Use of a novel peptide leukotriene receptor antagonist, Ly-163443, in splanchnic artery occlusion shock.

ABSTRACT

We studied the effects of LY-163443, a novel selective receptor antagonist of LTD4 and LTE4, in splanchic artery occlusion (SAO) shock. LY-163443 antagonized the bronchoconstrictor effect of LTD4 given intravenously to anesthetized rats. Anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 minutes developed a severe shock state usually resulting in a fatal outcome within two hours after release of the occlusion. SAO shock rats pre-treated with LY-163443 before the occlusion of the splanchnic arteries maintained post-release MABP at significantly higher values compared to rats receiving either the vehicle or LY-163443 as a post-treatment 15 min after occlusion (final MABP 96 +/- 8 vs 51 +/- 1, p less than 0.01 and 53 +/- 3, p less than 0.01, respectively). Pre-treatment with LY-163443 attenuated the release of the lysosomal hydrolase, cathepsin D (p less than 0.01 from vehicle and p less than 0.05 from post-treatment groups), and the plasma accumulation of free amino-nitrogen compounds (p less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in the pre-treatment group than in the vehicle group (27 +/- 3 vs 51 +/- 6 U/ml, p less than 0.01). SAO shock rats pretreated with LY-163443 also exhibited significantly higher survival rates (p less than 0.01 from vehicle and post-treatment groups), and prolonged survival times (p less than 0.01 from vehicle and post-treatment groups).(ABSTRACT TRUNCATED AT 250 WORDS)