title: Comparison of the effects of several calcium antagonistic drugs on the electrical activity of guinea pig Purkinje fibers.
abstract: 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.
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects*; D006632:Histamine / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D006632:Histamine; D014700:Verapamil; C036653:mesudipine; D009543:Nifedipine; D007545:Isoproterenol