"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 microM), cisapride (1 microM) 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 microM) decreased the inward rectifier K(+) current, an effect contributing to the proarrhythmic potential.