Beneficial effects of combined thromboxane and leukotriene receptor antagonism in hemorrhagic shock.

ABSTRACT

OBJECTIVE: Both thromboxane A2 and peptide leukotrienes D4/E4 have been implicated in the pathophysiology of circulatory shock. In the present study, we evaluated the effect of thromboxane A2 and leukotriene D4/E4 receptor antagonism in circulatory shock. DESIGN: Prospective, randomized, controlled trial. SETTING: Research laboratory. SUBJECTS: Male Sprague-Dawley rats (325 to 375 g). INTERVENTIONS: The effect of selective receptor antagonists of thromboxane A2 (i.e., SQ-29,548) and leukotrienes D4/E4 (i.e., LY-171883) was investigated, either alone or in combination, in a model of hemorrhagic circulatory shock. Animals were randomly assigned to one of eight experimental groups a) sham plus vehicle; b) sham plus LY-171883 (4 mg/kg); c) sham plus SQ-29,548 (2 mg/kg); d) sham plus SQ-29,548 (2 mg/kg) plus LY-171883 (4 mg/kg); e) hemorrhage plus vehicle; f) hemorrhage plus LY-171883 (4 mg/kg); g) hemorrhage plus SQ-29,548 (2 mg/kg); and h) hemorrhage plus SQ-29,548 (2 mg/kg) plus LY-171883 (4 mg/kg). Circulatory shock was induced by acute hemorrhage to a mean arterial pressure (MAP) of 45 mm Hg. We investigated the effect of SQ-29,548 and LY-171883 on the progression of circulatory shock. MEASUREMENTS AND MAIN RESULTS: Neither pharmacologic agent, alone or in combination, had any significant effect on MAP or heart rate in nonhemorrhaged rats. Both thromboxane receptor antagonism (p < .01) and combined thromboxane/leukotriene receptor antagonism (p < .001) significantly improved survival time after hemorrhage. However, leukotriene receptor antagonism alone did not significantly improve survival time after hemorrhage. After acute blood loss and 20% decompensation, the shed blood was returned to the animal; maximal postreinfusion blood pressures were not significantly different between experimental groups. The postreinfusion MAP was maintained at higher values in hemorrhaged rats given the thromboxane receptor antagonist or the combination of thromboxane and leukotriene receptor antagonists. Only the combined therapy significantly altered all of the measured indices of cardiovascular compensation (i.e., maximum bleed-out volume, time to maximum blood loss, and 20% decompensation time). Furthermore, only combined receptor antagonism resulted in a significant (p < .02) attenuation of plasma cathepsin D activity. CONCLUSIONS: The present findings support a role for thromboxane A2 and peptide leukotrienes D4/E4 as important mediators in circulatory shock and suggest that combined thromboxane/leukotriene receptor antagonism may have superior therapeutic efficacy to leukotriene receptor antagonism.