Inhibition of endothelin-1 improves survival and vasculopathy in rat cardiac transplants treated with cyclosporine.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Simonson
Michael S
MS
Department of Medicine, School of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA. mss5@po.cwru.edu
Robinson
Ann V
AV
Schulak
James A
JA
Hricik
Donald E
DE
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000072396:Endothelin-Converting Enzymes; D005355:Fibrosis; D006020:Glycopeptides / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008666:Metalloendopeptidases; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
D019332:Endothelin-1; D006020:Glycopeptides; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon