COCAINE-STIMULATED ENDOTHELIN-1 RELEASE IS DECREASED BY ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS IN CULTURED ENDOTHELIAL-CELLS

Objective: The primary aim was to determine the action of pathophysiol ogically relevant cocaine concentrations (10(-7)-10(-5) M) on endothel in-1 (ET-1) release from cultured endothelial cells under various cell ular conditions. Further aims were to evaluate the effect of angiotens in-converting enzyme inhibitors on cocaine-treated endothelial cells, to assess their potential for inhibition of ET-1-stimulated release. M ethods: Endothelin-1 release into the media was evaluated by radioimmu noassay under basal conditions and after 24 h treatment of endothelial cells with cocaine hydrochloride (HCl), or cocaine HCl and ACE inhibi tors, captopril and lisinopril. The effect of serum and plasma under t hese conditions was also investigated. Results: Cocaine HCl stimulated ET-1 release in a dose response fashion that was independent of plasm a or serum factors. Furthermore, cocaine-stimulated ET-1 release was i nhibited by administration of angiotensin-converting enzyme inhibitors captopril and lisinopril. Conclusions: These findings suggest that co caine can directly stimulate endothelial cells to release ET-1 and tha t the observed increase is independent of serum or plasma factors. Fur thermore, cocaine-stimulated endothelin-1 release appears to be mediat ed at least in part by the angiotensin system. These observations prov ide a framework for understanding the cellular mechanisms involved in cocaine-induced vasoconstriction.