All issues > Volume 38(8); 1995

Original Article

J Korean Pediatr Soc. 1995;38(8):1093-1106. Published online August 15, 1995.

The Effects of Adriamycin on Ionic Currents in Single Cardiac Myocytes of the Rabbit

Sejung Sj Sohn¹

¹Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea

Abstract

Purpose
: The study objective was to elucidate the possible pathophysiologic mechanism of Ca overload by adriamycin (ADR) which is associated with ADR- induced cardiotoxicity.
Methods
: The effects of ADR on ionic currents were studied using the whole cell voltage clamp technique in single cardiac myocytes of the rabbit.
Results
: The magnitude of the inward tail current, recorded at -70mV after depolarizing the membrane to +40mV for 3ms, decreased progressively after perfusing ADR. The degree of suppression of the inward current was proportional to ADR concentration. The maximum activation of the inward currents was at -70mV. Their magnitude decreased and the transient outward current appeared at -20mV when repolarizing potential became less negative. ADR suppressed the inward currents, but did not affect the transient outward currents. When voltage-sensitive transient outward currents were blocked by 4-aminopyridine, the activation of the inward currents was also voltage dependent and at +1-mV, the outward current activated by increased intracellular Ca appeared. ADR abolished not only the inard currents but also this Ca-dependent outward current. The degree of recovery of the inward current after washout from ADR was proportional to ADR concentration and the time elapsed. The amplitudes of the inward currents in the presence of c-AMO, divided by membrane capacitance, were suppressed by ADR in dose-dependent manner and so was the degree of recovery after washout from ADR. Ca cuttent appeared normal in the single atrial cell of which the inward current was almost completely abolished by ADR. Ca currents in single ventricular cell treated with ADR were activated by the various depolarizing pulses from the holding potential of -40mV and the result of plotting of the amplitude of peak imward current against the membrane potential showed bell-shaped relationship which is typical of Ca current. In addition, because the magnitude of Ca current increased compared with that of normal Ca current, ADR seemed to augment Ca current. Isoprenaline enhanced Ca current in the presence of ADR, but could not reverse the inhibitory effect of high ADR concentration on the inward tail current.
Conclusion
: Ca overload is likely to result from the inhibitory effect of ADR on the inward current generated by Na/Ca exchange and on Ca-dependent outward current and the stimulatory effect on Ca current. Therefore, it may play an important role in ADR-induced cardiotoxicity.

Keywords :Adriamycin, Cardiotoxicity, Whole cell voltage clamp technique, Inward tail current, Na/Ca exchange, Ca-dependent outward current, Ca current