Recovery of prostacyclin synthesis in human vascular endothelial cells following intermittent or continuous exposure to indomethacin.
Indomethacin is a potent prostaglandin synthesis inhibitor, which is widely used in treating arthritis and other inflammatory conditions. This study investigated the effect of physiological levels of indomethacin on synthesis of the antiplatelet substance prostacyclin, by human vascular endothelial cells in culture. The nature of the inhibition and its reversibility following removal of indomethacin were characterized. Almost complete inhibition of prostacyclin synthesis was obtained at concentrations of 5.6 microM indomethacin, which were within physiological blood levels (1.4-16.8 microM) attained during routine indomethacin therapy. Inhibition was essentially irreversible for all exposure periods in excess of one minute. Following inactivation by brief (5 minute) exposure to indomethacin, partial recovery of prostacyclin synthesis to between 45% and 60% of control values was attained 24 hours after indomethacin removal. Prolonged (24 hours) exposure of cells to indomethacin did not further impair subsequent recovery of prostacyclin synthesis and did not affect cell viability. Recovery of enzyme was much more rapid in confluent quiescent monolayers of endothelial cells than in dividing cultures. The results indicate that continuous or intermittent exposure to indomethacin may significantly impair vascular prostacyclin synthesis in vascular endothelium, but that substantial recovery may occur within 24 hours of drug removal.
D001345:Autoradiography; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D004727:Endothelium / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D014471:Umbilical Veins / Q000378:metabolism
D011464:Epoprostenol; D007213:Indomethacin