It is well accepted that multifactorial mechanisms are involved in the development and progression of cerebral ischemia. Recently, renewed attention has been drawn to the possible role of endothelium-derived mediators, in particular, nitric oxide (NO) and endothelin-1 (ET-1), as responsible for changes in vascular reactivity in the pathogenesis of this disease. Our previous studies suggested that NO and ET-1 may be involved in the vascular dysfunction associated with cerebral ischemia/reperfusion (I/R) injury. Subsequent experiments confirmed this supposition since treatment with ET-1 receptor antagonists completely recovered the postischemic hypoperfusion observed after I/R. Similar treatment of focal brain ischemia (4 h) significantly increased microvascular perfusion in the penumbra. The present study examined whether the ETA receptor-mediated improvement of postischemic cerebral circulation is associated with modulation of ischemia tissue injury in two models of brain ischemia. Mongolian gerbils were used to induce trabsient global ischemia by bilateral carotid artery occlusion (8 min) and release (72 h). Treatment consisted of i.v. injection (12.5 min after release) of the selective ETA receptor antagonist Ro 61-1790 (generous gift of Dr. S. Roux, F. Hoffmann-La Roche Ltd., Switzerland); saline-treated animals were controls. Adult male SHR were used to evaluate the effect of the same agent on focal brain ischemia (24 h). The left MCA was occluded by electrocoagulation. The selective ETA antagonist or saline was administered i.v. 5 min prior to and 5 hr after MCA occlusion. In gerbils, the ischemically induced hypoperfusion was reversed with Ro 61-1790. A bilateral loss of viable neurons (56-80%) was accompanied by increased neuronal TUNEL staining in the CA1 region of the hippocampus following I/R. In contrast, the Ro 61-1790-treated animals showed significantly less (26-36%) nonviable neurons and absence of cellular TUNEL staining. With regard to focal ischemia, the treatment of SHR with Ro 61-1790 significantly decreased (24%) the volume of the ischemic lesion. These findings further support the involvement of ETA-mediated hypoperfusion in the development of cerebral injury. Based on this and previous data, further exploration of the relationship between CBF and tissue injury is warranted. The clinical importance of this research is reflected by the potential benefit derived from using ETA antagonists alone or as part of a treatment regimen for multifactoral pathogenic processes such as strooke. These studies have been extended to include focal brain ischemia with reperfusion as a model that more closely resembles the clinical stroke seen in man. Additional research using this model will include using molecular probes and primers in conjunction with immunocytochemical techniques.
