Van't Klooster Mariet P, Foadi Nilufar, Hage Axel, Stoetzer Carsten, Wegner Florian, Eberhardt Mirjam, Leffler Andreas
Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
Department of Neurology, Hannover Medical School, Hannover, Germany.
Eur J Pharmacol. 2016 Oct 15;789:119-126. doi: 10.1016/j.ejphar.2016.07.020. Epub 2016 Jul 9.
5-hydroxytryptamine 3 receptor (5-HT3 receptor) antagonists are administered for prevention and therapy of nausea and vomiting. Although regarded as safe therapeutics, they can also provoke arrhythmias by prolonging the QRS interval. However, the mechanisms mediating this cardiotoxicity are poorly understood. Here we investigated effects of 5-HT3 receptor antagonists on the cardiac Na(+) channel Nav1.5. We explored the interaction of dolasetron, tropisetron, granisetron and ondansetron on the human α-subunit Nav1.5 heterologously expressed in HEK293 cells. Sodium currents were explored by means of whole-cell patch clamp recordings. All four substances inhibited the Nav1.5 in a concentration and state-dependent manner. Dolasetron displayed the lowest blocking efficacy, and tropisetron was the most potent blocker with a half maximum blocking concentration of 18µM for tonic block of inactivated channels. Tropisetron was also the most potent use-dependent inhibitor, and it also induced a strong open -channel block. Both tonic and use-dependent block by tropisetron were abbreviated on the local-anesthetic insensitive mutant Nav1.5-F1760A. Co-administration of tropisetron and the local anesthetic bupivacaine or the hypnotic propofol augmented inhibition of Nav1.5. Our data demonstrate that 5-HT3 receptor antagonists induce a local-anesthetic like inhibition of Nav1.5, and that they display different blocking efficacies. Reports on a relevant cardiotoxicity of dolasetron as opposed to other 5-HT3 receptor antagonists do not seem to correlate with a block of Nav1.5. As inhibition of Nav1.5 was enhanced by propofol and bupivacaine however, it is possible that a combined administration of Na(+) channel blockers and 5-HT3 receptor antagonists can provoke arrhythmias.
5-羟色胺3受体（5-HT3受体）拮抗剂用于预防和治疗恶心与呕吐。尽管被视为安全的治疗药物，但它们也可通过延长QRS间期引发心律失常。然而，介导这种心脏毒性的机制尚不清楚。在此，我们研究了5-HT3受体拮抗剂对心脏钠通道Nav1.5的影响。我们探讨了多潘立酮、托烷司琼、格拉司琼和昂丹司琼对在HEK293细胞中异源表达的人α亚基Nav1.5的相互作用。通过全细胞膜片钳记录来研究钠电流。所有这四种物质均以浓度和状态依赖性方式抑制Nav1.5。多潘立酮的阻断效力最低，而托烷司琼是最有效的阻断剂，对于失活通道的强直阻断，其半数最大阻断浓度为18µM。托烷司琼也是最有效的使用依赖性抑制剂，并且它还诱导强烈的开放通道阻断。托烷司琼的强直阻断和使用依赖性阻断在局部麻醉不敏感突变体Nav1.5-F1760A上均缩短。托烷司琼与局部麻醉药布比卡因或催眠药丙泊酚联合给药可增强对Nav1.5的抑制作用。我们的数据表明，5-HT3受体拮抗剂可诱导类似局部麻醉药的对Nav1.5的抑制作用，并且它们表现出不同的阻断效力。与其他5-HT3受体拮抗剂相比，关于多潘立酮相关心脏毒性的报道似乎与对Nav1.5的阻断无关。然而，由于丙泊酚和布比卡因可增强对Nav1.5的抑制作用，因此钠通道阻滞剂与5-HT3受体拮抗剂联合给药有可能引发心律失常。
