Compound PCA-4248 interferes with bronchopulmonary anaphylaxis and with in vitro hyperresponsiveness to platelet-activating factor

Abstract

The intravenous (i.v.) or oral administration of the platelet-activating factor (PAF) antagonist, PCA-4248, to guinea-pigs blocked selectively the bronchoconstriction induced by PAF, as well as the accompanying thrombocytopenia and leucopenia. In addition, PCA-4248 i.v. or intratracheal (i.t.) administration blocked the bronchoconstriction caused by the i.t. instillation of PAF. As in the case of other PAF antagonists, bronchoconstriction caused by the i.t. instillation of antigen was only inhibited by PCA-4248 in guinea-pigs that did not receive a booster injection of antigen during sensitization whereas the booster injection of antigen made anaphylactic bronchoconstriction resistant to the compound. In vitro, when lungs from non-sensitized guinea-pigs were perfused with Krebs-bovine serum albumin (BSA) solution supplemented with PCA-4248, bronchoconstriction and the formation of thromboxane A2 by PAF were blocked. In this in vitro model of perfused lungs, active sensitization with a booster injection of antigen leads to bronchopulmonary hyperresponsiveness to PAF and failure of other PAF antagonists to inhibit the effects of PAF itself. Surprisingly, in lungs isolated from actively sensitized and boosted guinea-pigs, PCA-4248 blocked the effects of PAF, indicating that this compound possesses additional original properties in this model.