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

To evaluate the pathogenic role of thromoboxane (Tx) in endotoxic shock, the potential protective effects of the Tx synthetase inhibitor, 7-(l-imidazolyl)-heptanoic acid (7-IHA) was assessed and compared to that of imidazole in the rat. 7-IHA (30 mg/kg) administered iv 30 minutes prior to Salmonella enteritidis endotoxin (20 mg/kg, iv) improved the survival rate from 42% (n = 24) at 5 hours in the vehicle-treated rats to 100% (n = 11). By 24 hours, 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 iv 30 minutes prior to endotoxin (20 mg/kg, iv). However, 7-IHA did not inhibit endotoxin-induced elevations in plasma prostaglandin E. Endotoxin induced a significant reduction in the platelet counts in vehicle-treated rats from 780 ± 64 x 10/mm to 179 ± 18 x 10/mm (n = 6, P< 0.01) by 15 minutes, whereas, in imidazole-pretreated rats, the platelet count fell significantly less to 402 ± 55 x 10/mm (n = 6, P < 0.05), and in the 7-IHA-pretreated rats, the platelet count fell to 541 ± 91 x 10/mm (n = 5, P < 0.05). Fibrinogen/fibrin degradation products were significantly increased (P < 0.01) in response to endotoxic shock, but both imidazole and 7-IHA significantly decreased (P< 0.05) this elevation. Imidazole and 7-IHA pretreatment prevented lysosomal labilization in endotoxic shock as denoted by significantly decreased elevations in serum acid phosphatase and figlucuronidase. Similarly, reduction in hepatic cellular damage, as assessed by decreased elevations of serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase, was apparent. These results are consistent with the hypothesis that TxA2 plays a significant role in the pathogenesis of endotoxic shock. Circ Res 46: 854-859, 1980