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 remains unclear. To determine whether the protein kinase C (PKC) signaling pathway is stimulated by endothelin, we pretreated rat aortic rings 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-isoquinolinesulfonyltmethyl)piperazine (H7), blocked ET-induced PGI2 release. ET-induced PGI2 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
Hypertension-Endocrine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Tate
J E
JE
Keiser
H R
HR
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001095:Arachidonic Acids / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D016232:Endothelins; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D010726:Phosphodiesterase Inhibitors; C081565:arachidonyltrifluoromethane; D015240:Phorbol 12,13-Dibutyrate; C059778:7,7-dimethyl-5,8-eicosadienoic acid; D011464:Epoprostenol; D011493:Protein Kinase C; D007213:Indomethacin