Beneficial actions of antagonism of peptide leukotrienes in hemorrhagic shock.

The peptide leukotrienes are biologically active eicosanoids which have recently been implicated as possible mediators of anaphylactic, endotoxic, traumatic, and splanchnic artery occlusion shock. We studied the effects of a novel selective peptide leukotriene antagonist, L-649,923, in a rat model of hemorrhagic shock. Hemorrhaged rats treated with L-649,923 (1 mg/kg/h) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving either 0.9% NaCl or a lower dose (0.2 mg/kg/h) of L-649,923 (final MABP 97 +/- 4 vs 60 +/- 5, p less than 0.01; vs 60 +/- 4 mm Hg, p less than 0.01, respectively). Both doses of L-649,923 attenuated the increase in plasma cathepsin D activity (p less than 0.01). L-649,923, at 1 mg/kg/h, also attenuated the plasma accumulation of free amino-nitrogen compounds (p less than 0.05). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in rats treated with L-649,923 (1 mg/kg/h) than in rats receiving the lower dose of the drug or the vehicle (36 +/- 5 U/ml vs. 61 +/- 4 U/ml, p less than 0.01; and 60 +/- 3 U/ml, p less than 0.01, respectively). Furthermore, L-649,923 does not inhibit platelet aggregation in platelet rich plasma. Our data suggest that peptide leukotrienes are important mediators of hemorrhagic shock and that blockade of leukotriene-induced vasoconstriction may underlie the beneficial effects of L-649,923 in hemorrhagic shock.