title: Bimodal effects of fluoxetine on cerebral nitrergic neurogenic vasodilation in porcine large cerebral arteries.
abstract: Fluoxetine-induced relaxation of the smooth muscle of small cerebral arteries is thought beneficial in treating mental disorders. The present study was designed to examine effect of fluoxetine on neurogenic nitrergic vasodilation in large cerebral arteries, using in vitro tissue myography, techniques of electrophysiology, calcium imaging and biochemistry. In isolated porcine endothelium-denuded basilar arteries in the presence of U-46619-induced active muscle tone, fluoxetine in low concentration (<0.03 μM) significantly enhanced nicotine- and choline-induced relaxations. The vasorelaxation, however, was blocked by higher concentration of fluoxetine (>0.3 μM) with maximum inhibition at 3 μM. At this concentration, fluoxetine did not affect the basal tone or vasorelaxations induced by transmural nerve stimulation, sodium nitroprusside, or isoproterenol. Furthermore, fluoxetine exclusively blocked nicotine-induced inward currents and calcium influx in cultured neurons of rat superior cervical ganglion and Xenopus oocytes expressing human α7-, α3β2-, or α4β2-nicotinic acetylcholine receptors (nAChRs). In addition, fluoxetine at 0.03 μM and 3 μM significantly enhanced and blocked, respectively, nicotine-induced norepinephrine (NE) release from cerebral perivascular sympathetic nerves. These results indicate that fluoxetine via axo-axonal interaction mechanism exhibits bimodal effects on nAChR-mediated neurogenic nitrergic dilation of basilar arteries. Fluoxetine in high concentrations decreases while in low concentrations it increases neurogenic vasodilation. These results from in vitro experimentation suggest that optimal concentrations of fluoxetine which increase or minimally affect neurogenic vasodilation indicative of regional cerebral blood flow may be important consideration in treating mental disorders.
authors.affiliation: Department of Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
authors.forename: Mei-Fang
authors.initials: MF
authors.lastname: Chen
authors.forename: Yi-Chiao
authors.initials: YC
authors.lastname: Huang
authors.forename: Cheng
authors.initials: C
authors.lastname: Long
authors.forename: Hui-I
authors.initials: HI
authors.lastname: Yang
authors.forename: Hui-Chao
authors.initials: HC
authors.lastname: Lee
authors.forename: Po-Yi
authors.initials: PY
authors.lastname: Chen
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Hoffer
authors.forename: Tony Jer-Fu
authors.initials: TJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000294:innervation; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000187:drug effects* / Q000294:innervation; D005473:Fluoxetine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D026602:Nitrergic Neurons / Q000187:drug effects* / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D017783:Superior Cervical Ganglion / Q000187:drug effects / Q000502:physiology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014981:Xenopus
chemical_list: D002118:Calcium; D005473:Fluoxetine; D009599:Nitroprusside; D017367:Selective Serotonin Reuptake Inhibitors; D014665:Vasodilator Agents