Fluoxetine induces vasodilatation of cerebral arterioles by co‐modulating NO/muscarinic signalling

Journal of Cellular and Molecular Medicine

Keren Ofek¹  Karl Schoknecht³  Naomi Melamed-Book¹  Uwe Heinemann³  Alon Friedman² 

[1] The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel;Department of Physiology and Neurobiology, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel;Institute for Neurophysiology, Charité Universitätsmedizin, Berlin, Germany

关键词: acetylcholinesterase;    fluoxetine;    Ischaemic stroke;    muscarinic receptors;    nitric oxide;    vasodilatation;   

DOI  :  10.1111/j.1582-4934.2012.01596.x

来源: Wiley

【 摘 要 】

Abstract

Ischaemic 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 vasodilatation (by 1.2 to 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 ischaemic brain. In brain endothelial b.End.3 cells, fluoxetine induced rapid muscarinic receptor-dependent increases in intracellular [Ca²⁺] 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 vasodilatation of cerebral arterioles suggests co-promotion of endothelial muscarinic and nitric oxide signalling, facilitated by albumin-dependent inhibition of serum AChE.

【 授权许可】

Unknown   
© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd