Protective effects of a new LTD4 antagonist (LY-171883) in traumatic shock.

We studied the effects of a selective antagonist of LTD4 (LY-171883, 2 and 4 mg/kg) in traumatic shock. Anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by a survival time of 1.7 +/- 0.3 h, a sixfold increase in plasma cathepsin D activity, and a fourfold increase in plasma myocardial depressant factor (MDF) activity. Administration of LY-171883 did not significantly inhibit the release of the lysosomal hydrolase cathepsin D during traumatic shock. However, LY-171883 (2 mg/kg) significantly attenuated the accumulation of MDF activity in the plasma (51 +/- 2 vs 37 +/- 3 U/ml), vehicle vs drug, respectively, and significantly (p less than 0.02) prolonged survival time to 2.7 +/- 0.2 h. Administration of the antagonist at a dose of 4 mg/kg further improved survival time (3.4 +/- 0.6 h, p less than 0.01) and additionally blunted circulating MDF activities compared to traumatized rats given only the vehicle. LY-171883 was found to antagonize the bronchoconstrictor effect of LTD4 given intravenously to anesthetized rats as well as the coronary vasoconstrictor actions of LTD4 in vitro. The beneficial effect of LTD4 antagonism in the present study is consistent with the concept that peptide leukotrienes are important mediators of the pathogenesis of traumatic shock.