Use-dependent effects of cisapride on postrest action potentials in rabbit ventricular myocardium

Repercussions of cisapride-induced blocking effects on repolarisation of K+ channels in open and inactivated states investigated in rabbit ventricular myocardium during rest and under stimulation were compared with effects of K+-blocking drugs (4-aminopyridine, dofetilide, terikalant). Major lengthening in the first postrest action potential indicates affinity for closed channels. Gradual lengthening during stimulation implies affinity for open channels. Four (control. add-in, steady-state, washout) 20-min rest periods were alternated with regular stimulation (0.5 Hz). Each drug was added during add-in and steady-state periods. Similarly to dofetilide (10 nM) and terikalant (0.3 muM), cisapride (1 muM) increasingly lengthened action potentials during stimulation, whereas 4-aminopyridine (1 mM) prolonged mostly the first postrest action potential. Our results indicate that cisapride induced use-dependent lengthening of repolarisation, compatible with an affinity for open K+ channels. We also found that in isolated rabbit ventricular myocytes. cisapride (1-10 muM) decreased the inward rectifier K+ current, an effect contributing to the proarrhythmic potential. (C) 2001 Elsevier Science B.V. All rights reserved.