Endothelin-induced prostacyclin production in rat aortic endothelial cells is mediated by protein kinase C.
Endothelin (ET) is a vasoconstrictor peptide released from endothelial cells that is known to cause prostaglandin (PG) release. The mechanism remains unclear. To determine whether the protein kinase C (PKC) signaling pathway is stimulated by endothelin, we pretreated rat aortic endothelial cells with either PKC activator or inhibitors and measured the release of prostacyclin (PGI2) by radioimmunoassay. ET (10(-9) M) produced a 10-fold increase in PGI2 release. Pretreatment with 10(-9) M of three different PKC inhibitors: 1-(5-isoquinolinesulfonyl) piperazine (CL), staurosporine, and 1-(5-isoquinolinesulfonyl-methyl) piperazine (H7) blocked ET induced PGI2 release. ET induced prostacyclin release was also blocked by pretreatment with inhibitors of either phospholipase A2 (7,7,dimethyleicosadienoic acid or trifluoromethyl ketone analogue) (10(-9) M) or cyclooxygenase (indomethacin) (10(-9) M). We conclude that ET activates PKC which activates phospholipase A2 which liberates arachidonic acid which increases PGI2 production and release.
Oriji
G K
GK
Department of Biology, College of Science and Health, William Paterson University, Wayne, NJ 07470, USA.
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D015777:Eicosanoids / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology
D015777:Eicosanoids; D016232:Endothelins; D004791:Enzyme Inhibitors; D016718:Arachidonic Acid; C080501:1-(5-isoquinolinylsulfonyl)-3-methylpiperazine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011464:Epoprostenol; D011493:Protein Kinase C; D019311:Staurosporine; D007213:Indomethacin