Cardiac actions of phencyclidine in isolated guinea pig and rat heart: possible involvement of slow channels.
The mechanisms responsible for the positive inotropic effect of phencyclidine were studied in isolated preparations of guinea pig and rat heart. In electrically paced left atrial muscle preparations, phencyclidine increased the force of contraction; rat heart muscle preparations were more sensitive than guinea pig heart muscle preparations. The positive inotropic effect of phencyclidine was not significantly reduced by a combination of phentolamine and nadolol; however, the effect was competitively blocked by verapamil in the presence of phentolamine and nadolol. Inhibition of the outward K+ current by tetraethylammonium chloride also produced a positive inotropic effect; however, the effect of tetraethylammonium was reduced by phentolamine and nadolol, and was almost insensitive to verapamil. The inotropic effect of phencyclidine was associated with a marked prolongation of the action potential duration and a decrease in maximal upstroke velocity of the action potential, with no change in the resting membrane potential. In partially depolarized atrial muscle preparations, which were reactivated by elevation of the extracellular Ca2+ level and stimulation at a high voltage, phencyclidine markedly increased the amplitude and the duration of the slow action potentials. Rat heart muscle preparations had higher sensitivity to these effects of phencyclidine. The specific [3H]phencyclidine binding observed with membrane preparations from guinea pig ventricular muscle was saturable with a single class of high-affinity binding site. This binding was inhibited by verapamil, diltiazem, or nitrendipine, but not by ryanodine or tetrodotoxin. These results suggest that the positive inotropic effect of phencyclidine results from enhanced Ca2+ influx via slow channels, either by stimulation of the channels or secondary to inhibition of outward K+ currents.
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D000818:Animals; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010622:Phencyclidine / Q000378:metabolism / Q000494:pharmacology*; D010646:Phentolamine / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014316:Tritium
D007473:Ion Channels; D013757:Tetraethylammonium Compounds; D014316:Tritium; D007649:Ketamine; D010622:Phencyclidine; D011188:Potassium; D002118:Calcium; D010646:Phentolamine