Interference of the Paf antagonist Ro 19–3704 with Paf and antigen‐induced bronchoconstriction in the guinea‐pig

Abstract

In vitro, Ro 19–3704, a structurally related antagonist of platelet‐activating factor (Paf) inhibited selectively rabbit platelet aggregation. In vivo, administered intravenously, it inhibited bronchoconstriction, leukopenia, thrombocytopenia and the accompanying accumulation of platelet aggregates in guinea‐pig lung microvessels induced by i.v. Paf. Administered by aerosol, Ro 19–3704 failed to inhibit bronchoconstriction, thrombocytopenia or leukopenia due to i.v. Paf. Bronchoconstriction induced by Paf, in aerosol form, was blocked by Ro 19–3704 administered by the i.v. or aerosol route, which suggests that it interacts with pulmonary cells responsible for bronchoconstriction. Ro 19–3704 has free radical scavenging properties, since it inhibited the production of superoxide anions by macrophages stimulated by Paf and by N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP). Ro 18–7715, another Paf antagonist and analogue of Ro 19–3704, failed to inhibit the production of superoxide anions by macrophages stimulated by FMLP at concentrations which were effective against Paf. Administered intravenously, Ro 19–3704 failed to block bronchoconstriction induced by an i.v. injection of ovalbumin to guinea‐pigs passively sensitized with anti‐ovalbumin antiserum. Passive pulmonary anaphylaxis due to an aerosol of ovalbumin was blocked by i.v. Ro 19–3704.

Interference of BN 52021, an antagonist of PAF, with different forms of active anaphylaxis in the guinea‐pig: importance of the booster injection

“…OA are probably accounted for by both PAF-dependent and independent mechanisms, which may explain the failure of BN 52021 to inhibit bronchoconstriction. Lagente et al (1988) suggested that local bronchopulmonary anaphylaxis is highly dependent upon the in situ generation of PAF and indeed, Fitzgerald et al (1985) demonstrated that large amounts of PAF are formed when antigen is given directly into the trachea of perfused lungs, which is much less apparent when the vascular route is used. For these reasons, we delivered BN 52021 as well as antigen i.t., to reach the bronchopulmonary system directly.…”

Inhibitory effects of OKY-046 on spasmogen-induced bronchoconstrictions in sensitized and non-sensitized guinea pigs.

“…Further more, Lagente et al (25) demonstrated that Ro 19-3704, a PAF antagonist. inhibits ana phylactic bronchoconstriction.…”

“…PAF induces platelet-dependent bronchoconstriction (26) and stimulates the release of TXA2 from guinea pig lung tissue (27). Furthermore, PAF causes platelet aggregation, platelet and neutrophil diapedesis immediately after its systemic administration in guinea pigs (25,28). Therefore, it is possible that the inhibitory effects of OKY-046 and indomethacin against PAF-induced bronchoconstrictions are at tributable to the inhibition of PAF-induced TXA2 generation through platelet aggregation.…”

Intracellular platelet‐activating factor regulates eicosanoid generation in guinea‐pig resident peritoneal macrophages

“…Thus, Paf may act to upregulate other transduction pathways. Superoxide anion production by guinea-pig alveolar macrophages in response to fMLP is inhibited by another Paf receptor antagonist, Ro 19-3704 (Lagente et al, 1988). These authors suggested that this effect was due to an ability to scavenge free radicals but did not directly test this hypothesis.…”