title: Chronic thromboxane inhibition preserves function of rejecting rat renal allografts.
abstract: 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-keto-PGF1 alpha. 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, Duke University, VA Medical Center, Durham, North Carolina.
authors.forename: T M
authors.initials: TM
authors.lastname: Coffman
authors.forename: P
authors.initials: P
authors.lastname: Ruiz
authors.forename: F
authors.initials: F
authors.lastname: Sanfilippo
authors.forename: P E
authors.initials: PE
authors.lastname: Klotman
mesh_terms: D000179:Acrylates / Q000627:therapeutic use*; D000818:Animals; D006084:Graft Rejection / Q000187:drug effects*; D007261:Infusions, Intra-Arterial; D016030:Kidney Transplantation; D008297:Male; D008689:Methacrylates / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D013928:Thromboxane A2 / Q000502:physiology; D013929:Thromboxane B2 / Q000502:physiology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000179:Acrylates; D008689:Methacrylates; D013929:Thromboxane B2; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase; C034364:ozagrel