Nifedipine Blocks Ondansetron Electrophysiological Effects in Rabbit Purkinje Fibers and Decreases Early Afterdepolarization Incidence

Rene      Rouet; Morel      Elvis Worou; Paolo      Emilio Puddu; Sandrine      Lemoine; Benoit      Plaud; Laurent      Salle; Jean-Louis      Gerard; Jean-Luc      Hanouz

doi:10.2174/157488412799218789

Abstract

We hypothesized that a high concentration of nifedipine (1 μM), known to inhibit at least 75%of L-type Ca++ current, might counteract proarrhythmic dose-dependent effects of ondansetron (0.1 to 10 μM) in rabbit Purkinje fibers. Ondansetron is a 5-HT3 receptor antagonist commonly prescribed to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery but may increase the risk of developing prolongation of the QT interval of the electrocardiogram, which can lead to an abnormal and potentially fatal heart rhythm and recently raised FDA concerns and warnings. Neostigmine, a quaternary nitrogen agent that was also used clinically concomitant to antiemetics after anesthesia was further investigated dose-dependently (0.1 to 10 μM) and at fixed concentration (10 μM) with 0.1 to 10 μM ondansetron. The protocol included use-dependent (1 to 0.33 Hz) studies. APD durations, triangulation and early after depolarization (EAD) incidence were assessed. Ondansetron increased APD50, APD70 and APD90 (0.01 > p < 0.05) dose-dependently. APD90 averaged 102±1%of baseline to 302±49%dose-dependently (p < 0.001) and, at the highest dose, increased to 511±73%reverse use-dependently (p < 0.001). EAD were seen at top concentrations (33%) which were increased at lower rates (50%). Neostigmine induced reverse use-dependent APD changes (p < 0.05) but no EAD. In preparations treated by nifedipine and ondansetron, APD90 changes averaged 101±2%of baseline to 151±8%dose-dependently (p < 0.01) and to 193±13%reverse use-dependently (p < 0.05) and no EAD were seen. Thus nifedipine significantly shortened ondansetron-induced APD changes (p < 0.01), whereas neostigmine only slightly shortened ondansetron-induced APD changes (p < 0.05). There was a tendency for increased incidence of EAD (p < 0.06) in the ondansetron and neostigmine group vs. neostigmine alone. It is concluded that inhibition of L-type Ca++ current by high concentration nifedipine may counteract the ondansetron effects on APD changes.

Keywords: Ondansetron, Neostigmine, Nifedipine, Rabbit Purkinje fibers, Action potential duration, Early afterdepolarization, electrophysiology in vitro, 5-HT3 receptor antagonist, APD durations, early after depolarization, L-type Ca++