phosphoramidon and Fibrosis

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

In animal models, endothelin-1 (ET-1) blockade attenuates transplant vasculopathy and chronic allograft dysfunction even in the absence of cyclosporine (CsA). As CsA has side effects and ET-1 antagonism alone has significant benefits, we postulated that allograft survival could be significantly improved by combining an endothelin-converting enzyme inhibitor with low-dose CsA.. Survival of Lewis to Fisher 344 rat heterotopic cardiac allografts was determined in untreated animals and compared with those treated with high-dose CsA (62 mg/kg i.m. on day 2), low-dose CsA (25 mg/kg), an endothelin-converting enzyme inhibitor, phosphoramidon (PA, 10 mg/kg/day), or low-dose CsA + PA.. Untreated allografts had a median survival of 16 days compared with 20 days for low-dose CsA. Grafts treated with PA survived for 28 days, and combination of PA and low-dose CsA improved median survival to 47 days (P<0.01). Median survival with combination therapy was similar to that for high-dose CsA (42 days). To explore mechanisms underlying the benefits of combination therapy, cardiac allografts treated as above (n=4 each group) were explanted at 20 d and analyzed for parenchymal rejection, neointimal vasculopathy, myocardial fibrosis, and macrophage infiltration. Low-dose CsA alone but not PA improved parenchymal rejection; in contrast, PA alone but not low-dose CsA improved vasculopathy. Both parenchymal rejection and vasculopathy were improved by combination therapy with low-dose CsA and PA. Unlike CsA, inhibition of ET-1 biosynthesis significantly reduced myocardial fibrosis in allografts.. These results suggest that the combination of low-dose CsA and endothelin-converting enzyme inhibition may prove useful to improve long-term graft survival while minimizing potential side effects of CsA.

Topics: Animals; Aspartic Acid Endopeptidases; Cyclosporine; Endothelin-1; Endothelin-Converting Enzymes; Fibrosis; Glycopeptides; Graft Rejection; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Male; Metalloendopeptidases; Myocardium; Rats; Rats, Inbred F344; Rats, Inbred Lew; Transplantation, Homologous