Analysis of the Ionic Basis for Cocaine's Biphasic Effect on Action Potential Duration in Guinea-pig Ventricular Myocytes

Abstract

The effects of cocaine on the duration of the cardiac action potential were investigated in isolated guinea-pig ventricular myocytes at 37°C. Following a 10-min exposure of cells to 3 μ mcocaine, APD 90increased significantly by +22±5% ( n=6). In contrast, following a ten minute exposure to 30 or 100 μ mcocaine, APD 90was 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°C. Cocaine produced a concentration-dependent reduction in the amplitude of I Ktail currents with an estimated IC 50of 4 μ 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 μ mcocaine. High (30 and 100 μ 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 μ mTTX also converted the APD-shortening effect of 30 μ mcocaine 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.