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The cardiovascular toxicity of the • older generation of antidepressant drugs such as tricyclic antidepressants is well documented. These drugs inhibit cardiac • and vascular ion channels causing life threatening hypotension and arrhythmias. Selective serotonin reuptake inhibitors (SSRI) were introduced during the last decade and their use is becoming increasingly popular. Although these new compounds are not more effective in treating psychiatric disorders than the old generation, they have fewer and more benign cardi vascular, anticholinergic and antihistaminic side effects. Recently, a number of case reports have demonstrated that the use of SSRIs is also associated with the incidence of cases of arrhythmia and orthostatic hypotension in some patients. However, the data available concerning the possible alteration by SSRIs of the vascular 4 neuroeffector system are not conclusive. The present study was designed to test the effect of one of the most popular SSRIs, sertraline on the mean arterial pressure (MAP) and heart rate (HR) of chronically catheterized conscious rats. This rat model was chosen to avoid the musking effect of anaesthesia on central and peripheral drug actions. The involvement of the al receptors, the endothelium derived releasing factor/nitric oxide (EDRF/NO) and prostaglandins in such effect was also investigated. The dependence of sertraline action on calcium or potassium entry through their specific channels was also explored. Sertraline bolus injection in 4 successive doses (10, 30, 100 and 300 μg/kg) did not induce any significant change in basal MAP or HR. However, the same doses induced dose dependent reduction of MAP elevated and maintained by angiotensin H (ATM or phenylephrine (PE) infusion and the nitric oxide synthase inhibitor L-nitro-arginine methyl ester (LNAME) injection. Infusion of sertraline (100 μg/kg/min) for 10 min neither abolished the pressor effect of ATII (I, 3, 10 and 30 ng/kg) or PE (10, 30, 100 and 300 ng/kg) nor shifted their DRCs to the right. The presence of indomethacin (1mg/kg) attenuated and the presence of verapamil (1mg/kg) potentiated the vasorelaxant effect of sertraline. In contrast, glibenclamide (1w/kg) injection neither changed L-NAME elevated MAP nor affected sertraline hypotensive response. Thus, sertraline is not hypotensive or arrhytlunogenic in basal states but inducrd a vasorelaxant effect when MAP is elevated. The vasorelaxant effect of sertraline may involve Cr entry and prostaglandins release but cc] receptor, K+ and NO independent.