Effects of the thromboxane synthesis inhibitor CGS-12970 on experimental acute renal allograft rejection
Mangino, M.J.; Brunt, E.M.; Von Doersten, P.; Anderson, C.B.
Journal of Pharmacology and Experimental Therapeutics 248(1): 23-28
1989
ISSN/ISBN: 0022-3565 PMID: 2643702 Document Number: 337120
The purpose of this study was to examine the effects and mechanisms of the selective thromboxane synthesis inhibitor CGS-12970 (3-methyl-2[3 pyridyl]-1-indoleoctanoic acid) on renal allograft function and eicosanoid production. Kidneys were transplanted between nonimmunosuppressed outbred mongrel dogs and renal allograft function, renal eicosanoid production and histologic signs of rejection were monitored. In the untreated animals, renal allograft blood flow and allograft glomerular filtration rate declined steadily over the 5-day observation period compared to animals with nonrejecting autotransplanted kidneys. However, renal blood flow and glomerular filtration rate of renal allografts from animals receiving the selective thromboxane synthesis inhibitor CGS-12970 (3 mg/kg p.o. b.i.d.) were significantly higher compared to nontreated allograft animals. Histologic examination of renal allografts harvested 5 days after transplantation revealed rejection with mononuclear infiltration in both the untreated and the CGS-12970-treated animals. In untreated dogs, renal allograft tissue production of thromboxane B2 (TXB2) Prostaglandin E2 (PGE2) and 6-Keto PG F1 alpha (6-K-PGF1 alpha) was significantly elevated 5 days after transplantation compared to normal renal tissue. In animals treated with CGS-12970, renal allograft tissue production of TXB2, PGE2 and 6-K-PGF1 alpha was significantly lower than the untreated allografts and was not different from normal kidneys. In-vitro dose-response experiments revealed that CGS-12970 nonselectively inhibited renal allograft tissue TXB2 and 6-K-PGF1 alpha production in a dose-dependent manner.