The effects of CGS 26303, a dual inhibitor of endothelin-converting enzyme (ECE) and neutral endopeptidase 24.11, and its prodrug, CGS 26393, on bovine cerebrovascular endothelial cells stimulated with hemolysate were investigated. Upon incubation with hemolysate for 48 h, cell density was significantly decreased, with concomitant increases in endothelin-1 (ET-1) (42 vs 11 pg/ml) and big ET-1 (79 vs 27 pg/ml) levels in culture medium when compared with controls. Simultaneous addition of CGS 26303 (10 and 100 μM) and hemolysate protected against cell loss and decreased cellular vacuolization caused by hemolysate. The levels of ET-1 and big ET-1 in the culture medium were decreased dose-dependently. More drastically, pretreatment with 100 μM CGS 26303 for 30 min decreased the production of ET-1 and big ET-1 by 94% and 87%, respectively, when compared with the untreated control. However, treatment with CGS 26393 was much less effective. These results suggest that suppression of ET-1 production by ECE inhibitors may prove to be efficacious for the treatment of hemolysate-induced cytotoxicity on cerebral endothelial cells.
Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan and *Metabolic and Cardiovascular Diseases Research, Novartis Pharmaceuticals Corporation, Summit, NJ, U.S.A.
Address correspondence and reprint requests to Aij-Lie Kwan, Department of Neurosurgery, Kaohsiung Medical University Hospital, No. 100, Shih-Chuan 1st road, Kaohsiung, Taiwan, Republic of China.
© 2000 Lippincott Williams & Wilkins, Inc.