title: SL65.0472 blocks 5-hydroxytryptamine-induced vasoconstriction in a dog hindlimb ischemia model.
abstract: We have studied the ability of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno[3,2-c]pyridin-4-yl)piperazin-1-yl]ethyl]-1,2-dihydroquinoline-1-acetamide), a 5-hydroxytryptamine (5-HT) 5-HT1B/5-HT2A receptor antagonist, to antagonise the vasoconstrictor effects of 5-HT and sumatriptan in a canine model of hindlimb ischemia. Dogs underwent right external iliac artery ligation and right superficial femoral artery excision, resulting in decreased perfusion (-31%, P<0.05) in the right hindlimb. Following pretreatment with L-NAME, phentolamine and propranolol, intra-aortic injection of 5-HT markedly reduced blood flow to the right ischemic hindlimb (-50 +/- 2%, P<0,05). 5-HT induced vasoconstriction was significantly inhibited (-66%, P<0.05) by SL65.0472 (300 microg/kg i.v.), but unaffected by ketanserin (300 microg/kg i.v.), a 5-HT2A receptor antagonist. SL65.0472 also blocked sumatriptan-induced vasoconstriction in ischemic and normally perfused hindlimbs. Thus, SL65.0472 is an effective antagonist of 5-HT-receptor mediated hindlimb vasoconstriction.
authors.affiliation: Sanofi-Synthélabo Research, Cardiovascular Thrombosis Research Department, 1 Avenue Pierre Brossolette, 91380 Chilly-Mazarin, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Barbe
authors.forename: Etienne
authors.initials: E
authors.lastname: Gautier
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bidouard
authors.forename: Alain
authors.initials: A
authors.lastname: Grosset
authors.forename: Stephen E
authors.initials: SE
authors.lastname: O'Connor
authors.forename: Philip
authors.initials: P
authors.lastname: Janiak
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D010879:Piperazines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000008:administration & dosage* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: C416534:7-fluoro-2-oxo-4-(2-(4-(thieno(3,2-c)pyridin-4-yl)piperazin-1-yl)ethyl)-1,2-dihydroquinoline-1-acetamide; D010879:Piperazines; D011804:Quinolines; D012702:Serotonin Antagonists; D012701:Serotonin; D019331:NG-Nitroarginine Methyl Ester