Block of gating currents related to K + channels as a mechanism of action of clofilium and d‐sotalol in isolated guinea‐pig ventricular heart cells

The possibility that the class III antiarrhythmic drugs clofilium and d‐sotalol might affect delayed rectifier potassium channels at the level of their gating currents was assessed with the whole‐cell patch‐clamp technique in guinea‐pig isolated ventricular heart cells. Clofilium (up to 20 μ M ) and d‐sotalol (1 μ M ) did not decrease the Na current, the L‐type Ca current or the background K current i Kl , but significantly depressed the time‐dependent delayed outward K current i K . Clofilium partially decreased in a dose‐dependent manner (1–20 μ M ) Q ON of intramembrane charge movements (ICM) elicited by a depolarizing pulse applied from a holding potential of −110 mV or following a 100 ms inactivating prepulse to −50 mV. D‐sotalol (1 μ M ) also decreased Q ON . Channel density estimated from the clofilium‐sensitive ICM closely matched that of the delayed rectifier channels. Clofilium and d‐sotalol decreased Q OFF seen on repolarization in a dose‐ and voltage‐dependent manner. The kinetics of the decay of the OFF gating currents were not affected, and only the fast phase was depressed. In control conditions, Q ON availability with voltage was most of the time well described by two inactivating components. In the presence of clofilium and d‐sotalol, a complex behaviour of Q ON availability was observed, unmasking additional components. The reactivation kinetics of Q ON after a 500 ms inactivating pulse to 0 mV was not affected. We conclude that delayed rectifier K channels significantly contribute to Q ON and Q OFF of ICM in guinea‐pig ventricular heart cells, besides Na and Ca channels, and that clofilium and d‐sotalol directly interact with these K channels proteins by affecting their gating properties.British Journal of Pharmacology (1999) 128 , 301–312; doi: 10.1038/sj.bjp.0702768