Background: Use-dependent effects of antiarrhythmic drugs on phase 0 sodium current result in rate-dependent conduction slowing with important potential clinical consequences. The purpose of the present study was to determine whether state-dependent interactions of procainamide with sodium channels can be analyzed based on conduction changes in vivo.
Methods and results: Procainamide infusions were used to produce stable drug concentrations causing greater than or equal to 25% conduction slowing at a basic cycle length (BCL) of 300 msec in morphine/chloralose-anesthetized dogs with formalin-induced atrioventricular block. Computer-based epicardial activation mapping was applied to assess the time course and pattern of conduction over a wide range of BCLs before and after drug administration. Action potential duration was measured from recordings of monophasic action potentials. The onset and steady-state values of fractional sodium channel block estimated from conduction changes were fitted to equations obtained from a stepwise exponential analysis. The rate constant for the onset of block (lambda *) decreased, as predicted, with decreasing cycle length. The slope of the relation between lambda * and recovery time at each BCL averaged 0.29 +/- 0.03 sec-1, resulting in a calculated recovery time constant (3.4 seconds) similar to values previously obtained by direct measurement. Estimates of binding and unbinding rate constants for the sodium channel during the action potential plateau and after repolarization were of the same order as previous results obtained using microelectrode methods in vitro.
Conclusions: Use-dependent conduction changes produced by procainamide in vivo closely follow the predictions of mathematical models of drug-channel interactions, and underlying kinetic interactions with the sodium channel inferred from conduction changes agree with previous, more direct observations. These results support the relevance of basic concepts about antiarrhythmic drug actions on sodium channels for understanding drug effects on conduction in vivo and advance analytical tools that can be used to explore the latter in humans.