Efficacy of a combination thromboxane receptor antagonist and lipoxygenase inhibitor in traumatic shock

The effects of a thromboxane receptor antagonist having lipoxygenase inhibitory activity, L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]2,2-dimethylpropa noic acid) (1 mg/kg per h) were studied in a standardized model of traumatic shock. Pentobarbital (35 mg/kg) anesthetized rats subjected to Noble-Collip drum trauma were characterized by a 82 +/- 12 min survival time, a 20-fold increase in plasma cathepsin D activity, and a 6-fold increase in plasma myocardial depressant factor (MDF) activity. L-655,240 significantly attenuated the accumulation of MDF activity in the plasma (74 +/- 3 vs. 46 +/- 4 units/ml), vehicle vs. drug, respectively, and significantly (P less than 0.01) prolonged survival time to 206 +/- 26 min. However, plasma cathepsin D was not significantly altered with L-655,240 administration during traumatic shock. L-655,240 at 20 micrograms/ml markedly attenuated minced rat lung fragments from producing LTC4 and LTD4.L-655,240 exhibited significant anti-proteolytic activity in pancreatic homogenates. Therefore, L-655,2340 does not stabilize lysosomal membranes directly, but exerts an anti-proteolytic action which appears to curtail the production of a myocardial depressant factor by the ischemic pancreas, thus protecting during traumatic shock. A combination anti-eicosanoid drug such as L-655,240 may therefore prove to be an important therapeutic agent in acute ischemic disorders including traumatic shock.