Reversal of the vasoconstrictor step of hyperacute xenogeneic rejection ofthe liver by endothelin antagonists

1 The role of endothelin in the initial vasoconstrictor step of hyperacute xenogeneic rejection was investigated. 2 Isolated rat livers were perfused in recirculation. Perfusion with human sera provided an ex vivo model of hyperacute rejection in a discordant comb ination. 3 Perfusion of 10% xenogeneic serum induced a marked (70%) and sustained re duction of the liver flow and induced the release of endothelin into the pe rfusion medium. In contrast, perfusion of 10% allogeneic serum or of 10% de complemented human serum induced a weak (35%) and transient reduction of th e liver flow and induced the release of minimal amounts of endothelin. The simultaneous administration of BQ 123 and BQ 788, the respective antagonist s of ETA and ETB endothelin receptors, or that of bosentan, a mixed ETA/ETB antagonist, antagonized the vasoconstrictor effect of 10% xenogeneic human serum, as well as that of 10(-9) M endothelin-1. 4 The vasoconstrictor effects of xenogeneic serum on liver circulation are, at least partly, mediated through the release of endothelin by the graft.