Differential effects on action potential duration of class IA, B and C antiarrhythmic drugs: modulation by stimulation rate and extracellular K+ concentration.

1. Standard microelectrode techniques were used to study the effects on the action potential duration (APD) of canine Purkinje fibres of a therapeutic concentration of nine Class I antiarrhythmic drugs. At an extracellular K+ concentration of 5.6 mmol/L all nine agents reduced APD at all drive rates studied (range of interstimulus intervals = 200-1000 ms). At lower levels of K+, quinidine (5 mumol/L) and disopyramide (10 mumol/L) (Class Ia agents) revealed dual effects on APD. At the lowest levels of K+ (2 mmol/L) and the longest interstimulus interval used (2000 ms), both agents significantly prolonged APD. Under all other conditions, APD was either unchanged or reduced. Lignocaine, 15 mumol/L (Class Ib agent) reduced APD at all rates and all K+ concentrations and this effect was greatest at the slowest rates. 2. Flecainide (1 mumol/L) (Class Ic) shortened APD at K+ = 5.6 and 4 mmol/L but had no effect at K+ = 2 mmol/L. 3. We conclude that these data result from opposing drug actions on inward sodium and outward potassium currents flowing during the plateau of the action potential. 4. Class Ia drugs exhibit significant depression of both currents, with the resultant effect on APD being modulated by external K+ concentration and drive rate. 5. Class Ib agents predominantly depress the sodium current and hence shorten APD, and Ic compounds have intermediate actions. 6. These differential effects on APD must be considered when planning antiarrhythmic therapy, and are directly relevant to the proarrhythmic propensities of these agents.