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 language | English (US) |
|---|---|
| Pages (from-to) | 499-504 |
| Number of pages | 6 |
| Journal | Journal of Cerebral Blood Flow and Metabolism |
| Volume | 20 |
| Issue number | 3 |
| State | Published - 2000 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Administration of selective endothelin receptor type A antagonist Ro 61- 1790 does not improve outcome in focal cerebral ischemia in cat
AU - Bhardwaj, Anish
AU - Wu, Ying
AU - Hum, Patricia D.
AU - Kirsch, Jeffrey
AU - Traystman, Richard J.
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
KW - Endothelin
KW - Endothelin receptor type A antagonist
KW - Focal ischemia
KW - Middle cerebral artery occlusion
KW - Neuroprotection
UR - http://www.scopus.com/inward/record.url?scp=0034066699&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034066699&partnerID=8YFLogxK
M3 - Article
C2 - 10724114
AN - SCOPUS:0034066699
VL - 20
SP - 499
EP - 504
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 3
ER -