Differential Effects of the New Class III Agent Dofetilide on Potassium Currents in Guinea Pig Cardiomyocytes

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Abstract
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 (IKr) and its slow component (IKs), (b) inward rectifier potassium current (IK1), (c) fast sodium current (INa), and (d) L-type calcium current (ICa). Dofetilide in 10(-6) M reduced the amplitude of IKr to 61% of control currents, as measured by 200-ms test pulses and analysis of the deactivating tail currents of IKr. On the deactivating tail currents of IKs, 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 IKs. When the concentration of dofetilide was increased, these effects were more pronounced. Rapid application of the substance to the cells showed that IKr 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 IK1. 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 IKr, but also delays deactivation of IKs.

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