Comparison of the effects of cyclosporin G (OG37-325), cyclosporin A, and their metabolites on the release of endothelin and prostacyclin from primary renal and aortic endothelial cell lines.
Cyclosporin G (OG37-325) (CsG), an analogue of cyclosporin-A (CsA), has been reported in preliminary clinical trials to induce fewer renal side-effects than CsA. CsA and its metabolites have been shown to alter release of vasoactive substance both in vitro and in vivo, and this may be a contributing factor to the decreased renal blood flow and glomerular thrombosis associated with CsA-induced renal side-effects. However, the effects of CsG and its metabolites on release of such substances has not been investigated. In this study, the toxic effects of several CsG metabolites were investigated in primary cultures of rabbit endothelial and mesangial cells. The majority of the metabolites had little effect on cell growth and DNA synthesis. GM9 was the most cytotoxic metabolite, having a potency ratio of 0.18-0.36 for inhibition of cell growth. The effects of individual metabolites were examined on basal release of prostacyclin (PGI2) and endothelin (ET-1). The majority of metabolites had no effect on release of these analytes; however, GM1, at 5,000 micrograms/L resulted in a significant (p < 0.05) increase in ET-1, while GM9 at both 500 and 5,000 micrograms/L resulted in a significant (p < 0.01) decrease in PGI2 from mesangial cells. To more accurately compare the effects of CsA, CsG, and metabolites, parent drug and metabolites were added to cultures at concentrations comparable to those trough values observed at steady state in transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
L J
LJ
Langman
R W
RW
Yatscoff
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016572:Cyclosporine / Q000378:metabolism* / Q000494:pharmacology*; D003524:Cyclosporins / Q000378:metabolism* / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D016232:Endothelins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D011817:Rabbits
D003524:Cyclosporins; D016232:Endothelins; D007166:Immunosuppressive Agents; C045571:cyclosporin G; D016572:Cyclosporine; D004247:DNA; D011464:Epoprostenol