Onset and recovery kinetics of V̇max reduction by class I antiarrhythmic agents: Relation to frequency dependence

Abstract

AbstractThe onset and recovery kinetics of rate‐dependent n̈max reduction in guinea pig papillary muscles were measured for a new class I antiarrhythmic agent, bidisomide (SC‐40230), and compared to standard agents lidocaine, flecainide, and disopyramide. Frequency‐independent reduction of n̈max was found to be associated with long recovery time rather than onset kinetics or other factors, such as molecular weight. Bidisomide and flecainide had the slowest onset rates (τ=4 and 6 sec at 3.3 Hz, respectively) while lidocaine and disopyramide had much faster onset rates (τ=0.2 and 0.5 sec at 3.3 Hz, respectively). Recovery time constants were obtained by using the first n̈max value following a variable recovery time period after a stimulus train used to produce drug blockade. Flecainide and lidocaine had recovery time constants on the order of seconds (19 and 1 sec, respectively). Disopyramide, unlike previously reported, and bidisomide had very slow recovery time constants, on the order of minutes (2.4 and 8.8 min, respectively). The onset of n̈max reduction caused by bidisomide was most similar to flecainide, but the recovery time was most similar to disopyramide. The n̈max reduction caused by bidisomide and disopyramide was frequency‐independent (between 1 and 3.3 Hz), while that caused by flecainide and lidocaine was frequency‐dependent. Both bidisomide and disopyramide are frequency‐independent, which may be due to their long time constants for recovery from block.