Effects of the calmodulin inhibitor, trifluoperazine, on membrane potentials and slow action potentials of cultured heart cells.
The effects of an inhibitor of calmodulin, trifluoperazine (TFP), were determined on the electrical activity of cultured cell reaggregates derived from chick embryonic hearts (15-day-old). The cells exhibited naturally occurring slowly rising action potentials (APs) having a maximum rate of rise (+Vmax) of less than 35 V/s. After superfusion with 100 microM TFP, the maximal diastolic potential (MDP) decreased, within 30 min, from -66.0 to -55.5 mV. The frequency of discharge decreased, and there was also a decrease in AP amplitude and in +Vmax (from 10.0 to 4.9 V/s). By 90 min, all spontaneous activity had stopped, and the resting potential was about -10 mV. Input resistance increased, consistent with a decrease in K+ conductance. Hyperpolarization by current pulses did not allow the production of APs upon electrical stimulation, suggesting that the TFP blocks slow inward current (Isi). No recovery occurred upon washout (up to 48 h). Higher concentrations of TFP (200-500 microM), or injection of the inhibitor intracellularly be means of phosphatidylcholine liposomes, accelerated the time course of the blockade (e.g. within 15 min). In fresh (non-cultured) chick ventricle with fast-rising APs, TFP (400 microM) caused excitation-contraction uncoupling within 10 min, presumably by blocking the slow Ca2+ channels; the the fast APs were depressed (+Vmax) within 45 min, before any depolarization occurred. The cells became completely depolarized (Em congruent to -4 mV) by 195 min; hyperpolarization by current pulses did not allow the production of APs, suggesting that the fast Na+ channels were blocked.(ABSTRACT TRUNCATED AT 250 WORDS)
D000200:Action Potentials / Q000187:drug effects; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D002642:Chick Embryo; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects*; D008081:Liposomes / Q000138:chemical synthesis; D008345:Manganese / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010713:Phosphatidylcholines / Q000138:chemical synthesis; D013779:Tetrodotoxin / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D002147:Calmodulin; D008081:Liposomes; D010713:Phosphatidylcholines; D014268:Trifluoperazine; D008345:Manganese; D013779:Tetrodotoxin; D000244:Adenosine Diphosphate