Thromboxane synthetase inhibitors in septic shock.
Thromboxane (TX) has been reported to cause mortality in endotoxin or septic shock. Cyclooxygenase inhibition improves survival in gram-negative or gram-positive shock. The exact level in the prostaglandin system of which the protection occurs is unknown. This study was designed to compare the effects of a cyclooxygenase inhibitor (indomethacin, IND) to a thromboxane synthetase inhibitor (IMI) on survival and on the production of Tx and prostacyclin (PGI2) in a clinically relevant rat gram-negative sepsis model. Three groups were studied: 1) control (N = 35) animals received E coli only; 2) IND (N = 35) treated animals received 3 mg/kg IP; 3) IMI (N = 35) treated animals received 30 mg/kg IP. All drugs were given 1 h after an IP injection of E coli (LD70) organisms. In this model only IND significantly improved survival. IND and IMI significantly blocked the production of Tx seen in septic shock. IND blocked PGI2 production whereas IMI increased the production. These results show that Tx may not be important in the irreversible stages of shock. Shunting prostaglandin production to PGI2 with thromboxane synthetase inhibitors needs to be considered when using this group of compounds. The mechanism of protection by IND remains unknown.
D000818:Animals; D003864:Depression, Chemical; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011460:Prostaglandins F / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D012772:Shock, Septic / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D011460:Prostaglandins F; D013929:Thromboxane B2; C029899:imidazole; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase; C100006:prostaglandin F1; D007213:Indomethacin