Implications for thromboxane A2 in the pathogenesis of endotoxic shock.
During endotoxemia there is increased synthesis of arachidonic-acid-derived metabolites. We investigated the potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A2, an arachidonic acid metabolite, in the endotoxic shocked rat. Plasma levels of thromboxane B2, the stable metabolite of thromboxane A2, 6-keto-PGF1 alpha, the stable metabolite of PGI2, and PGE were measured via radioimmunoassay. We also investigated the therapeutic efficacy of the fatty acid cyclo-oxygenase imidazole and 7(1-imidazolyl)-heptanoic acid (7-IHA), in endotoxic shocked rats. Thirty minutes after intravenous (IV) administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma immunoreactive thromboxane B2 (TxB2) was increased from nondetectable levels (less than 200 pg/ml) in normal nonshocked rats to 2207 +/- 282 pg/ml (N = 16). The 6-keto-PGF1 alpha level was increased from nondetectable levels to 840 +/- 59 pg/ml (N = 8), and prostaglandin E rose from 146 +/- 33 to 2160 +/- 606 pg/ml (N = 5). Ibuprofen (3.75 mg/kg) or indomethacin (10 mg/kg) administered IV 30 min prior to endotoxin (20 mg/kg) improved the survival rate to 81% (N = 15, P less than 0.001) and 78% (N = 17, P less than 0.001), respectively, compared to the 24-hr survival of 8% (N = 26) in the vehicle-treated rats. Ibuprofen also inhibited the endotoxin-induced elevation of TxB2, 6-keto-PGF1 alpha, and fibrinogen/fibrin degradation products. Imidazole (30 mg/kg) or 7-IHA (30 mg/kg), IV, 30 min prior to endotoxin improved survival 65% (N = 11) and 81% (N = 15), respectively. These drugs also inhibited endotoxin-induced elevations in TxB2 and fibrinogen/fibrin degradation products, but did not inhibit endotoxin-induced elevations in plasma PGE. These results are consistent with the suggestion that TxA2 plays a role in the pathogenesis of endotoxic shock.
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D015237:Dinoprost; D004211:Disseminated Intravascular Coagulation / Q000097:blood; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D007052:Ibuprofen / Q000008:administration & dosage; D007213:Indomethacin / Q000008:administration & dosage; D008297:Male; D009115:Muridae; D011458:Prostaglandins E / Q000097:blood; D011460:Prostaglandins F / Q000097:blood; D012772:Shock, Septic / Q000097:blood* / Q000188:drug therapy; D013928:Thromboxane A2 / Q000097:blood*; D013931:Thromboxanes / Q000097:blood*
D005338:Fibrin Fibrinogen Degradation Products; D011458:Prostaglandins E; D011460:Prostaglandins F; D013931:Thromboxanes; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D015237:Dinoprost; D007052:Ibuprofen; D007213:Indomethacin