A selective endothelin ETA receptor antagonist, SB 234551, improves cerebral perfusion following permanent focal cerebral ischemia in rats

In recent experimental studies, a selective antagonist of endothelin ETA receptors, SB 234551, improved neurological and histological outcome in both head trauma and transient focal cerebral ischemia. The present study was conducted to ascertain the degree to which hemodynamic alterations are responsible for this therapeutic effect in a model of permanent middle cerebral artery occlusion (MCAo) in rats. Anesthetized Sprague-Dawley rats were subjected to permanent MCAo by insertion of an intraluminal nylon suture coated with poly-l-lysine. The agent (SB 234551, 30 μg/kg/min = 1.8 mg/kg/h) or vehicle (PBS; 0.6 ml/h) was administered by i.v. infusion beginning 15 min after onset of MCAo and lasting for 23.75 h. Autoradiographic measurement of local cerebral blood flow (lCBF) was performed at 24 h. Physiological data were similar among groups. SB 234551 augmented perfusion by 1.7- to 1.8-fold in both the ischemic hemisphere and in the contralateral (non-ischemic) hemisphere when compared to vehicle-treated ischemic animals. In the ischemic hemisphere, the brain regions significantly benefited were those lying outside the zone of most dense ischemia (i.e., paramedian cortex and thalamus), while in the non-ischemic hemisphere all regions measured showed significant lCBF augmentation. This study demonstrates that SB 234551 therapy results in significant improvement of local cerebral perfusion in the ischemic as well as in the non-ischemic hemispheres after permanent MCAo.