Abstract
Chronic thromboxane inhibition preserves function of rejecting rat renal allografts. Increased production of thromboxane (TX) by rejecting renal allografts results in significant and partially reversible renal vasoconstriction. In this study, we evaluated the potential benefit of chronically administering the TX synthetase inhibitor OKY-046 from the time of transplantation in a rat model of acute renal allograft rejection. In animals which received 75 mg/kg/day of OKY-046 by intermittent i.p. injection, allograft function was not improved, but renal thromboxane production was not significantly inhibited. However, animals which received an equivalent dose of OKY-046 by continuous intra-arterial infusion for four days maintained clearances of inulin (4.46 ± 0.79 ml/min/kg) and PAH (23.86 ± 1.81 ml/min/kg) at normal levels not different from non-rejecting isografts (4.83 ± 0.93 and 18.33 ± 2.55 ml/min/kg, respectively). In contrast, animals which received continuous infusion of saline vehicle alone developed a significant reduction in renal function (CIn: 1.58 ± 0.27 ml/min/kg; CPAH: 9.12 ± 1.51 ml/min/kg) by the fourth day after transplantation Intra-arterial infusion of OKY-046 significantly reduced four-day allograft TXB2 production, as well as urinary TXB2 excretion, but had no effect on allograft production of PGE2 or 6-ketoPGF1α. Despite the beneficial effects on allograft function, OKY-046 neither altered the morphologic appearance of the cellular infiltrate nor the systemic proliferative and Cytotoxic anti-donor cellular immune responses. Six days following transplantation, renal TXB2 production was only partially inhibited in animals given continuous infusions of OKY-046, and remained markedly elevated. This partial inhibition of TX production resulted in a slight but insignificant functional improvement. These studies demonstrate that TX is a hemodynamic mediator of primary importance during the early stages of acute renal allograft rejection, but its role in later stages is unclear. Furthermore, these findings suggest that thromboxane antagonists may be a novel and potentially useful form of adjunctive therapy for acute renal allograft rejection.
