Effects of the thromboxane synthesis inhibitor CGS-12970 on experimental acute renal allograft rejection

M. J. Mangino, E. M. Brunt, P. Von Doersten, C. B. Anderson

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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 F(1α) (6-K-PGF(1α)) 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-PGF(1α) 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-PGF(1α) production in a dose-dependent manner. However, CGS-12970 given in-vivo selectively inhibited renal allograft TXB2 production and did not alter 6-K-PGF(1α) production indicating that selective inhibitory activity of this compound may be due to an active biologic metabolite. In conclusion, this study indicates that CGS-12970 improves renal allograft function possibly by selective inhibition of allograft TXA2. These effects may be attributable to an active biologic metabolite of the parent compound.

Original languageEnglish
Pages (from-to)23-28
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Jan 1 1989


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