ANTAGONISM OF THE PULMONARY EFFECTS OF THE PEPTIDOLEUKOTRIENES BY A LEUKOTRIENE-D4 ANALOG

Abstract

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 [may represent novel antiallergic therapy]. 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 LT, 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. [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. A structural analog of the peptidoleukotrienes can evidently pharmacologically antagonize the potent actions of these LT.