title: Inhibitors of lipoxygenase products improve survival in traumatic shock.
abstract: We have used three selective inhibitors of arachidonic acid metabolism in order to investigate the role of lipoxygenase metabolites in the pathogenesis of traumatic shock (LD90). The following inhibitors were used: CGS-5391B (2.5 mg/kg), a cyclooxygenase and lipoxygenase inhibitor, CGS-5677 (2.0 mg/kg), a selective lipoxygenase inhibitor, and U-60,257 (0.3 mg/kg), a putative inhibitor of glutathione-s-transferase. These inhibitors did not alter arterial blood pressure or heart rate when given to sham shock rats. The traumatic shock model was characterized by a 4.5-fold increase in plasma cathepsin D activity, a 4-fold increase in plasma myocardial depressant factor (MDF) activity, and a mean survival time of 1.5 +/- 0.2 h. Only the dual inhibitor significantly blunted the accumulation of cathepsin D in the plasma (7.5 +/- 0.8 vs 11.3 +/- 0.8 U/ml, p less than 0.01). However, all three inhibitors significantly suppressed plasma MDF accumulation by 50-60%: CGS-5391B, CGS-5677, and U-60,257 (p less than 0.01). Moreover, these three agents significantly improved survival time in traumatic shock. The increased survival time and reduced MDF activity afforded by these inhibitors suggest a significant role for lipoxygenase metabolites, particularly LTC4 and LTD4, in the pathogenesis of traumatic shock.
mesh_terms: D000818:Animals; D001091:Arachidonate Lipoxygenases; D001582:Benzothiepins / Q000627:therapeutic use; D001794:Blood Pressure; D016861:Cyclooxygenase Inhibitors; D011464:Epoprostenol / Q000627:therapeutic use / Q000031:analogs & derivatives; D006321:Heart / Q000187:drug effects; D008084:Lipoxygenase / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors; D008297:Male; D008954:Models, Biological; D009930:Organic Chemicals; D051381:Rats; D011919:Rats, Inbred Strains; D012769:Shock / Q000188:drug therapy / Q000401:mortality*; D013997:Time Factors
chemical_list: D001582:Benzothiepins; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D009930:Organic Chemicals; C044156:CGS 5677; D011464:Epoprostenol; D001091:Arachidonate Lipoxygenases; D008084:Lipoxygenase; C035296:piriprost; C044155:enolicam