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)