Rouet R H, Tisne-Versailles J, Adamantidis M M, Vincent A, Dupuis B A
Laboratoire de Pharmacologie, Faculté de Médecine, Lille, France.
Fundam Clin Pharmacol. 1989;3(3):237-44. doi: 10.1111/j.1472-8206.1989.tb00454.x.
Midalcipran is a new antidepressant drug inhibiting both noradrenaline and serotonin uptake without any postsynaptic and anticholinergic activities. Its cardiac effects were compared with those of imipramine, a tricyclic antidepressant drug. In anaesthetised guinea-pigs intravenous perfusion of imipramine and midalcipran (1 ml/min from a solution at 0.66 mg/ml) brought about ventricular arrhythmias, respectively at 16.5 and 26.4 mg/kg and cardiac arrest at 58 and 97 mg/kg. The safety index (ratio of i.v. lethal dose and ED50 evaluated by the yohimbine test) is 22 times wider for midalcipran than imipramine. In in vitro studies on guinea-pig ventricular myocardium, imipramine exerted a greater class 1 antiarrhythmic effect than midalcipran. The reduction of Vmax was significant at 3 X 10(-6) M for imipramine and 1 X 10(-5) M for midalcipran in normal (4 mM K+) and hyperpolarizing (2.7 mM K+) conditions. At the concentration of 1 X 10(-5) M midalcipran significantly lengthened, whereas imipramine non significantly shortened the action potential durations (APD50, APD90). The results provide confirmation of a lesser depression in sodium conductance with midalcipran as compared to imipramine. Therefore it is proposed that less adverse cardiac effects may be observed at therapeutic doses.
米氮平是一种新型抗抑郁药，可抑制去甲肾上腺素和5-羟色胺的摄取，且无任何突触后和抗胆碱能活性。将其心脏效应与三环类抗抑郁药丙咪嗪的心脏效应进行了比较。在麻醉的豚鼠中，静脉灌注丙咪嗪和米氮平（以0.66mg/ml的溶液，1ml/分钟）分别在16.5mg/kg和26.4mg/kg时引起室性心律失常，在58mg/kg和97mg/kg时引起心脏骤停。米氮平的安全指数（通过育亨宾试验评估的静脉致死剂量与ED50之比）比丙咪嗪宽22倍。在豚鼠心室肌的体外研究中，丙咪嗪比米氮平具有更强的Ⅰ类抗心律失常作用。在正常（4mM钾）和超极化（2.7mM钾）条件下，丙咪嗪在3×10（-6）M时Vmax的降低显著，米氮平在1×10（-5）M时Vmax的降低显著。在1×10（-5）M的浓度下，米氮平显著延长动作电位持续时间（APD50、APD90），而丙咪嗪则非显著缩短动作电位持续时间。结果证实，与丙咪嗪相比，米氮平对钠电导的抑制作用较小。因此，有人提出在治疗剂量下可能观察到较少的不良心脏效应。
