title: Chronic treatment with fluoxetine modulates vascular adrenergic responses by inhibition of pre- and post-synaptic mechanisms.
abstract: Fluoxetine, a serotonin reuptake inhibitor (SSRI), has other effects in addition to blocking serotonin reuptake, including changes in the vasomotor tone. Whereas many studies focused on the acute effects of fluoxetine in the vasculature, its chronic effects are still limited. In the present study, we tested the hypothesis that chronic fluoxetine treatment modulates adrenergic vascular responses by interfering with post- and pre-synaptic mechanisms. Wistar rats were treated with vehicle (water) or chronic fluoxetine (10mg/kg/day) for 21 days. Blood pressure (BP) and heart rate were measured. Vascular reactivity was evaluated in perfused mesenteric arterial beds (MAB) and in mesenteric resistance arteries. Protein expression by western blot analysis or immunohistochemistry, β-arrestin recruitment by BRET and calcium influx by FLIPR assay. Fluoxetine treatment decreased phenylephrine (PE)-induced, but not electrical-field stimulation (EFS)-induced vasoconstriction. Fluoxetine-treated rats exhibited increased KCl-induced vasoconstriction, which was abolished by prazosin. Desipramine, an inhibitor of norepinephrine (NA) reuptake, increased EFS-induced vasoconstrictor response in vehicle-treated, but not in fluoxetine-treated rats. Chronic treatment did not alter vascular expression of α1adrenoceptor, phosphorylation of PKCα or ERK 1/2 and RhoA. On the other hand, vascular contractions to calcium (Ca2+) as well as Ca2+influx in mesenteric arteries were increased, while intracellular Ca2+storage was decreased by the chronic treatment with fluoxetine. In vitro, fluoxetine decreased vascular contractions to PE, EFS and Ca2+, but did not change β-arrestin activity. In conclusion, chronic treatment with fluoxetine decreases sympathetic-mediated vascular responses by mechanisms that involve inhibition of NA release/reuptake and decreased Ca2+stores.
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, 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, SP, Brazil.
authors.forename: Fernanda L
authors.initials: FL
authors.lastname: Rodrigues
authors.affiliation: Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Ruginsk
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Camila Z
authors.initials: CZ
authors.lastname: Zanotto
authors.affiliation: Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: José A
authors.initials: JA
authors.lastname: Rodrigues
authors.affiliation: Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Duarte
authors.affiliation: Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Costa-Neto
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Leonardo B
authors.initials: LB
authors.lastname: Resstel
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, 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, SP, Brazil. Electronic address: rtostes@usp.br.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004558:Electric Stimulation; D005473:Fluoxetine / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D002118:Calcium; D005473:Fluoxetine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011189:Potassium Chloride; D018340:Receptors, Adrenergic, alpha-1; D017367:Selective Serotonin Reuptake Inhibitors; D000071557:beta-Arrestins
keywords: Calcium; Chronic treatment; Fluoxetine; Norepinephrine; Vascular reactivity