title: Functional role of thromboxane production by acutely rejecting renal allografts in rats.
abstract: We investigated the role of thromboxane in mediating the reduction in renal function and renal blood flow characteristic of acute renal allograft rejection. We transplanted kidneys from Lewis rats to Brown-Norway recipients. By the third day after transplantation, histologic changes that were consistent with cellular rejection occurred in the kidney. These changes were associated with a moderate reduction in renal function. By day 6, histologic changes of rejection were advanced and included interstitial and perivascular infiltration by mononuclear cells. The clearances of inulin and para-aminohippuric acid were also markedly reduced. As renal function deteriorated, thromboxane B2 (TXB2) production by ex vivo perfused renal allografts increased progressively from 2 to 6 d after transplantation. However, prostaglandin (PG) E2 and 6-keto PGF1 alpha production remained essentially unchanged. There was a significant inverse correlation between the in vivo clearance of inulin and the log of ex vivo TXB2 production. Infusion of the thromboxane synthetase inhibitor UK-37248-01 into the renal artery of 3-d allografts significantly decreased urinary TXB2 excretion and significantly increased renal blood flow (RBF) and glomerular filtration rate (GFR). Although renal function improved significantly after the acute administration of UK-37248-01, GFR and RBF did not exceed 33 and 58% of native control values, respectively. In other animals, daily treatment with cyclophosphamide improved the clearances of inulin and para-aminohippuric acid and reduced thromboxane production by 6-d renal allografts. These studies demonstrate that histologic evidence of rejection is associated with increased renal thromboxane production. Inhibition of thromboxane synthetase improves renal function in 3-d allografts. Cytotoxic therapy improves renal function, reduces mononuclear cell infiltration, and decreases allograft thromboxane production. Thus, the potent vasoconstrictor thromboxane A2 may play a role in the impairment of renal function and renal blood flow during acute allograft rejection.
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D006084:Graft Rejection; D007093:Imidazoles / Q000494:pharmacology; D007444:Inulin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D016030:Kidney Transplantation; D008297:Male; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D013931:Thromboxanes / Q000096:biosynthesis*; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D007093:Imidazoles; D011453:Prostaglandins; D013931:Thromboxanes; C029166:dazoxiben; D003520:Cyclophosphamide; D007444:Inulin; D010130:p-Aminohippuric Acid