ELECTROPHYSIOLOGICAL PROPERTIES OF SD-3211, A NOVEL PUTATIVE CA-2+ ANTAGONIST, IN ISOLATED GUINEA-PIG AND RABBIT HEARTS

The cardiac effects of SD-3211, a novel non-dihydropyridine type of Ca2+ antagonist, were examined in isolated guinea pig and rabbit hearts using an electrophysiological technique. SD-3211 (10-6-10-5 M) shortened the action potential duration of guinea pig papillary muscles in a concentration-dependent manner without affecting the resting potential or the maximum upstroke velocity (V̇(max)). The V̇(max) of slow responses induced by high extracellular K+ and isoproterenol was inhibited by SD-3211 at concentrations of > 10-6 M. Elevation of extracellular Ca2+ by 2 mM reversed this inhibited response. The inhibitory effect of SD-3211 on the slow response was enhanced as the stimulation frequency was increased. In Langendorff-perfused rabbit hearts electrically driven at 2.0 Hz, SD-3211 (10-8-10-6 M) produced a concentration-dependent prolongation of the atrium-His bundle conduction time (A-H interval) as well as a reduction in the developed tension of ventricular muscle, whereas SD-3211 did not affect the His bundle-ventricular conduction time (H-V interval) significantly. The potency of SD-3211 in A-H prolongation was greater than those of diltiazem and bepridil, but weaker than those of nicardipine, nifedipine, and verapamil. The effect of SD-3211 on the A-H interval was more pronounced at higher stimulation frequencies. SD-3211 was intermediate between nicardipine and verapamil in its intensity of frequency-dependent effects on the A-H interval. These results suggest that SD-3211 has a preferential and frequency-dependent inhibitory action on cardiac slow Ca2+ channels.