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Tricyclic antidepressants (TCAs) are among the most widely used therapeutic agents for depression, but they can cause profound cardiovascular toxicity. There is increasing evidence that nitric oxide plays a role in the cardiac toxic effects of TCAs. In this study, we examined the role of peroxynitrite in the toxicity of TCAs. In platelets, peroxynitrite is formed from superoxide and nitric oxide. Fluorometric, chemiluminescent, and enzymatic measurements demonstrate that TCAs (imipramine, amitriptyline, clomipramine) increase platelet peroxynitrite formation. This was dependent on both activation of phospholipase A2 and on depletion of extracellular Ca2+. N(G)-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, prevented the production of peroxynitrite by TCAs. In cultured vascular smooth muscle cells, TCAs increased nitric oxide and superoxide formation in a concentration-dependent manner. Pretreatment with L-NMMA or antioxidants (phenyl-tert-butyl-hydroperoxide; E,Z-4-hydroxy-2-nonenal) prevented the TCAs-induced nitric oxide formation and toxicity. Superoxide dismutase mimetics (Mn,CuZnSOD and Mn,FeSOD) also blocked the TCAs-induced toxicity but had no effect on nitric oxide formation. When H2O2 was employed instead of TCAs, there was no formation of peroxynitrite. In conclusion, TCAs produce peroxynitrite, which may play a role in the cardiovascular toxicity of this class of antidepressants.A female California State University student said she is confused and frustrated after she received multiple text messages from a man she says is her ex-boyfriend that falsely lead her to believe she had been raped.

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