A new site for the activation of cardiac calcium channels defined by the nondihydropyridine FPL 64176.
We examined the effects of a new ligand, FPLnM-64176, on L-type Ca++ channels in cardiac tissue. FPL 64176 (10-1 microM) enhanced Ca++ influx into neonatal rat ventricular myocytes, a response which was blocked by nifedipine. FPL 64176 had no effect on [3H]PN200-110 binding in rat ventricular membranes, but dramatically increased L-type Ca++ channel current amplitude. FPL 64176 (1 microM) slowed both the activation and the inactivation kinetics of the L-channel in neonatal rat ventricular cells. We also noted a hyperpolarizing shift in the threshold and peak potential of the Ca++ channel current-voltage relationship in response to the compound. Additionally, the binding site for FPL 64176 appeared to be located on the extracellular face of the channel. We conclude that FPL 64176 is a potent new activator of L-type Ca++ channels with a novel mechanism and site of action.
Rampe
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Marion Merrell Dow Research Institute, Cincinnati, Ohio.
Lacerda
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D000818:Animals; D001464:Barium / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D017275:Isradipine; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D016276:Ventricular Function
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D011758:Pyrroles; C071658:FPL 64176; D001464:Barium; D011188:Potassium; D002118:Calcium; D017275:Isradipine