Session 22 : Pharmacologie cardiovasculaire

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Session 22 : Pharmacologie cardiovasculaire

207

DIFFERENTIAL ELECTROPHYSIOLOGIC EFFECTS OF DOLASETRON, ONDANSETRON AND GRANISETRON ON CARDIAC ACTION POTENTIALS RECORDED FROM RABBIT PURKINJE FIBERS AND VENTRICULAR MUSCLE

M.M. Adamantidis, B.M. Dumotier, R.C. Bordet and B.A. Dupuis.

Laboratoire de Pharmacologie, Faculté de Médecine,l Place de Verdun, 59045 Lille cedex, France.

Dolasetron, ondansetron and granisetron are 5-HT3 receptor antagonists that are used clinically to prevent nausea and vomiting induced by chemotherapy. They have been reported to cause ECG interval changes in cancer patients, namely increase in QRS duration and JT prolongation. Thus our aim was to compare their electrophysiological effects on the action potentials recorded from rabbit Purkinje fibers (PF) and ventricular cells (VC). Action potentials were recorded using standard glass microelectrodes in multicellular preparations stimulated at the rate of 1 Hz and 0.2 Hz.

In concentrations [C] from 0.1 to 30 µM, the three drugs resulted in a significant [C]-related depression in the maximal rate of phase 0 depolarization and action potential amplitude with in order of potency dolasetron>granisetron>ondansetron and with an intensity higher on PF than VC (e.g. 10 µM dolasetron decreased Vmax by -69% vs -45% respectively) and clear frequency-dependence. Ondansetron strongly lengthened the repolarization phase, this effect showing reverse rate-dependence (e.g. at 10 µM, +62% at 1 Hz, +122% at 0.2 Hz in PF) and leading at 30 µM early afterdepolarizations to occur in 2/6 PF and 2/6 VC. Dolasetron depressed strongly the plateau in PF without altering final repolarization. However, this latter was prolonged at 0.2 Hz (+19% at 10 µM). In contrast, dolasetron exerted prolonging effects in VC at both 1 Hz and 0.2 Hz (+20% and +33% respectively at 10 µM). No significant alteration in PF repolarization was obtained with granisetron which slightly lengthened action potential duration in VC (+8% at 10 µM).

Our results indicate that ondansetron affects predominantly repolarization phase whereas dolasetron and to a lesser extent granisetron predominantly alter depolarization, so fitting well with previous clinical data.

208

CISAPRIDE EFFECTS ON POSTREST ACTION POTENTIAL DURATION IN ISOLATED RABBIT VENTRICULAR MUSCLE: NO EVIDENCE FOR REVERSE USE-DEPENDENT BLOCK

B. Dumotier, M. Adamantidis, M. Bastide, R. Bordet, B. Dupuis

Laboratoire de Pharmacologie, Faculté de Médecine, place de Verdun, 59045 Lille Cédex, France.

Cisapride has been reported to exert reverse rate-dependent class III antiarrhythmic effects on action potential duration (APD) and to block the rapid component of the delayed rectifier current (IKr). We used standard microelectrode to investigate cisapride effects on APD in rabbit ventricular muscle and to precise whether drug-channel interaction takes place during rest or under stimulation. Regular pacing (0.5 Hz) was interrupted by four rest periods (20 min): predrug control (C), wash-in (W-I), steady-state (S-S) and wash-out (W-O). Cisapride (1 µM) prolonged APD increasingly with repetitive pacing during 40 min of W-I, 10 min of S-S and 10 min of W-O periods, this suggesting an use-dependent blocking effect at channel level. The intensity of this effect was different depending on the plateau height. APD was more prolonged in APs with low plateau (n=8) as compared with APs with high plateau (n=9): at 10 min, +17

± 2% vs +13± 3% in W-I, +56± 8% vs +32± 6% (p