Administration of selective endothelin receptor type A antagonist Ro 61- 1790 does not improve outcome in focal cerebral ischemia in cat

Anish Bhardwaj, Ying Wu, Patricia D. Hum, Jeffrey Kirsch, Richard J. Traystman

Research output: Contribution to journalArticle

22 Citations (Scopus)

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-yl-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.

Original languageEnglish (US)
Pages (from-to)499-504
Number of pages6
JournalJournal of Cerebral Blood Flow and Metabolism
Volume20
Issue number3
StatePublished - 2000
Externally publishedYes

Fingerprint

Brain Ischemia
Cats
Endothelins
Reperfusion
Endothelin A Receptors
Middle Cerebral Artery Infarction
Wounds and Injuries
Sulfonic Acids
Arterioles
Halothane
Vasoconstriction
Switzerland
Intravenous Infusions
Nervous System
Endothelin A Receptor Antagonists
clazosentan
Salts
Sodium
Stroke
Mortality

Keywords

  • Endothelin
  • Endothelin receptor type A antagonist
  • Focal ischemia
  • Middle cerebral artery occlusion
  • Neuroprotection

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

Administration of selective endothelin receptor type A antagonist Ro 61- 1790 does not improve outcome in focal cerebral ischemia in cat. / Bhardwaj, Anish; Wu, Ying; Hum, Patricia D.; Kirsch, Jeffrey; Traystman, Richard J.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 20, No. 3, 2000, p. 499-504.

Research output: Contribution to journalArticle

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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-yl-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.",
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AU - Traystman, Richard J.

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