COMPARISON OF THE EFFECTS OF CYCLOSPORINE AND ITS METABOLITES ON THE RELEASE OF PROSTACYCLIN AND ENDOTHELIN FROM MESANGIAL CELLS

CsA-induced alterations in mesangial cell production of potent vasoactive substances may be a contributing factor to the decreased renal blood flow and glomerular thrombosis associated with CsA nephrotoxicity. In this study the toxic effects of several CsA metabolites, previously isolated and characterized by mass spectrometry and nuclear magnetic resonance, were investigated in cultured rabbit mesangial cells. AM4N and AM9 were the most cytotoxic metabolites examined, having potency ratios of 0.28-0.56 with respect to CsA for the inhibition of cell growth and DNA synthesis. In addition the effects of several CsA metabolites were examined on the basal release of prostacyclin and endothelin. A concentration-dependent decrease in prostacyclin production, as measured by release of its stable metabolite, 6-keto-PGF1-alpha, was observed in cells treated with CsA and metabolites. CsA metabolites were equipotent as parent drug resulting in a significant (P < 0.05) 20-40% reduction in prostacyclin production. The dihydroxylated metabolites of CsA, AM19, and AM1c9 resulted in a significantly (P < 0.05) increased production of endothelin from the cells. In contrast parent drug resulted in a slight decrease in its production. In general CsA metabolites were found to be significantly less cytotoxic than parent drug in mesangial cells. However, the finding that certain CsA metabolites could alter production of vasoactive substances from these cells suggests that CsA metabolites may directly alter the renal hemodynamics, producing alterations consistent to that observed for CsA-induced renal side effects in vivo.