Comparison of the effects of several calcium antagonistic drugs on the electrical activity of guinea pig Purkinje fibers.

The effects of several slow channel blockers were compared on the normal fast action potentials (APs) and the slow APs of guinea pig Purkinje fibers. In spontaneously-firing Purkinje fibers perfused with normal Tyrode solution, mesudipine (analog of nifedipine) at 10(-7) and 10(-6) M, had no significant effect on the fast AP parameters (at 5 X 10(-6) M, excitability was abolished due to depolarization to about -45 mV). Washout of the drug rapidly (within 3 min) repolarized the preparations and restored automatic activity. In order to determine the effect of the calcium antagonists on the slow APs, the fast Na+ channels were inactivated by partial depolarization (to about -45 mV) by perfusing with 20 mM K+-Tyrode solution and isoproterenol (10(-6) M), or histamine (10(-5) M) were used to induce slow APs upon stimulation. Verapamil (10(-6) M) and nifedipine (10(-7) M) completely blocked the slow APs. Mesudipine at 10(-8) and 4 X 10(-8) M depressed the Vmax, amplitude and duration of the slow APs and abolished excitability within 11 min at 10(-7) M. At 10(-7) M, mesudipine blocked the slow APs earlier (within 3 min) at higher stimulation frequency (from the usual drive rate of 0.5-1.5 Hz). Lowering the stimulation frequency to 0.1 Hz restored the slow APs; however, the mesudipine block was independent of the stimulating frequency after 20 min. The dose/response curve for the mesudipine effect was shifted to the right in high Ca2+ concentration (5.4 mM). Washout of mesudipine and nifedipine restored the slow APs within 15 min, whereas verapamil required about 1 h. The results indicate that mesudipine has potent Ca2+ slow channel blocking properties in Purkinje fibers. Mesudipine and nifedipine are about ten times more potent than verapamil. This effect is not mediated by beta-adrenergic receptor antagonism, because the histamine-induced slow APs were also blocked.