ENDOTHELIN RECEPTOR ANTAGONIST INCREASES CEREBRAL PERFUSION AND REDUCES ISCHEMIC DAMAGE IN FELINE FOCAL CEREBRAL-ISCHEMIA

These investigations characterised the cerebrovascular effects of an e ndothelin ET(A)-receptor antagonist PD156707 in normal and ischaemic c at brain. A dose of PD156707 that inhibited the effects of exogenous e ndothelin-1 was established in nonischaemic cerebral resistance arteri oles. Perivascular microapplication of the endothelin-receptor antagon ist PD156707 (0.03-3 mu M) had a minimal effect on nonischaemic pial r esistance arterioles. The perivascular coapplication of PD 156707 and ET-1 (10 nM) effected a dose-dependent attenuation of the ET-I vasocon strictive response (IC50 = 0.1 mu M). Intravenous administration of PD 156707 (3 mu mol/kg bolus + 5 mu mol/kg/h infusion) attenuated the vas oconstriction elicited by perivascular ET-1 (10 nM) in normal pial art erioles (ET-1 vasoconstriction: -37 +/- 13% from preinjection baseline : after intravenous PD156707: 6 +/- 10% from preinjection baseline). I n the focal ischaemia studies, cerebral perfusion was measured in the suprasylvian and ectosylvian gyri (by laser Doppler flowmetry). Occlus ion of the middle cerebral artery reduced cerebral perfusion in the su prasylvian and ectosylvian gyri by similar to 50%. Intravenous adminis tration of PD 156707 (3 mu mol/kg bolus + 5 mu mol/kg/h infusion), ini tiated 30 min after middle cerebral artery occlusion, effected a progr essive increase in cerebral perfusion up to preocclusion baseline leve ls, whereas cerebral perfusion in vehicle-treated animals did not vary from its postocclusion level. In these animals, the intravenous admin istration of PD156707 reduced the hemispheric volume of ischaemic dama ge by 45% (vehicle: 2,376 +/- 1,107 mm(3); PD156707: 1,307 +/- 548 mm( 3) p < 0.05). Our investigations indicate that endothelin receptor ant agonism may be a new therapeutic strategy for the amelioration of foca l ischaemic damage.