Fluoxetine induces vasodilatation of cerebral arterioles by co-modulating NO/muscarinic signalling Academic Article uri icon

abstract

  • Ischemic stroke patients treated with Selective Serotonin Reuptake Inhibitors (SSRI) show improved motor, cognitive and executive functions, but the underlying mechanism(s) are incompletely understood. Here, we report that cerebral arterioles in the rat brain superfused with therapeutically effective doses of the SSRI fluoxetine showed consistent, dose-dependent vasodilation (by 1.2-1.6-fold), suppressible by muscarinic and Nitric-Oxide-Synthase (NOS) antagonists (atropine, NG-nitro-L-arginine methyl ester (L-NAME)) but resistant to nicotinic and serotoninergic antagonists (mecamylamine, methylsergide). Fluoxetine administered 10-30 min following experimental vascular photo-thrombosis increased arterial diameter (1.3-1.6), inducing partial, but lasting reperfusion of the ischemic brain. In brain endothelial b.End.3 cells, fluoxetine induced rapid muscarinic receptor-dependent increases in intracellular [Ca(2+) ] and promoted albumin- and eNOS-dependent Nitric-Oxide (NO) production and HSP90 interaction. In vitro, fluoxetine suppressed recombinant human Acetylcholinesterase (rhAChE) activity only in the presence of albumin. That fluoxetine induces vasodilation of cerebral arterioles suggests co-promotion of endothelial muscarinic and nitricoxide signaling, facilitated by albumin-dependent inhibition of serum AChE. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

publication date

  • January 1, 2012