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.