In Vivo Canine Model Comparison of Cardiovascular Effects of Antidepressants Milnacipran and Imipramine

• Published in: Cardiovascular toxicology 2010-12, Vol.10 (4), p.275-282
• Main Authors: Mitsumori, Yoshitaka, Nakamura, Yuji, Hoshiai, Kiyotaka, Nagayama, Yukitoshi, Adachi-Akahane, Satomi, Koizumi, Schuichi, Matsumoto, Masahiko, Sugiyama, Atsushi
• Format: Article
• Language: English
• Subjects: Adrenergic Uptake Inhibitors - administration & dosage; Adrenergic Uptake Inhibitors - blood; Adrenergic Uptake Inhibitors - pharmacology; Adrenergic Uptake Inhibitors - toxicity; Animals; Antidepressants; Antidepressive Agents, Tricyclic - administration & dosage; Antidepressive Agents, Tricyclic - blood; Antidepressive Agents, Tricyclic - pharmacology; Antidepressive Agents, Tricyclic - toxicity; Biomedical and Life Sciences; Biomedicine; Blood pressure; Cardiology; Catheters; Comparative analysis; Cyclopropanes - administration & dosage; Cyclopropanes - blood; Cyclopropanes - pharmacology; Cyclopropanes - toxicity; Depression, Mental; Diagnosis; Dogs; Dose-Response Relationship, Drug; Drug dosages; Effective refractory period; Electrocardiography; Electrophysiologic Techniques, Cardiac; Female; Heart Conduction System - drug effects; Hemodynamics - drug effects; Imipramine; Imipramine - administration & dosage; Imipramine - blood; Imipramine - pharmacology; Imipramine - toxicity; Infusions, Intravenous; Interdisciplinary aspects; Long QT Syndrome - chemically induced; Long QT Syndrome - physiopathology; Male; Medicine; Milnacipran; Monophasic action potential; Pharmacology; Pharmacology/Toxicology; Risk Assessment; Serotonin; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - blood; Serotonin Uptake Inhibitors - pharmacology; Serotonin Uptake Inhibitors - toxicity; Sinuses; Time Factors; Torsades de pointes; Veins & arteries; Ventricular Function - drug effects
• ISSN: 1530-7905; 1559-0259
• DOI: 10.1007/s12012-010-9084-9

Milnacipran is a specific serotonin and norepinephrine reuptake inhibitor, which has been widely used against major depressive episodes. In this study, cardiovascular effects of milnacipran were assessed in comparison with those of a typical tricyclic antidepressant imipramine using the halothane-anesthetized dogs. Milnacipran (n = 6) or imipramine (n = 6) was intravenously administrated in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. Clinically relevant plasma concentrations were obtained after 0.1-1 mg/kg of milnacipran in this study, whereas therapeutic dose and plasma concentration of imipramine were reported to be similar to those of milnacipran. The low and middle doses of milnacipran hardly affected cardiohemodynamic or electrophysiological variables except that they slightly increased vascular tone and ventricular contraction, whereas same doses of imipramine delayed repolarization process without affecting the other variables. The high dose of both milnacipran and imipramine induced similar extent of negative chronotropic, inotropic and dromotropic effects together with vasoconstriction and repolarization delay. Thus, the effects of milnacipran may be more selective for cardiohemodynamics than for repolarization delay, whereas reverse will be true for imipramine, supporting lack of clinical report of patients with milnacipran-induced long QT syndrome unlike imipramine.