Protective effects of thromboxane synthetase inhibitors in rats in endotoxic shock.

Abstract

To evaluate the pathogenic role of thromoboxane (Tx) in endotoxin [etox] shock, the potential protective effects of the Tx synthetase inhibitor, 7-(1-imidazolyl)-heptanoic acid (7-IHA) was assessed and compared to that of imidazole in the rat. 7-IHA (30 mg/kg) administered i.v. 30 min prior to Salmonella enteritidis etox (20 mg/kg, i.v.) improved the survival rate from 42% (n [number tested] = 24) at 5 h in the vehicle-treated rats to 100% (n = 11). By 24 h, only 8% of the vehicle-treated rats survived, whereas 80% of the treated group survived. Venous plasma thromboxane B2 elevation did not occur if 7-IHA (30 mg/kg) was administered i.v. 30 min prior to etox (20 mg/kg, i.v.). 7-IHA did not exhibit etox-induced elevations in plasma prostaglandin E. Etox induced a significant reduction in the platelet counts in vehicle-treated rats from 780 .+-. 64 .times. 103/mm3 to 179 .+-. 18 .times. 103/mm3 (n = 6, P < 0.01) by 15 min, whereas in imidazole-pre-treated rats, the platelet count fell significantly less to 402 .+-. 55 .times. 103/mm3 (n = 6, P < 0.05) and in the 7-IHA-pre-treated rats, the platelet count fell to 541 .+-. 91 .times. 103/mm3 (n = 5, P < 0.05). Fibrinogen/fibrin degradation products were significantly increased (P < 0.01) in response to etox shock, but imidazole and 7-IHA significantly decreased (P < 0.05) this elevation. Imidazole and 7-IHA pre-treatment prevented lysosomal labilization in etox shock as denoted by significantly decreased elevations in serum acid phosphatase and .beta.-glucuronidase. Reduction in hepatic cellular damage, as assessed by decreased elevations of serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase, was apparent. TxA2 may play a significant role in the pathogenesis of etox shock.