INHIBITION OF ENDOTHELIN-CONVERTING ENZYME ATTENUATES TRANSPLANT VASCULOPATHY AND REJECTION IN RAT CARDIAC ALLOGRAFTS1

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Abstract
Transplant vasculopathy in kidney and heart allografts is associated with marked elevation of endothelin-1 (ET-1), but a role for ET-1 in the pathogenesis of transplant vasculopathy and chronic rejection has not been established. We, therefore, tested whether inhibition of ET-1-converting enzyme by phosphoramidon (PA) would attenuate rejection in a rat model of chronic cardiac allograft rejection (Lewis [LEW] to F344). Donor LEW rats were pretreated 24 hr before transplantation with a bolus injection of vehicle (water) or PA. Twenty- four hour after transplantation, water or PA was continuously administered through an osmotic mini-pump. Plasma ET-1 levels in Fisher 344 (F344) recipients were 0.8±0.1 pg/ml in water-treated rats and 0.2±0.2 pg/ml (P LEW cardiac allografts treated with water survived (i.e., palpable heart beat) for 16.0±0.5 days (n=6). Inhibition of ET-1 secretion by PA improved allograft survival to 28.8±3.3 days (PP We conclude that, even in the absence of concomitant immunosuppression, inhibition of ET-1 biosynthesis significantly attenuates transplant vasculopathy and improves survival of LEW to F344 cardiac allografts.