Electrophysiological characterization of the class III activity of sotalol and its enantiomers. New interpretation of use-dependent effects

Abstract

1. Sotalol (Sotalex) and both its optical isomers were studied in electrophysiological experiments with respect to their class III activity of antiarrhythmic drugs. The three substances prolonged action potentials (AP) of guinea-pig papillary muscle and left atrium in concentrations greater than or equal to 3 mumol/l, whereas other AP parameters (resting potential, amplitude and upstroke velocity) remained unchanged. Similar results were observed if papillary muscles were partially depolarized by elevating the extracellular potassium concentration from 4.7 mmol/l to 10-12 mmol/l. 2. The effects of sotalol showed marked frequency dependence (0.017-2 Hz): At slow driving rates sotalol brought about an enhanced AP prolongation as measured by APD30 and APD90. 3. The results were compatible with numerical AP simulation studies on the basis of the assumption that sotalol inhibits time-dependent K-outward current. This leads to the consequence that longer control APs (at low driving rates) are prolonged more effectively by sotalol than shorter ones (at high driving rates). 4. Sotalol effects dynamically followed APD changes due to alterations of driving rate: If APD was decreased under increasing driving frequencies, AP prolongation was diminished. 5. Paired pulse experiments showed that class III activity of sotalol was preserved in premature or delayed single action potentials.