Competitive inhibition of cardiac sodium channels by aprindine and lidocaine studied using a maximum upstroke velocity of action potential in guinea pig ventricular muscles

I Kodama, J Toyama and K Yamada

An interaction between aprindine and lidocaine on cardiac fast sodium channels was investigated in isolated guinea pig ventricular muscles. A conditioning clamp pulse was applied from -90 to 0 mV through the single sucrose gap voltage clamp, and the maximum upstroke velocity (Vmax) of action potential elicited after the clamp pulse was measured as an index of sodium channel availability. In the presence of aprindine (2 and 5 microM) or lidocaine (20 and 40 microM), Vmax of test action potential 100 msec after the clamp pulse was decreased progressively as the clamp pulse duration was prolonged. The time constant of this inactivated channel block by aprindine was much slower than by lidocaine. Vmax after a 1000 msec clamp pulse recovered exponentially with a time constant of 4.75 to 4.81 sec for aprindine and 254 to 260 msec for lidocaine. In the presence of both aprindine and lidocaine, Vmax recovered in dual exponential function, where the short and the long time constant corresponded to the values for single treatment with each drug. In preparations treated with aprindine alone the use-dependent decrease of Vmax was observed during stimulation trains at rates higher than 0.1 Hz. This use-dependent block was attenuated significantly after additional application of lidocaine resulted in a net increase in Vmax at 0.5 to 1.0 Hz. These findings suggest that aprindine and lidocaine may block the sodium channels by binding to a common receptor site with different kinetics, leading to a competitive displacement with each other at their high concentrations.

Volume 241, Issue 3, pp. 1065-1071, 06/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics