title: Chronic fluoxetine treatment increases NO bioavailability and calcium-sensitive potassium channels activation in rat mesenteric resistance arteries.
abstract: 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 (KCa) blocker, but not by an inhibitor of KATP 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 KCa channels activation. These effects may contribute to the cardiovascular effects associated with chronic fluoxetine treatment.
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil. Electronic address: mila_cap@yahoo.com.br.
authors.forename: Camila A
authors.initials: CA
authors.lastname: Pereira
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: Nathanne S
authors.initials: NS
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: Fabiola L
authors.initials: FL
authors.lastname: Mestriner
authors.affiliation: Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: José
authors.initials: J
authors.lastname: Antunes-Rodrigues
authors.affiliation: Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: Paulo R B
authors.initials: PR
authors.lastname: Evora
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: Leonardo B M
authors.initials: LB
authors.lastname: Resstel
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Carneiro
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil. Electronic address: rtostes@usp.br.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005473:Fluoxetine / Q000008:administration & dosage*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000819:agonists / Q000096:biosynthesis*; D009924:Organ Culture Techniques; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D024681:Potassium Channels, Calcium-Activated; D005473:Fluoxetine; D009569:Nitric Oxide
keywords: Chronic treatment; Fluoxetine; Nitric oxide; Potassium channel; Vascular reactivity