Rouet Rene, Worou Morel Elvis, Puddu Paolo Emilio, Lemoine Sandrine, Plaud Benoit, Salle Laurent, Gerard Jean-Louis, Hanouz Jean-Luc
Groupe Coeur et Ischémie EA3212, University of Caen, France.
Curr Clin Pharmacol. 2012 Feb 1;7(1):41-8. doi: 10.2174/157488412799218789.
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.
我们推测，已知可抑制至少75%L型Ca++电流的高浓度硝苯地平（1μM），可能会抵消昂丹司琼（0.1至10μM）在兔浦肯野纤维中促心律失常的剂量依赖性效应。昂丹司琼是一种5-HT3受体拮抗剂，常用于预防癌症化疗、放射治疗和手术引起的恶心和呕吐，但可能会增加心电图QT间期延长的风险，这可能导致异常且潜在致命的心律，最近引起了美国食品药品监督管理局（FDA）的关注并发出警告。新斯的明是一种季铵类药物，在麻醉后也与止吐药一起临床使用，我们进一步研究了其与0.1至10μM昂丹司琼的剂量依赖性（0.1至10μM）和固定浓度（10μM）的情况。该方案包括使用依赖性（1至0.33Hz）研究。评估了动作电位时程（APD）、三角测量和早期后去极化（EAD）发生率。昂丹司琼剂量依赖性地增加了APD50、APD70和APD90（0.01＞p＜0.05）。APD90平均从基线的102±1%剂量依赖性地增加到302±49%（p＜0.001），在最高剂量时，反向使用依赖性地增加到511±73%（p＜0.001）。在最高浓度时可见EAD（33%），在较低速率时增加（50%）。新斯的明诱导反向使用依赖性的APD变化（p＜0.05）但未见EAD。在硝苯地平和昂丹司琼处理的制剂中，APD90变化平均从基线的101±2%剂量依赖性地增加到151±8%（p＜0.01），反向使用依赖性地增加到193±13%（p＜0.05），未见EAD。因此，硝苯地平显著缩短了昂丹司琼诱导的APD变化（p＜0.01），而新斯的明仅轻微缩短了昂丹司琼诱导的APD变化（p＜0.05）。与单独使用新斯的明相比，昂丹司琼和新斯的明组中EAD的发生率有增加的趋势（p＜0.06）。结论是，高浓度硝苯地平抑制L型Ca++电流可能会抵消昂丹司琼对APD变化的影响。
