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.

1 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. 2 Clofilium (up to 20 microM) and d-sotalol (1 microM) did not decrease the Na current, the L-type Ca current or the background K current iKl, but significantly depressed the time-dependent delayed outward K current iK. 3 Clofilium partially decreased in a dose-dependent manner (1-20 microM) QON 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 microM) also decreased QON. Channel density estimated from the clofilium-sensitive ICM closely matched that of the delayed rectifier channels. 4 Clofilium and d-sotalol decreased QOFF 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. 5 In control conditions, QON 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 QON availability was observed, unmasking additional components. The reactivation kinetics of QON after a 500 ms inactivating pulse to 0 mV was not affected. 6 We conclude that delayed rectifier K channels significantly contribute to QON and QOFF 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.