title: Prostaglandin E2 and prostacyclin inhibit the production and secretion of endothelin from cultured endothelial cells.
abstract: 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 vasodilator compounds. To understand the interactions of endothelin with the vasoactive prostaglandins (PGs), we determined the effects of prostaglandin E2 (PGE2), prostacyclin (PGI2), and thromboxane A2 on ET-1 synthesis and secretion from cultured bovine aortic endothelial cells and on ET-1 action in aortic smooth muscle cells. Both PGE2 and PGI2 (vasodilator prostaglandins) caused an approximately 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 A2, had no effect on ET-1 secretion. PGE2 and PGI2 similarly inhibited the basal production of new ET-1 protein (translation) by 40-50% and inhibited the basal steady-state mRNA expression of ET-1 in bovine aortic endothelial cells by 60-70%. Both prostaglandins also caused an approximately 55% inhibition of ET-1 transcription, as shown by chloramphenicol acetyltransferase reporter studies. PGE2 and PGI2 strongly stimulated cGMP generation; both the PG stimulation of cGMP and the inhibition of ET-1 secretion and translation were reversed by LY83583, a general inhibitor of cGMP generation. The PG-induced inhibition of ET-1 secretion and translation was also reversed by KT5823, an inhibitor of cGMP-dependent protein kinase, but not by (Rp)-adenosine cyclic 3':5'-monophosphate, an inhibitor of protein kinase A activation. PGE2 and PGI2 also inhibited both basal and ET-1-stimulated DNA synthesis in aortic smooth muscle cells by approximately 45% through a cGMP-dependent mechanism. Therefore, 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 results, in part, from their ability to inhibit the production of this potent vasoconstrictor.
authors.affiliation: Department of Pharmacology, University of California, Irvine 92717.
authors.forename: B A
authors.initials: BA
authors.lastname: Prins
authors.forename: R M
authors.initials: RM
authors.lastname: Hu
authors.forename: B
authors.initials: B
authors.lastname: Nazario
authors.forename: A
authors.initials: A
authors.lastname: Pedram
authors.forename: H J
authors.initials: HJ
authors.lastname: Frank
authors.forename: M A
authors.initials: MA
authors.lastname: Weber
authors.forename: E R
authors.initials: ER
authors.lastname: Levin
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D002227:Carbazoles; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011464:Epoprostenol / Q000494:pharmacology*; D007211:Indoles; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger / Q000378:metabolism*; D013189:SRS-A / Q000037:antagonists & inhibitors; D013936:Thymidine / Q000378:metabolism; D014162:Transfection
chemical_list: D000470:Alkaloids; D000634:Aminoquinolines; D002227:Carbazoles; D016232:Endothelins; D007211:Indoles; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D013189:SRS-A; C073601:KT 5823; D004247:DNA; C041715:6-anilino-5,8-quinolinedione; D011464:Epoprostenol; D015500:Chloramphenicol O-Acetyltransferase; D006152:Cyclic GMP; D015232:Dinoprostone; D013936:Thymidine