The pharmacologic activities of leukotrienes C-i and D (LTC-1 and LTD), constituents of slow reacting substance of anaphylaxis (SRS-A), were evaluated in vitro on airway contractile tissues and in vivo on pulmonary mechanical function, mean systemic arterial pressure, and cutaneous microcirculation. In vitro both LTC-Land LTD were potent and selective peripheral airway agonists, being more active than histamine; furthermore, LTD was active on peripheral airways at concentrations 1/100th those of LTC-1. The concentration-effect relationship for LTD and the profile of antagonism by FPL 55712 are consistent with the activity. of this molecule at two separate peripheral airway receptors. Ii vivo, LTC1 and LTD were nearly equally active in their effects on pulmonary mechanics, and the pattern of alterations was consistent with the predominant site of action being in the lung periphery. Furthermore, both agents had a direct systemic arterial hypotensive effect and were vasoactive on the cutaneous microcirculation. Thus, these compounds are likely to be major mediators of the pathologic alterations in immediate type hypersensitivity reactions in which peripheral airway constriction and hypotension are prominent features.Slow reacting substance of anaphylaxis (SRS-A) (1), which is an activity generated during immediate type hypersensitivity reactions (2), has been found to be composed of leukotrienes C-i (LTC-1) and D (LTD) (3). Native SRS-A has a unique profile of contractile activity in vitro in smooth muscle preparations (4). Both partially and highly purified native SRS-A produced by an anaphylactic reaction in the rat peritoneal cavity (SRS-Arat) exhibit a preferential contractile activity for guinea pig pulmonary parenchymal strips compared to musculus trachealis (5), and LTC-1 and LTD exhibit the same differential effect, at concentrations less than 0.1% of those required for histamine to be active (3). Partially purified SRS-Arat augments vascular permeability when injected into guinea pig skin (6). When administered intravenously into the unanesthetized guinea pig, it produces an alteration in pulmonary mechanics consistent with peripheral rather than central airway action (7). We have now demonstrated that intravenous infusion of LTC-1 and LTD alters pulmonary mechanics in unanesthetized and anesthetized guinea pigs in a manner similar to native partially purified SRS-Arat and that, in addition, these newly described products of arachidonate metabolism (8-10) can differ in their actions on the cutaneous microvasculature and on mean systemic arterial pressure.MATERIALS AND METHODS LTC-1 and LTD were prepared as described (3, 10), sealed in ampoules in 10% methanol under argon, and stored frozen until the day of use. Histamine diphosphate was obtained from Sigma. FPL 55712, a specific SRS-A antagonist, was a gift from P. Sheard (Fisons Pharmaceuticals, Ltd., U.K.).Tracheal spirals and parenchymal strips were prepared for recording isometric contractile activity (5) and allowed to relax to baseline tensi...
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