A leukotriene and thromboxane inhibitor (Sch 37224) blocks antigen- induced immediate and late responses and airway hyperresponsiveness in allergic sheep

WM Abraham, JS Stevenson and R Garrido

Pulmonary Division, Harry Pearlman Biomedical Research Institute, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida.

Peptide leukotrienes and thromboxane A2 are putative mediators of allergen-induced late responses and allergen-induced airway hyperresponsiveness (AHR), respectively. Sch 37224 blocks antigen- induced leukotriene D4 and thromboxane B2 release in guinea pig lung fragments. It also inhibits leukotriene-mediated allergic guinea pig bronchospasm. Sch 37224 was, therefore, tested in allergic sheep (n = 6) with documented immediate and late airway responses and AHR to inhaled Ascaris suum antigen. For these studies, base-line airway dose- response curves to histamine and carbachol were determined on the same day. The sheep were challenged 1 to 2 days later with Ascaris suum antigen, once after placebo treatment and once after 10 mg/kg of Sch 37224, administered orally 18 and 2 hr before challenge (total dose, 20 mg/kg). Airway dose-response curves were subsequently performed 24 hr after antigen challenge. In the placebo trial, antigen challenge caused significant peak immediate and peak late increases over base line in specific lung resistance (SRL) of 286 +/- 51 and 196 +/- 29%, respectively. SRL returned to baseline values 24 hr later, but the sheep had AHR to both histamine and carbachol as indicated by 2.6- and 3.1-fold increases in the slopes of the dose-response curves (P less than .05). Sch 37224 treatment reduced the peak immediate and peak late increases in SRL to 128 +/- 32 and 43 +/- 17%, respectively (both P less than .05 vs. placebo). Furthermore, 24 hr later, the antigen- induced AHR to both histamine and carbachol was blocked (P less than .05 vs. placebo).(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 247, Issue 3, pp. 1004-1011, 12/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics