Abstract
The effects of clofilium and its tertiary homolog, LY97119 (LY), on K+ currents in isolated ventricular myocytes from adult rat were examined using the whole-cell patch-clamp technique. Acute exposure (less than 30 min) to high concentrations of clofilium (30-100 microM) produced a slowly developing reduction in the peak of the transient outward current (Ito) and an apparent increase in the rate of current inactivation. In addition, inhibition exhibited a marked dependence on the frequency of stimulation (i.e., use-dependent inhibition). For "short" exposure times (i.e., less than 30 min), steady-state inhibition was not attained. Therefore, myocytes were preincubated with clofilium for at least 3 hr before use. Under these conditions, the median inhibitory concentration for steady-state use-dependent inhibition of Ito was 0.5 microM. Recovery of Ito from use-dependent inhibition followed a biexponential time course; tau fast = 75 msec, tau slow = 17 sec. The relative magnitude of the slow component (but not its time constant) increased with higher clofilium concentrations. LY, like clofilium, also induced a time-dependent inhibition of Ito (median inhibiting concentration 0.9 microM). However, unlike clofilium, steady state with LY was reached within 5 min. Furthermore, LY (3 microM) produced very little use-dependent inhibition (29% at 1 Hz compared with 92% for clofilium). This is possibly due to a "fast" unbinding rate upon repolarization (tau = 1.8 s). In contrast to clofilium, LY (1-10 microM) also inhibited the inward rectifier (IK1). The present results suggest that inhibition of Ito may contribute to clofilium's class III antiarrhythmic action.
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