Inhibition of endothelin-converting enzyme attenuates transplant vasculopathy and rejection in rat cardiac allografts

Background. Transplant vasculopathy in kidney and heart allografts is assoc iated 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 b een established. We, therefore, tested whether inhibition of ET-1-convertin g enzyme by phosphoramidon (PA) would attenuate rejection in a rat model of chronic cardiac allograft rejection (Lewis [LEW] to F344). Methods. Donor LEW rats were pretreated 24 hr before transplantation with a bolus injection of vehicle (water) or PA. Twenty- four hour after transpla ntation, 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<0.01) in PA-treated rats, d emonstrating that the PA treatment protocol effectively lowered ET-1 biosyn thesis. Results. 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 (P<0.01, n=8). An analysis o f cardiac arteries demonstrated that PA treatment attenuated transplant vas culopathy. A morphometric scale of neointima formation (0-5) was 1.4+/-0.2 and 3.6+/-0.2 in PA- or water-treated rats, respectively (P<0.01), The perc ent of luminal occlusion, as measured by microscopic image analysis, was 19 +/-6% in PA-treated animals and 38+/-6% (P<0.01) in animals treated with wa ter. PA treatment also reduced infiltration of ED-1-positive monocytes/macr ophages into the vascular neointima. Conclusions. We conclude that, even in the absence of concomitant immunosup pression, inhibition of ET-I biosynthesis significantly attenuates transpla nt vasculopathy and improves survival of LEW to F344 cardiac allografts.