Does oxidative stress contribute in tricyclic antidepressants-induced cardiotoxicity?
Different members of tricyclic antidepressants (TCAs) were found to induce free radical and oxidative stress in vitro. Accordingly, in the present study we tried to explore the possible role of oxidative stress in TCAs-induced cardiotoxicity. Rats were given a single injection of clomipramine (45 mg/kg). The cardiotoxicity was assessed by measuring ECG parameters (heart rate and QRS widening) and serum lactate dehydrogenase activity. The oxidative stress was assessed by measuring the myocardial reduced glutathione and lipid peroxides levels as well as different antioxidant enzyme activities after 24h of drug injection. In addition, we specifically investigated whether clomipramine could induce hydroxyl radical generation in vitro. The study revealed that clomipramine-induced a significant increase in lipid peroxides level (133%) and a significant decrease in glutathione level (84%) as well as a significant decrease in the activity of glutathione peroxidase and superoxide dismutase by 64% and 73%, respectively, as compared with the control group. In addition, clomipramine at concentrations 10 microM, 25 microM, 50 microM and 100 microM increased hydroxyl radical generation by 148%, 204%, 268% and 391%, respectively. Addition of hydroxyl radical scavenger or iron chelator significantly counteracted the effect of clomipramine. In conclusion, the present study demonstrates that free radical generation and oxidative stress play a role in clomipramine-induced cardiotoxicity. In addition, clomipramine can induce hydroxyl radical in vitro.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Abasia, Cairo, Egypt. ebthal_dm@menanet.net
Ebtehal
E
El-Demerdash
Ahmed M
AM
Mohamadin
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D002997:Clomipramine / Q000008:administration & dosage / Q000633:toxicity*; D003676:Deferoxamine / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004562:Electrocardiography; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007770:L-Lactate Dehydrogenase / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D002614:Chelating Agents; D016166:Free Radical Scavengers; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; D003676:Deferoxamine; D002997:Clomipramine; D004121:Dimethyl Sulfoxide