Abstract
Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) has properties that go beyond its antidepressant effects and alters mechanisms involved in the regulation of vasomotor tone. While there are many studies demonstrating the acute effects of fluoxetine in the vasculature, studies on the chronic effects of this SSRI are still limited. Here we postulated that chronic treatment with fluoxetine enhances vascular reactivity to vasodilator stimuli by increasing nitric oxide (NO) signaling. The effects of chronic treatment with fluoxetine on vascular reactivity were determined in resistance mesenteric arteries from Wistar rats, which were treated with (I) vehicle (water for 21 days) or (II) fluoxetine (10 mg/kg/day for 21 days in the drinking water). Fluoxetine treatment increased endothelium-dependent (pEC50, Veh = -7.08±0.07; Fluox = -7.4±0.11, p<0.05) and -independent relaxant response (pEC50, Veh = -7.75±0.08; Fluox = -8.5 ± 0.11, p<0.05). Fluoxetine also increased vascular NOx (NO metabolites) levels (Veh = 1.2±0.13 μM/μg; Fluox = 2.0 ± 0.13 μM/μg, p <0.05), nitric oxide sintase (NOS) activity (Fluox = 76%) and phosphorylation of endothelial NOS (eNOS) at serine1177 [arbitrary units (a.u.), Veh = 0.36±0.10; Fluox = 1.2 ± 0.08, p <0.05]. Fluoxetine treatment did not change neuronal NOS (nNOS) or soluble guanylate cyclase (sGC) expression neither vascular responses to cyclic guanosine monophosphate (cGMP) or sGC activators. However, pinacidil- (KATP channels activator)-induced relaxation was increased by fluoxetine treatment (pEC50, Veh = -5.9±0.12; Fluox = -6.5±0.17, p>0.05). In conclusion, chronic treatment with fluoxetine increases endothelium-dependent and -independent relaxation response in resistance mesenteric arteries by mechanisms that involve increased NOS activity, NO generation and KATP channels activation. These effects may contribute to the cardiovascular side effects associated with fluoxetine treatment.
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