Antagonism of the pulmonary effects of the peptidoleukotrienes by a leukotriene D4 analog

BM Weichman, MA Wasserman, DA Holden, RR Osborn, DF Woodward, TW Ku and JG Gleason

4R-hydroxy-5S-cysteinylglycine-6-Z-nonadecenoic acid (4R,5S, 6Z-2-nor- LTD1), a structural analog of leukotriene (LT) D4 (LTD4), significantly antagonized the pulmonary actions of LTD4 in several guinea pig models of LT-mediated bronchoconstriction and edema formation. In vitro, 4R,5S,6Z-2-nor-LTD1 (10(-5) and 10(-4) M) antagonized the LTD4-induced contraction of tracheal spirals and lung parenchymal strips. This antagonist action of 4R,5S,6Z-2-nor-LTD1 was specific for the LTs, in that LTC4- and LTE4-induced contractions of the trachea were also antagonized, whereas the contractions elicited by other spasmogens, e.g., histamine, carbachol, prostaglandin F2 alpha and KCl, were not antagonized. In vivo, the LTD4-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs as reflected by decreases in dynamic lung compliance and airway conductance were attenuated significantly by a 1-min pretreatment with 4R,5S,6Z-2-nor- LTD1 at 5 mg/kg i.v. Similarly, the LTD4-induced increase in tracheal microvascular permeability, as assessed by extravasation of [125I]bovine serum albumin, was blocked by pretreatment with 4R,5S,6Z-2- nor-LTD1. These results provide the first demonstration that a structural analog of the peptidoleukotrienes can pharmacologically antagonize the potent actions of these LTs.

Volume 227, Issue 3, pp. 700-705, 12/01/1983
Copyright © 1983 by American Society for Pharmacology and Experimental Therapeutics