title: Administration of selective endothelin receptor type A antagonist Ro 61-1790 does not improve outcome in focal cerebral ischemia in cat.
abstract: The authors examined the effect of selective endothelin (ET) receptor type A (ET(A)) antagonism on histological and functional recovery in cat at 24 hours after reversible middle cerebral artery occlusion (MCAO). A novel and specific ET(A) antagonist, Ro 61-1790 [5-methylpyridine-2-sulfonic acid-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-y l-pyridin-4-yl)-pyrimidin-4-ylamide sodium salt (1:2)] (Roche, Basel, Switzerland), was used at doses that produced steady-state plasma concentrations and abolished ET-induced pial arteriolar vasoconstriction. In a cranial window preparation, 8 nmol/L ET constricted pial arterioles by 33 +/- 18% (mean +/- SD), but this response was ablated by intravenous Ro 61-1790 treatment (10-mg/kg bolus, 4-mg/kg/h infusion). In additional animal cohorts, halothane-anesthetized cats were treated with 90 minutes of MCAO and 24 hours of reperfusion. Animals received Ro 61-1790 infusion beginning at the onset of reperfusion and continuing for 6 or 24 hours (n = 41). Control cats were treated with 0.9% saline by intravenous infusion throughout reperfusion. There was no difference in injury volume or neurologic evaluation score in saline-treated cats (n = 11; caudate 24 +/- 28%, cortical injury 7.5 +/- 5% of ipsilateral structure; score 52 +/- 8) versus the results in cats treated with Ro 61-1790 for either 24 hours (n = 6; caudate 22 +/- 23%, cortex 6 +/- 5%, injury volume of ipsilateral structure; score 55 +/- 3) or 6 hours (n = 11; caudate 33 +/- 30%, cortex 12 +/- 14%, injury volume of ipsilateral structure; score 50 +/- 10). Mortality was greatest in the 24-hour drug treatment group. These data suggest that blockade of ET(A) receptor activity is not beneficial to tissue or functional outcomes from experimental stroke in cat.
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bhardwaj
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: P D
authors.initials: PD
authors.lastname: Hurn
authors.forename: J R
authors.initials: JR
authors.lastname: Kirsch
authors.forename: R J
authors.initials: RJ
authors.lastname: Traystman
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D001160:Arterioles / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy / Q000209:etiology; D002415:Cats; D002536:Cerebral Arteries; D004146:Dioxanes / Q000627:therapeutic use*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D008297:Male; D010841:Pia Mater / Q000098:blood supply; D011725:Pyridines; D011743:Pyrimidines / Q000627:therapeutic use*; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013777:Tetrazoles; D017211:Treatment Failure; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D004146:Dioxanes; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D011725:Pyridines; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan