IONIC BASIS FOR OPC-8212-INDUCED INCREASE IN ACTION-POTENTIAL DURATION IN ISOLATED RABBIT, GUINEA-PIG AND HUMAN VENTRICULAR MYOCYTES

Changes in transmembrane ionic currents induced by OPC-8212 dimethoxyb enzoyl)-l-piperazinyl]-2(1H)-quinoline), a recently introduced positiv e inotropic agent which lengthens cardiac action potential duration, w ere examined using whole-cell voltage-clamp techniques in single rabbi t, guinea pig and human ventricular myocytes. In rabbit, OPC-8212 (12 mumol/l) significantly increased membrane action potential duration me asured at 90% of repolarization by an average of 88 ms (from 462 +/- 2 5 to 550 +/- 35 ms, n = 4; P < 0.05). In rabbit this increase in durat ion was not associated with significant changes in either the inward r ectifier or transient outward K+ currents. The magnitude of the second ary inward current evoked from a holding potential of -50 mV was signi ficantly increased by 97 +/- 8% (n = 6; P < 0.01) while a demonstrable delayed rectifier outward current could not be identified in the rabb it myocytes examined at room temperature. In guinea pig ventricular my ocytes, where the delayed rectifier was large, 12 mumol/l OPC-8212 sig nificantly depressed the current by 58 +/- 10% (n = 6; P < 0.01). The effects of OPC-8212 in human ventricular myocytes obtained from the ex planted heart of a single patient having an idiopathic cardiomyopathy most closely resembled those observed in isolated rabbit ventricular m yocytes. Thus, in rabbit and a few human ventricular myocytes examined at room temperature, OPC-8212 appeared to lengthen cardiac membrane a ction potential duration primarily by increasing the amplitude of the secondary inward current believed to primarily represent current throu gh L-type Ca2+ channels. In guinea pig preparations, OPC-8212 also dec reased the delayed rectifier outward K+ current which also would accou nt for an increase in action potential duration. OPC-8212 could not be demonstrated to affect Na+ current inactivation in a manner similar t o that produced by 1 mg/l veratrine, a recognized Na + channel agonist , which dramatically slowed this process.