THERAPEUTIC POTENTIAL OF ENDOTHELIN RECEPTOR ANTAGONISTS IN EXPERIMENTAL STROKE

This investigation demonstrates an increase in endothelin (ET)-mediate d vascular tone in peri-ischemic areas after experimental focal cerebr al ischemia (middle cerebral artery occlusion) in the cat. Adventitial application of the butenolide antagonist PD 155080 (30 mu M), after M CA occlusions resulted in marked increases in caliber of dilated (10.6 +/- 1.6% change from preinjection baseline) and constricted vessels ( 68.7 +/- 17.5% change from preinjection baseline). Cerebral blood flow (measured by laser Doppler flowmetry) was reduced after MCA occlusion to 50% of preocclusion levels. Intravenous administration of PD156707 30 min after MCA occlusion restored cerebral blood flow to preocclusi on baseline levels at 6 h. The volume of ischemic damage in the cerebr al hemisphere after MCA occlusion was significantly reduced (by 45%) a fter intravenous administration of PD156707.