title: Endothelin receptor antagonist increases cerebral perfusion and reduces ischaemic damage in feline focal cerebral ischaemia.
abstract: These investigations characterised the cerebrovascular effects of an endothelin ETA-receptor antagonist PD156707 in normal and ischaemic cat brain. A dose of PD156707 that inhibited the effects of exogenous endothelin-1 was established in nonischaemic cerebral resistance arterioles. Perivascular microapplication of the endothelin-receptor antagonist PD156707 (0.03-3 microM) had a minimal effect on nonischaemic pial resistance arterioles. The perivascular co-application of PD156707 and ET-1 (10 nM) effected a dose-dependent attenuation of the ET-1 vasoconstrictive response (IC50 = 0.1 microM). Intravenous administration of PD156707 (3 mumol/kg bolus + 5 mumol/kg/h infusion) attenuated the vasoconstriction elicited by perivascular ET-1 (10 nM) in normal pial arterioles (ET-1 vasoconstriction: -37 +/- 13% from preinjection baseline; after intravenous PD156707: 6 +/- 10% from preinjection baseline). In the focal ischaemia studies, cerebral perfusion was measured in the suprasylvian and ectosylvian gyri (by laser Doppler flowmetry). Occlusion of the middle cerebral artery reduced cerebral perfusion in the suprasylvian and ectosylvian gyri by approximately 50%. Intravenous administration of PD156707 (3 mumol/kg bolus + 5 mumol/kg/h infusion), initiated 30 min after middle cerebral artery occlusion, effected a progressive increase in cerebral perfusion up to preocclusion baseline levels, whereas cerebral perfusion in vehicle-treated animals did not vary from its postocclusion level. In these animals, the intravenous administration of PD156707 reduced the hemispheric volume of ischaemic damage by 45% (vehicle: 2,376 +/- 1,107 mm3; PD156707: 1,307 +/- 548 mm3; p < 0.05). Our investigations indicate that endothelin receptor antagonism may be a new therapeutic strategy for the amelioration of focal ischaemic damage.
authors.affiliation: Wellcome Surgical Institute, University of Glasgow, Scotland, U.K.
authors.forename: T R
authors.initials: TR
authors.lastname: Patel
authors.forename: S
authors.initials: S
authors.lastname: Galbraith
authors.forename: D I
authors.initials: DI
authors.lastname: Graham
authors.forename: H
authors.initials: H
authors.lastname: Hallak
authors.forename: A M
authors.initials: AM
authors.lastname: Doherty
authors.forename: J
authors.initials: J
authors.lastname: McCulloch
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects; D002415:Cats; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004149:Dioxoles / Q000008:administration & dosage / Q000627:therapeutic use*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D005260:Female; D007262:Infusions, Intravenous; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology; D010841:Pia Mater / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; C093321:PD 156707