Voltage- and time-dependent depression of maximum rate of depolarisation of guinea-pig ventricular action potentials by two new antiarrhythmic drugs, flecainide and lorcainide

Abstract

The voltage- and rate-dependence of the depression of the maximum rate of depolarisation (V̇_max) by therapeutic concentrations of flecainide and lorcainide were studied in guinea-pig ventricle by standard microelectrode techniques. At normal resting potentials the drugs produced only minor depression of V̇_max in the absence of stimulation (“resting block”) but trains of stimuli at inter-stimulus intervals (ISI) less than 4800 ms led to an exponential decline in V̇_max to a new plateau over 20 to 50 beats. This “rate-dependent block” (RDB) increased with rate over the range ISI – 4800 ms to ISI = 200 ms. The rates of onset of RDB in response to sudden increases in rate were very similar for both drugs and significantly slower than those reported for other anti-arrhythmic drugs. The time constants of recovery from RDB were 15.5±0.5s for flecainide and 13.2±1.3s for lorcainide. Both drugs shifted the steady-state relationship between V̇_max and membrane potential in the hyperpolarising direction thus producing enhanced depression of V_max in depolarised cells.