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: F C Barone, R F White, J D Elliott, G Z Feuerstein, E H Ohlstein
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 26 Suppl 3 Pg. S404-7 ( 1995) ISSN: 0160-2446 [Print] United States
• PMID: 8587428 (Publication Type: Journal Article)

Chemical References

• Carboxylic Acids
• Endothelin Receptor Antagonists
• Indans
• enrasentan

Topics

• Animals
• Brain Ischemia (drug therapy)
• Carboxylic Acids (therapeutic use)
• Endothelin Receptor Antagonists
• Indans (therapeutic use)
• Rats
• Rats, Inbred SHR