Cyclosporine inhibits endothelial cell prostacyclin production.
Cyclosporine (CsA)-induced alterations in endothelial production of prostacyclin (PGI2) may be a contributing factor to the decreased renal blood flow and glomerular thromboses associated with CsA nephrotoxicity. This study was performed to determine the effects of clinically relevant doses of CsA on arachidonic acid-stimulated production of PGI2 by cultured human vein endothelial cells (HUVEC). Confluent monolayers of HUVEC were incubated at 37 degrees C under 5% CO2/95% air for 15 min in Hanks'/Hepes buffer containing 0.01-5.0 microM CsA in 0.01% absolute alcohol. PGI2 production was then stimulated by the addition of 20 microM arachidonic acid and further incubation for 15 min. Supernatants were assayed for 6-keto-PGF1 alpha by radioimmunoassay. The results of this experiment indicate that CsA had a dose-dependent effect on arachidonic acid-stimulated PGI2 production by HUVEC which varied linearly with the log of the dose (r = -0.48, P = 0.003). Concentrations of 0.01, 0.05, and 0.1 microM were stimulatory and 0.5, 1.0, and 5.0 microM were inhibitory. Separate experiments demonstrated that 0.1-5.0 microM CsA had no effect on cell viability (trypan blue exclusion) or growth. These results indicate that CsA inhibits arachidonic acid-stimulated production of PGI2 by HUVEC in a dose-dependent fashion beginning at concentrations comparable to the high end of the therapeutic range. This suggests that CsA-induced decreases in endothelial production of PGI2 may contribute to the development of CsA nephrotoxicity.
Rosenthal
R A
RA
Department of Surgery, State University of New York, Brooklyn.
Chukwuogo
N A
NA
Ocasio
V H
VH
Kahng
K U
KU
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis*; D006801:Humans; D009994:Osmolar Concentration; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
D001095:Arachidonic Acids; D003524:Cyclosporins; D016718:Arachidonic Acid; D011464:Epoprostenol