Cyclosporine suppression of endothelial prostacyclin generation. A possible mechanism for nephrotoxicity.
The effects of cyclosporine (CsA) on prostacyclin (PGI2) release by cultured human umbilical vein endothelial cells were investigated. PGI2 production was measured by radioimmunoassay of its stable metabolite 6-Keto-PGF1 alpha. CsA induced a time and concentration-dependent reduction in unstimulated (basal) and Ca++ ionophore (A23187)-stimulated release of PGI2. A 16-hr incubation with CsA reduced A23187 PGI2 release by 64% (P less than 0.05); CsA at concentrations of 1.0, 10.0, and 100.0 micrograms/ml reduced A23187 PGI2 release by 67%, 80%, and 90%, respectively (P less than 0.05). This suppression was reversed within 24 hr after withdrawal of CsA. Arachidonic acid-stimulated PGI2 release was also decreased in CsA-treated cells, indicating an inhibitory effect distal to phospholipase A2. 3H-deoxyglucose release, an indicator of cell injury, was not increased by CsA, thus excluding nonspecific cell damage as a mechanism of the observed suppressive effect. This inhibition of PGI2 release from endothelial cells by CsA may explain the increased renal vascular resistance and renal microvascular thrombosis seen on occasion with CsA administration.
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003524:Cyclosporins / Q000494:pharmacology* / Q000633:toxicity; D003847:Deoxyglucose / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D007700:Kinetics; D011448:Prostaglandin Antagonists / Q000494:pharmacology*
D001095:Arachidonic Acids; D003524:Cyclosporins; D011448:Prostaglandin Antagonists; D016718:Arachidonic Acid; D003847:Deoxyglucose; D011464:Epoprostenol