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Prevention and reversal of aerosol LTD4-induced changes in guinea pig pulmonary mechanics by Wy-48252, an orally active LTD4/E4 receptor antagonist.

Anesthetized male albino guinea pigs were prepared for recording changes in the pulmonary mechanics parameters, dynamic compliance (Cdyn) and airway conductance (Gaw). Two aerosol leukotriene D4 (LTD4) challenges (0.125 microgram/ml, 3-7 breaths, 1 h apart) were administered via an ultrasonic nebulizer to each animal and, produced reductions in Cdyn that were approximately 60% of those of Gaw. Intraduodenal administration of the LTD4/E4 receptor antagonists Wy-48252 (30 min), Wy-45911 and Ly-171883 (15 min) produced dose-related inhibition of the second LTD4 challenge. From the data, ID50 values were calculated and, Wy-48252 was 8- to 17-fold more potent (mg/kg) than Wy-45911 or Ly-171883. Responses to histamine were not altered by the antagonists. In separate experiments, Wy-48252 (0.3 and 1 mg/kg i.v.) rapidly reversed aerosol LTD4-induced decreases of Cdyn and Gaw, but did not reverse pulmonary mechanics decreases produced by prostaglandin F2 alpha. The results indicate that systemically administered LTD4 receptor antagonists can both prevent and reverse bronchoconstriction produced by aerosol LTD4 in the guinea pig.