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 (Vmax) 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 Vmax 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 Vmax 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 Vmax and membrane potential in the hyperpolarising direction thus producing enhanced depression of Vmax in depolarised cells. It is concluded that these long recovery times may explain the marked depression of conduction of normal sinus beats seen with these drugs. The selective depression of depolarised cells may be of clinical relevance in ischaemic states.