Regulation of endothelial cell cyclic nucleotide metabolism by prostacyclin.
An analysis of prostaglandin-stimulated adenosine 3',5'-cyclic monophosphate (cyclic AMP) accumulation in cultured human umbilical vein endothelial cells showed prostacyclin (PGI2) to be the most potent agonist followed by prostaglandin (PG)H2, which was more potent than PGE2, while PGD2 was essentially inactive. The endothelial cells studied apparently have a high rate of cyclic AMP phosphodiesterase activity because significant PGI2-mediated increases in cyclic AMP could not be shown in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (MIX). Endoperoxide PGH2-stimulation of cyclic AMP accumulation was inhibited 75--80% by the prostacyclin synthetase inhibitors 12-hydroperoxyeicosatetraenoic acid or 9,11-azoprosta-5,13-dienoic acid. These data indicate that the PGH2-stimulation is due primarily to conversion to PGI2. The beta-adrenergic agonist L-isoproterenol stimulated cyclic AMP accumulation in the endothelial cells. This accumulation was completely blocked by propranolol. However, stimulation of cyclic AMP accumulation by the beta-adrenergic agent did not equal that induced by PGI2. Furthermore, the PGI2 response could not be blocked by propranolol. Thrombin-stimulated PGI2 biosynthesis was attenuated by PGE1 or isoproterenol in the presence of MIX. MIX alone was less effective than a combination of PGE1 or isoproterenol plus MIX. These data suggest two potential effects of PGI2 biosynthesis by endothelial cells: first, the PGI2 can elevate cyclic AMP in platelets, and second, endothelial cell cyclic AMP can be elevated as well, so that subsequent PGI2 synthesis will be attenuated.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis / Q000494:pharmacology*; D006801:Humans; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology*; D011458:Prostaglandins E / Q000494:pharmacology; D011463:Prostaglandins H / Q000494:pharmacology; D013268:Stimulation, Chemical; D013917:Thrombin / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology
D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D011458:Prostaglandins E; D011463:Prostaglandins H; D011464:Epoprostenol; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D013917:Thrombin; D000262:Adenylyl Cyclases; D007545:Isoproterenol