Inhibitors of lipoxygenase products improve survival in traumatic shock.
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.
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
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