Gentamicin and indomethacin in the treatment of septic shock: effects on prostacyclin and thromboxane A2 production.
We investigated the effects of the thromboxane synthetase inhibitor 7-(1-imidazolyl)heptanoic acid (7-IHA) and the fatty acid cyclooxygenase inhibitors indomethacin or ibuprofen in the treatment of fecal peritonitis in the rat. The effects of gentamicin alone and in combination with reduction of arachidonic acid metabolism by either treatment with indomethacin or essential fatty acid deficiency was also investigated. 7-IHA (60 mg/kg), administered i.p. 30 min before i.p. instillation of a fecal suspension, significantly reduced the plasma levels of immunoreactive (i) TxB2 from 1066 +/- 194 pg/ml (N = 14) to nondetectable (less than 200 pg/ml; N = 9) (P less than .01) at 1 hr and from 1695 +/- 218 (N = 16) to 508 +/- 56 pg/ml (N = 6) (P less than .01) at 4 hr after instillation of feces. In contrast, the levels of i6-keto-prostaglandin (PG)F1 alpha, the stable metabolite of prostacyclin, were significantly elevated by 7-IHA pretreatment from vehicle-treated septic control levels of 3777 +/- 414 (N = 16) to 5185 +/- 467 pg/ml (N = 9) (P less than .05) at 1 hr. Plasma i6-keto-PGF1 alpha at 4 hr in 7-IHA-treated rats (5503 +/- 665 pg/ml) (N = 6) was not different from vehicle-treated controls. Survival associated with fecal peritonitis was not altered by 7-IHA pretreatment. Indomethacin (10 mg/kg) or ibuprofen (5 mg/kg) administered i.p. 30 min before the fecal suspension significantly decreased both iTxB2 and i6-keto-PGF1 alpha, plasma levels when measured at 4 hr and prolonged survival time (P less than .05). Fibrinogen/fibrin degradation products were elevated (P less than .01) during fecal peritonitis and were reduced by indomethacin (P less than .01) or 7-IHA (P less than .05). Gentamicin significantly increased mean survival time from 8.6 +/- 0.2 (N = 50) to 23.8 +/- 2.6 hr (N = 16) (P less than .01). Gentamicin in combination with indomethacin or essential fatty acid deficiency further improved mean survival time and resulted in long-term survivals (greater than 48 hr) of 35 (N = 17) and 30% (N = 7), respectively (P less than .01 compared with gentamicin). Gentamicin pretreatment did not significantly alter plasma iTxB2 levels, but decreased i6-keto-PGF1 alpha from 9465 +/- 792 (N = 7) to 3096 +/- 1,174 pg/ml (N = 5; P less than .01) at 6 hr after induction of fecal peritonitis. These studies raise the possibility that inhibition of fatty acid cyclooxygenase may be a useful adjunct to antibiotic therapy in the treatment of septic shock.
D000818:Animals; D011464:Epoprostenol / Q000096:biosynthesis*; D005228:Fatty Acids, Essential / Q000172:deficiency; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005839:Gentamicins / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D007052:Ibuprofen / Q000008:administration & dosage; D007093:Imidazoles / Q000008:administration & dosage; D007213:Indomethacin / Q000008:administration & dosage*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D010538:Peritonitis / Q000150:complications / Q000401:mortality; D011453:Prostaglandins / Q000096:biosynthesis*; D011460:Prostaglandins F / Q000097:blood; D051381:Rats; D012772:Shock, Septic / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013929:Thromboxane B2 / Q000097:blood; D013931:Thromboxanes / Q000096:biosynthesis*
D005228:Fatty Acids, Essential; D005338:Fibrin Fibrinogen Degradation Products; D005839:Gentamicins; D007093:Imidazoles; D011453:Prostaglandins; D011460:Prostaglandins F; D013931:Thromboxanes; D013929:Thromboxane B2; D013928:Thromboxane A2; C024335:1-(7-carboxyhexyl)imidazole; D011464:Epoprostenol; C100006:prostaglandin F1; D007052:Ibuprofen; D007213:Indomethacin