PROSTAGLANDIN E(2) AND PROSTACYCLIN INHIBIT THE PRODUCTION AND SECRETION OF ENDOTHELIN FROM CULTURED ENDOTHELIAL-CELLS

Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor yet identified. This peptide plays an important role in the regulation of arterial tone, in part through its interaction with endogenous vasodil ator compounds. To understand the interactions of endothelin with the vasoactive prostaglandins (PGs), we determined the effects of prostagl andin E(2) (PGE(2)), prostacyclin (PGI(2)), and thromboxane A(2) on ET -1 synthesis and secretion from cultured bovine aortic endothelial cel ls and on ET-1 action in aortic smooth muscle cells. Both PGE(2) and P GI(2) (vasodilator prostaglandins) caused an similar to 40% inhibition of basal ET-1 secretion and a 50% inhibition of serum-stimulated ET-1 secretion in a dose-related and time course fashion. In contrast, the vasoconstrictor prostaglandin, thromboxane A(2), had no effect on ET- 1 secretion. PGE(2) and PGI(2) similarly inhibited the basal productio n of new ET-1 protein (translation) by 40-50% and inhibited the basal steady-state mRNA expression of ET-1 in bovine aortic endothelial cell s by 60-70%. Both prostaglandins also caused an similar to 55% inhibit ion of ET-1 transcription, as shown by chloramphenicol acetyltransfera se reporter studies. PGE(2) and PGI(2) strongly stimulated cGMP genera tion; both the PG stimulation of cGMP and the inhibition of ET-1 secre tion and translation were reversed by LY83583, a general inhibitor of cGMP generation. The PG-induced inhibition of ET-1 Secretion and trans lation was also reversed by KT5823, an inhibitor of cGMP-dependent pro tein kinase, but not by (R(p))-adenosine cyclic 3':5'-monophosphate, a n inhibitor of protein kinase A activation. PGE(2) and PGI(2) also inh ibited both basal and ET-1-stimulated DNA synthesis in aortic smooth m uscle cells by similar to 45% through a cGMP-dependent mechanism. Ther efore, two endogenous PGs, known to be important vasodilators in vivo, significantly inhibit the transcription, translation, secretion, and action of ET-1. We propose that the vasodilator action of the PGs resu lts, in part, from their ability to inhibit the production of this pot ent vasoconstrictor.