Comparative in vivo and in vitro study of the cardiac effects of midalcipran and imipramine.
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.
Laboratoire de Pharmacologie, Faculté de Médecine, Lille, France.
R H
RH
Rouet
J
J
Tisne-Versailles
M M
MM
Adamantidis
A
A
Vincent
B A
BA
Dupuis
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003521:Cyclopropanes / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D007099:Imipramine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D000078764:Milnacipran; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology
D000928:Antidepressive Agents; D003521:Cyclopropanes; D000078764:Milnacipran; D007099:Imipramine; D011188:Potassium