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: A Bhardwaj, Y Wu, P D Hurn, J R Kirsch, R J Traystman
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 20 Issue 3 Pg. 499-504 (Mar 2000) ISSN: 0271-678X [Print] United States
• PMID: 10724114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Dioxanes
• Endothelin Receptor Antagonists
• Endothelins
• Pyridines
• Pyrimidines
• Receptor, Endothelin A
• Sulfonamides
• Tetrazoles
• clazosentan

Topics

• Animals
• Arterial Occlusive Diseases (complications)
• Arterioles (drug effects)
• Brain Ischemia (drug therapy, etiology)
• Cats
• Cerebral Arteries
• Dioxanes (therapeutic use)
• Endothelin Receptor Antagonists
• Endothelins (pharmacology)
• Male
• Pia Mater (blood supply)
• Pyridines
• Pyrimidines (therapeutic use)
• Receptor, Endothelin A
• Sulfonamides
• Tetrazoles
• Treatment Failure
• Vasoconstriction (drug effects)