Limited interference of specific Paf antagonists with hyper-responsiveness to Paf itself of lungs from actively sensitized guinea-pigs

Abstract

1. The interference of various platelet-activating factor (Paf) antagonists with Paf- and antigen-induced effects in isolated lungs from actively sensitized guinea-pigs was investigated. 2. WEB 2086 and BN 52021, two antagonists structurally unrelated to Paf, at concentrations 10-100 fold above those exerting a potent and selective inhibition of the effects of Paf in lungs from non-immunized guinea-pigs, failed to inhibit bronchoconstriction and mediator release evoked by the phospholipid when administered into lungs from actively sensitized animals. 3. In contrast to WEB 2086 and BN 52021, antagonists such as Ro 19-3704 and Ro 19-1400, structurally related to the Paf molecule, at concentrations which abrogate the effects of Paf in lungs from non-immunized guinea-pigs, inhibited bronchoconstriction and release of histamine and leukotriene-like material evoked by the intra-arterial administration of Paf into lungs from actively sensitized animals. 4. Ro 19-3704 and Ro 19-1400 also inhibited markedly the release of leukotriene C4 (LTC4)-like material and, to a smaller extent, the histamine secretion induced by 10 micrograms arachidonic acid. 5. CV 6209, another Paf antagonist structurally related to the phospholipid, failed to antagonize its bronchopulmonary and secretory effects in sensitized lungs. 6. All the antagonists used, irrespective of their ability to interfere or not with bronchoconstriction and mediator release triggered by Paf, suppressed oedema formation as measured by the increase in lung wet weight induced by either Paf or ovalbumin. 7. Our results indicate that: (i) the increase in vascular permeability and the subsequent oedema formation on one hand and the bronchopulmonary effects of Paf on the other hand are mediated by different mechanisms; and (ii) active sensitization provokes a marked modification of the lung reactivity to Paf.