DIFFERENTIAL-EFFECTS OF THE NEW CLASS-III AGENT DOFETILIDE ON POTASSIUM CURRENTS IN GUINEA-PIG CARDIOMYOCYTES

The electrophysiologic effects of dofetilide (UK 68,798), a new class III antiarrhythmic drug were investigated on the following currents in guinea pig left ventricular cardiomyocytes by whole-cell patch-clamp technique: (a) delayed rectifier potassium current with its fast component (I-Kr) and its slow component (I-Ks), (b) inward rectifier potassium current (I-K1), (c) fast sodium current (I-Na), and (d) L-type calcium current (I-Ca). Dofetilide in 10(-6)M reduced the amplitude of I-Kr to 61% of control currents, as measured by 200-ms test pulses and analysis of the deactivating tail currents of I-Kr. On the deactivating tail currents of I-Ks, dofetilide caused no significant amplitude change, but time constants of deactivation became 2.3 times slower, as measured by 2,000-ms test pulses and analysis of the deactivating tail currents of I-Ks. When the concentration of dofetilide was increased, these effects were more pronounced. Rapid application of the substance to the cells showed that I-Kr was reduced in the first minute to 60% of control currents. For complete current suppression, at least 3 min were necessary. The suppression effect remained unchanged during a 10-min washout phase. Dofetilide had no effect on I-K1. Neither were amplitudes and Hodgkin-Huxley parameters of sodium current influenced by dofetilide. Calcium currents were not blocked by dofetilide. Dofetilide is not only a highly selective blocker of I-Kr, but also delays deactivation of I-Ks.