In vivo canine model comparison of cardiovascular effects of antidepressants milnacipran and imipramine.
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.
Mitsumori
Yoshitaka
Y
Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan.
Nakamura
Yuji
Y
Hoshiai
Kiyotaka
K
Nagayama
Yukitoshi
Y
Adachi-Akahane
Satomi
S
Koizumi
Schuichi
S
Matsumoto
Masahiko
M
Sugiyama
Atsushi
A
D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D003521:Cyclopropanes / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D007099:Imipramine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D000078764:Milnacipran; D018570:Risk Assessment; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors; D016276:Ventricular Function / Q000187:drug effects*
D018759:Adrenergic Uptake Inhibitors; D000929:Antidepressive Agents, Tricyclic; D003521:Cyclopropanes; D007099:Imipramine; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors