Beneficial effects of LY203647, a novel leukotriene C₄/D₄ antagonist, on pulmonary function and mesenteric perfusion in a porcine model of endotoxic shock and ARDS

The sulfidopeptide leukotrienes (LT) have been implicated as important pathophysiological mediators in septic shock. To further define the role of these compounds, we utilized a porcine endotoxicosis model to study the effects of pre- and concurrent treatment with LY203647, a novel LT receptor antagonist. Pentobarbital-anesthetized pigs (13-20 kg) were mechanically ventilated with 100% O₂. Superior mesenteric arterial flow (Q̇sma) was measured using an ultrasonic flow probe. Ileal intramucosal hydrogen ion concentration, [H⁺]₁, was estimated tonometrically. Pigs in groups I and II were infused with endotoxin (250 μg/kg) and resuscitated with saline (1.2 ml/kg min). Group I (n = 8) were controls; Group II (n = 8) were pretreated with LY203647 (30 mg/kg bolus, then 10 mg/kg h). Treatment with LY203647 persistently and significantly (P < .05) improved post-LPS pO₂ and transiently improved Q̇sma. Treatment with LY203647 did not affect [H⁺]₁. Lung extravascular wet-to-dry weight ratios were 7.13 ± .33 and 5.43 ± .09 in groups I and II, respectively (P < .001). These data suggest that sulfidopeptide LT are important mediators of key pathophysiologic events in this porcine model of endotoxic shock and the adult respiratory distress syndrome (ARDS).