title: Contribution of oxidative stress and prostanoids in endothelial dysfunction induced by chronic fluoxetine treatment.
abstract: OBJECTIVE
  The effects of chronic fluoxetine treatment were investigated on blood pressure and on vascular reactivity in the isolated rat aorta.
  
  
  RESULTS
  Male Wistar rats were treated with fluoxetine (10 mg/kg/day) for 21 days. Fluoxetine increased systolic blood pressure. Chronic, but not acute, fluoxetine treatment increased the contractile response induced by phenylephrine, serotonin (5-HT) and KCl in endothelium-intact rat aortas. L-NAME and ODQ did not alter the contraction induced by phenylephrine and 5-HT in aortic rings from fluoxetine-treated rats. Tiron, SC-560 and AH6809 reversed the increase in the contractile response to phenylephrine and 5-HT in aortas from fluoxetine-treated rats. Fluoxetine treatment increased superoxide anion generation (O2(-)) and the expression of cyclooxygenase (COX)-1 in the rat aorta. Reduced expression of nNOS, but not eNOS or iNOS was observed in animals treated with fluoxetine. Fluoxetine treatment increased prostaglandin (PG)F2α levels but did not affect thromboxane (TX)B2 levels in the rat aorta. Reduced hydrogen peroxide (H2O2) levels and increased catalase (CAT) activity were observed after treatment.
  
  
  CONCLUSIONS
  The major new finding of our study is that chronic fluoxetine treatment induces endothelial dysfunction, which alters vascular responsiveness by a mechanism that involves increased oxidative stress and the generation of a COX-derived vasoconstrictor prostanoid (PGF2α). Moreover, our results evidenced a relation between the period of treatment with fluoxetine and the magnitude in the increment of blood pressure. Finally, our findings raise the possibility that fluoxetine treatment increases the risk for vascular injury, a response that could predisposes to cardiovascular diseases.
authors.affiliation: Programa de Pós-Graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil; Departamento de Enfermagem Psiquiátrica e Ciências Humanas, Escola de Enfermagem de Ribeirão Preto, Laboratório de Farmacologia, USP, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Janaina A
authors.initials: JA
authors.lastname: Simplicio
authors.affiliation: Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Leonardo B
authors.initials: LB
authors.lastname: Resstel
authors.affiliation: Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Daniela P C
authors.initials: DP
authors.lastname: Tirapelli
authors.affiliation: Département de Pharmacologie, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Québec, Canada.
authors.forename: Pedro
authors.initials: P
authors.lastname: D'Orléans-Juste
authors.affiliation: Departamento de Enfermagem Psiquiátrica e Ciências Humanas, Escola de Enfermagem de Ribeirão Preto, Laboratório de Farmacologia, USP, Ribeirão Preto, São Paulo, Brazil. Electronic address: crtirapelli@eerp.usp.br.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Tirapelli
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D002374:Catalase / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D015237:Dinoprost / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005473:Fluoxetine / Q000633:toxicity*; D058851:GPI-Linked Proteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D014662:Vasoconstrictor Agents; D005473:Fluoxetine; D013481:Superoxides; D015237:Dinoprost; D006861:Hydrogen Peroxide; D002374:Catalase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat; D013482:Superoxide Dismutase; D000110:Acetylcholinesterase; C548246:Ache protein, rat
keywords: Endothelial dysfunction; Fluoxetine; Oxidative stress; Prostanoids; Vascular reactivity