Analysis of the ionic basis for cocaine's biphasic effect on action potential duration in guinea-pig ventricular myocytes

The effects of cocaine on the duration of the cardiac action potential were investigated in isolated guinea-pig ventricular myocytes at 37 degrees C. Following a 10-min exposure of cells to 3 mu M cocaine, APD(90) increased significantly by +22+/-5% (n=6). In contrast, following a ten minute exposure to 30 or 100 mu M cocaine, APD(90) was reduced by -24+/-6% (n=5) and -53+/-2% (n=8), respectively. The ionic basis for cocaine's effects on the APD was investigated using the whole cell voltage-clamp technique at 37 degrees C. Cocaine produced a concentration-dependent reduction in the amplitude of I-K tail currents with an estimated IC50 of 4 mu M. The kinetics and voltage dependence of the cocaine-sensitive current indicate that cocaine selectively blocks a current identical to the E-4031 sensitive current I-Kr. No significant reduction of the slow component of I-K (I-Ks) was observed during exposure to 30 or 100 mu M cocaine. High (30 and 100 mu M) concentrations of cocaine also produced a significant reduction of both the L-type calcium current and the TTX-sensitive plateau current. Pre-treatment of cells with 10 mu M TTX also converted the APD-shortening effect of 30 mu M cocaine to one of APD-prolonging. This implies that cocaine block of a TTX-sensitive window current contributes to the APD-shortening effects produced by high concentrations of cocaine. We conclude that: (1) cocaine produces a biphasic concentration-dependent effect on repolarization in guinea-pig ventricular myocytes; and (2) this biphasic effect on repolarization results from differences in the sensitivity of inward and outward currents to the blocking effects of cocaine. (C) 1996 Academic Press Limited