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.