ENDOTHELIN-INDUCED PROSTACYCLIN PRODUCTION IN RAT AORTIC RINGS IS MEDIATED BY PROTEIN-KINASE-C

Endothelin (ET) is a vasoconstrictor peptide released from endothelial cells that is known to cause prostaglandin release. The mechanism rem ains unclear. To determine whether the protein kinase C (PKC) signalin g pathway is stimulated by endothelin, we pretreated rat aortic rings with either PKC activator or inhibitors and measured the release of pr ostacyclin (PGI(2)) by radioimmunoassay. ET (10(-9) M) produced a 10-f old increase in PGI(2) release. Pretreatment with 10(-9) M of three di fferent PKC inhibitors, 1-(5-isoquinolinesulfonyl)piperazine(CL), stau rosporine, and 1-(5-isoquinolinesulfonyltmethyl)piperazine (H7), block ed ET-induced PGI(2) release. ET-induced PGI(2) release was also block ed by pretreatment with inhibitors of either phospholipase A(2)7,7-dim ethyleicosadienoic acid or trifluoromethyl ketone analogue) (10(-9) M) or cyclooxygenase (indomethacin) (10(-9) M). We conclude that ET acti vates PKC, which activates phospholipase A(2), which liberates arachid onic acid, which increases PGI(2) production and release.