Prostaglandin E2 (PGE2) may be an important negative feedback modulator of endothelin-1 (ET-1)-stimulated mesangial cell proliferation and contraction. Recent studies suggest that ET-1 may induce prolonged mesangial cell PGE2 production, however the mechanism of this effect is unknown. The current study was undertaken, therefore, to examine the long-term effect of ET-1 on mesangial cell PGE2 synthesis. ET-1 markedly increased PGE2 release by rat mesangial cells for at least six hours. Cyclooxygenase (COX) activity was increased by one hour and persisted for at least six hours. ET-1 increased COX-2, but not COX-1, protein and mRNA levels. Actinomycin D reduced ET-1-stimulated PGE2 synthesis and COX-2 mRNA expression, while cycloheximide superinduced COX-2 mRNA. Dexamethasone decreased ET-1-stimulated PGE2 release and COX-2 protein and mRNA levels. ET-1-stimulated PGE2 release was prevented by BQ-123, an endothelin receptor A antagonist. We conclude that ET-1, via activation of the endothelin A receptor, causes a prolonged increase in mesangial cell PGE2 production that is partially dependent on induction of dexamethasone-inhibitable COX-2.