Inhibition by SRI 63-072 and SRI 63-119 of PAF-acether and immune complex effects in the guinea pig.

We have examined two PAF-acether receptor antagonists, SRI 63-072 and SRI 63-119, for their ability to inhibit PAF-acether and immune complex effects in the guinea pig. Both compounds exhibited dose-dependent inhibition of bronchoconstriction and hemoconcentration induced by 0.1 micrograms kg-1 PAF-acether, where the ED50 values of SRI 63-072 were 0.3/0.4 mg kg-1 i.a. and 0.14/0.17 mg kg-1 i.a. for SRI 63-119 for each response, respectively. The d and 1 chiral forms of both antagonists were equipotent towards inhibition of hemoconcentration and bronchoconstriction, suggesting a lack of enantiomeric selectively. SRI 63-072 was further evaluated for its ability to inhibit dermal extravasation in the reverse passive Arthus reaction. Guinea pigs given 125I-BSA i.v as antigen and anti-BSA antibodies by intradermal injection exhibited plasma leakage that was dose- and time-dependent relative to the antibody amount. SRI 63-072 exhibited 46% maximal inhibition of dermal plasma leakage when injected in the skin (100 micrograms site-1 i.d.) with the antibody but less than 10% inhibition when administered intra-arterially (3.0 mg kg-1 i.a.) with the antigen. Therefore, these antagonists effectively inhibit systemic effects of PAF-acether and are partially effective towards inhibition of the dermal extravasation induced by immune complexes. Furthermore, unlike the enantiomeric differences between R and S PAF-acether, the chiral molecules of 63-119 and 63-072 effectively antagonized hemoconcentration and bronchoconstriction induced by PAF-acether.