A. Bhardwaj et al., Administration of selective endothelin receptor type A antagonist Ro 61-1790 does not improve outcome in focal cerebral ischemia in cat, J CEREBR B, 20(3), 2000, pp. 499-504
The authors examined the effect of selective endothelin (ET) receptor type
A (ETA) antagonism on histological and functional recovery in cat at 24 hou
rs after reversible middle cerebral artery occlusion (MCAO). A novel and sp
ecific ETA antagonist, Ro 61-1790 [5-methylpyridine-2-sulfonic acid-6-(2-hy
droxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrim
idin-4-ylamide sodium salt (1:2)1 (Roche, Basel, Switzerland), was used at
doses that produced steady-state plasma concentrations and abolished ET-ind
uced pial arteriolar vasoconstriction. In a cranial window preparation. 8 n
mol/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 ca
ts were treated with 90 minutes of MCAO and 24 hours of reperfusion. Animal
s received Ro 61-1790 infusion beginning at the onset of reperfusion and co
ntinuing for 6 or 24 hours (n = 41). Control cats were treated with 0.9% sa
line by intravenous infusion throughout reperfusion. There was no differenc
e in injury volume or neurologic evaluation score in saline-treated cats (n
= 11; caudate 24 +/- 28%, cortical injury 7.5 +/- 5% of ipsilateral struct
ure; 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
+/- 19). Mortality was greatest in the 24-hour drug treatment group. These
data suggest that blockade of ETA receptor activity is not beneficial to t
issue or functional outcomes from experimental stroke in cat.