Protective Effects of trans-13-APT, a Thromboxane Receptor Antagonist, in Endotoxemia

Abstract

The effect of the thromhoxane A₂prosta-glandin H₂ (TxA₂PGH₂) receptor antagonist trans- 712-(p-hydroxyphenethylamino)-cyclopentyl]-heptanoic acid Trans-13-APT) on certain pathogenic sequelae of endotoxic shock and associated changes in araehidonic acid metabolism in the rat was investigated. trans-13-APT. an analog of 13-aprostanoic acid, was synthesized and found lo block human platelet aggregation induced by the thromboxane mimetic U46619. Pretreatment with iraus-13-APT did not significantly alter the elevations in plasma immunoreactive (i) TxB, or iPGE, 0.5 or 4 h after the intravenous administration of Salmonella enterilidis endotoxin. However, in the trans-13-APT-pretreated group, 4 h after administration of the endotoxin. plasma i6-keto-PGI was significantly (p < 0.05) reduced to 1.2 ± 0.3 ng/ml (n - 17) compared with vehicle-treated rats (2.4 ± 0.5 ng/ml: n - 18). The elevation in plasma i6-kelo-PGI seen 0.5 h (n 17/grottp) after endotoxin infusion was not altered by trans-13-APT. trans-13-APT also significantly (p < 0.05) attenuated the endotoxinindticed fall in platelet count (135 + 27 × 10/mm vs. 350 + 65 × 10/mm and hypoglycemia (73 9 vs. 97 + 7 mg/dl). but not the leukopenia. Since the reticulo-endothelial system may be an important source of iTxB₂, and i6-keto-PGF during endotoxemia, in vitro studies were conducted with adherent peritoneal cells. High concentrations of trans-13-APT (50 and 100 μ) significantly reduced (p < 0.05) basal but not endotoxin-induced synthesis of iTxB₂ and i6-keto-PGF by isolated adherent rat peritoneal cells. The attenuated rise in plasma i6-keto-PGF in the trans-13-APT-pretreated rats may be the result of lessened shock severity or may represent antagonism of a stimulatory effect of TxA₂ on PGI₂ synthesis. The results also raise the possibility that thromboxane receptor antagonists may be of benefit during endotoxemia.