolarization (to .apprx. -40 mV) by perfusing with 25 mM K+-Tyrode solution. Slow-rising overshooting AP and contractions were elicited on stimulation when isoproterenol (10-6 M), theophylline (10-4 M), or histamine (10-5 M) were added. The slow-channel blockers verapamil (5 .times. 10-6 M) and nifedipine (10-7 M) completely blocked the slow AP. Mesudipine, at 4 .times. 10-8 M, depressed +.ovrhdot.Vmax, amplitude and duration of the isoproterenol-induced slow AP, whereas at 10-7 M, excitability was abolished within 12 min. The contractions accompanying the slow AP were depressed by mesudipine in a parallel manner. The effect of mesudipine on the slow AP was reversed by washout of the drug after 20-40 min. The dose/response curve for the mesudipine effect was shifted to the right in high Ca2+ concentration (5.4 mM). Lowering the stimulation frequency from 0.5 Hz (usual drive rate) to 0.1 Hz restored the slow AP blocked by 10-7 M mesudipine (< 20 min); after 20 min, the mesudipine block was independent of frequency. Mesudipine completely abolished the histamine-induced slow AP at 10-6 M and the theophylline-induced slow AP at 3 .times. 10-7 M. Mesudipine evidently has Ca2+ slow-channel blocking properties. This effect is not mediated by .beta.-adrenergic receptor antagonism. Mesudipine has about the same potency as nifedipine and is .apprx. 10 times more potent than verapamil.