Fluoxetine induces vasodilatation of cerebral arterioles by co-modulating NO/muscarinic signalling.
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 [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 vasodilatation of cerebral arterioles suggests co-promotion of endothelial muscarinic and nitric oxide signalling, facilitated by albumin-dependent inhibition of serum AChE.
Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Keren
K
Ofek
Karl
K
Schoknecht
Naomi
N
Melamed-Book
Uwe
U
Heinemann
Alon
A
Friedman
Hermona
H
Soreq
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply* / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008784:Methysergide / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000600:supply & distribution; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism; D015424:Reperfusion; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D000110:Acetylcholinesterase; D001285:Atropine; D002118:Calcium; D005473:Fluoxetine; D018841:HSP90 Heat-Shock Proteins; D008464:Mecamylamine; D008784:Methysergide; D018727:Muscarinic Antagonists; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D011976:Receptors, Muscarinic; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C496316:Nos3 protein, rat