Chronic fluoxetine treatment increases NO bioavailability and calcium-sensitive potassium channels activation in rat mesenteric resistance arteries

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• 作者：Camila A. Pereira^a ; ^{mila_cap@yahoo.com.br" class="auth_mail" title="E-mail the corresponding author} ; Nathanne S. Ferreira^a ; Fabiola L. Mestriner^a ; José ; Antunes-Rodrigues^b ; Paulo R.B. Evora^c ; Leonardo B.M. Resstel^a ; Fernando S. Carneiro^a ; Rita C. Tostes^a ; ^{rtostes@usp.br" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Fluoxetine ; Chronic treatment ; Vascular reactivity ; Nitric oxide ; Potassium channel
• 刊名：European Journal of Pharmacology
• 出版年：2015
• 出版时间：15 October 2015
• 年：2015
• 卷：765
• 期：Complete
• 页码：375-383
• 全文大小：2468 K

文摘

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has effects beyond its antidepressant properties, altering, e.g., mechanisms involved in blood pressure and vasomotor tone control. Although many studies have addressed the acute impact of fluoxetine on the cardiovascular system, there is a paucity of information on the chronic vascular effects of this SSRI. We tested the hypothesis that chronic fluoxetine treatment enhances the vascular reactivity to vasodilator stimuli by increasing nitric oxide (NO) signaling and activation of potassium (K⁺) channels. Wistar rats were divided into two groups: (I) vehicle (water for 21 days) or (II) chronic fluoxetine (10 mg/kg/day in the drinking water for 21 days). Fluoxetine treatment increased endothelium-dependent and independent vasorelaxation (analyzed by mesenteric resistance arteries reactivity) as well as constitutive NO synthase (NOS) activity, phosphorylation of eNOS at Serine¹¹⁷⁷ and NO production, determined by western blot and fluorescence. On the other hand, fluoxetine treatment did not alter vascular expression of neuronal and inducible NOS or guanylyl cyclase (GC). Arteries from fluoxetine-treated rats exhibited increased relaxation to pinacidil. Increased acetylcholine vasorelaxation was abolished by a calcium-activated K⁺ channel (K_Ca) blocker, but not by an inhibitor of K_ATP channels. On the other hand, vascular responses to Bay 41-2272 and 8-bromo-cGMP were similar between the groups. In conclusion, chronic fluoxetine treatment increases endothelium-dependent and independent relaxation of mesenteric resistance arteries by mechanisms that involve increased eNOS activity, NO generation, and K_Ca channels activation. These effects may contribute to the cardiovascular effects associated with chronic fluoxetine treatment.