Endothelin-1 (ET-1) synthesis is up-regulated after cerebral ischemia; and ET-1 mediated vasoconstriction may exacerbate ischemic injury. Previously, we showed that ET-1 is involved in postischemic hypoperfusion in gerbil transient global ischemia. This study further explores the efficacy of an ET-1 antagonist in protecting and/or treating global ischemia/reperfusion or permanent focal ischemia in gerbils and rats, respectively. Postischemic intravenous (i.v.) administration of mixed ET-1 receptor antagonists (donated by Hoffman-La Roche) showed that RO 61-1790 (affinity for ETA was greater than ETB) in contrast to bosentan (affinity for ETA was less than ETB) completely reversed the hypoperfusion. In addition, RO 61-1790 (1 mg/kg) improved by about 60% the survival of hippocampal CA1 neurons as compared to those in untreated gerbils at 72 hours after global ischemia (8 min). SHR were pretreated with RO 61-1790 (10 mg/kg i.v.) prior to permanent middle cerebral artery occlusion (MACO). Microvascular perfusion was assessed by a fluorescent tracer technique: 4 hr post-MCAO, tracers were sequentially administered i.v. 10 seconds and 5 seconds prior to decapitation. The number of perfused (fluorescent) microvessels were counted in cortical areas representing nonischemic, penumbral, and core ischemic regions. Ischemic lesion volume was also determined. RO 61- 1790 significantly increased perfusion in penumbral regions; this effect was associated with a 27% reduction in lesion volume. This result shows that RO 61-1790 attenuates focal ischemia and, together with the above previous studies, indicates that endogenous ET-1 is an important contributor to cerebrovascular pathology in both focal and global ischemia, in rats and gerbils.
