title: The endothelin receptor antagonist SB 217242 reduces cerebral focal ischemic brain injury.
abstract: Previously, we demonstrated that cerebral focal ischemic tissue exhibits a significant increase in immunoreactive endothelin (ET). Because increased ET might exacerbate the consequences of cerebral ischemia, we evaluated the effects of the orally active ETA/B receptor antagonist SB 217242 on middle cerebral artery occlusion (MCAO) in the spontaneously hypertensive rat (SHR). SHRs were treated b.i.d. with vehicle or with 3 or 15 mg/kg SB 217242 p.o. for 7 days. Permanent MCAO was performed on day 7 and animals were sacrificed on day 8. Forebrains were stained and the extent of cerebral (i.e., cortical) infarction was determined using image analysis. Hemispheric swelling (%), hemispheric infarct (%), and infarct volume (mm3) were quantitated for each animal. SB 217242 treatment produced a significant decrease in ischemic brain injury. Hemispheric infarction and infarct volume were reduced after the 15 mg/kg treatment (12.0 +/- 1.1% and 69 +/- 6 mm3) compared to vehicle (17.3 +/- 1.5% and 99 +/- 8 mm3) (p < 0.05). No significant effects on hemispheric swelling were observed. This is the first demonstration of an ET receptor antagonist exhibiting efficacy in cerebral focal ischemia. The fact that a 30% reduction in ischemic brain injury can be demonstrated after oral administration of SB 217242 suggests that ET antagonists may be of therapeutic utility in focal stroke.
authors.affiliation: Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
authors.forename: F C
authors.initials: FC
authors.lastname: Barone
authors.forename: R F
authors.initials: RF
authors.lastname: White
authors.forename: J D
authors.initials: JD
authors.lastname: Elliott
authors.forename: G Z
authors.initials: GZ
authors.lastname: Feuerstein
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D002264:Carboxylic Acids / Q000627:therapeutic use*; D065128:Endothelin Receptor Antagonists; D007189:Indans / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D007189:Indans; C098288:enrasentan