"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.
Dumotier
B M
BM
Novartis Pharma AG, Toxicology-Pathology, WSH 2881.230A, CH 4002, Bale, Switzerland.
Bastide
M
M
Adamantidis
M M
MM
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D020117:Cisapride / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006352:Heart Ventricles / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D010627:Phenethylamines; D010880:Piperidines; D013449:Sulfonamides; D015761:4-Aminopyridine; C063899:terikalant; C063533:dofetilide; D020117:Cisapride