The role of endothelin-1 (ET-1) in cerebral ischemic injury remains the subject of much debate. Vasoconstriction in large conduit vessels may not be associated with reductions in flow at the tissue level. We present two studies examining the effects on local cerebral blood flow of topical application of ET-1 to the surgically exposed middle cerebral artery (MCA) in adult male Sprague-Dawley rats. In the first series using 14C-iodoantipyrine autoradiography, 10 min following application of ET-1 (1 nmol) to the MCA, up to 80% reduction in blood flow in the territory of distribution of the MCA is seen (e.g., dorsolateral caudate nucleus--flow reduced from 131 +/- 3 ml/100 g/min to 29 +/- 25 ml/100 g/min). These levels of flow are comparable with those seen with permanent bipolar diathermy occlusion and division of the proximal MCA--a standard rat model of focal cerebral ischemia. In a second series using hydrogen clearance technique for measurement of local cerebral blood flow in the caudate nucleus, we have shown that flow ipsilateral to application of ET-1 (0.25 nmol) is significantly reduced compared with saline controls for 80 min. Such reduction of flow, at the tissue level, sustained over this duration is consistent with the induction of ischemic cell damage by ET-1.