Effects of L-652,731, a platelet-activating factor (PAF) receptor antagonist, on PAF- and complement-induced...

Thromboxane-mediated pulmonary hypertension, pulmonary edema, arterial hypoxia and pulmonary leukostasis occur in response to the infusion of plasma containing zymosan-activated complement (ZAP) in sheep. Platelet-activating factor (PAF) is a potential mediator of some of these effects. We investigated the effects of PAF infusions in unanesthetized sheep and the effects of the PAF receptor antagonist L-652,731 [trans-2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran] on the hematologic, hemodynamic and biochemical alterations produced by infusions of both ZAP and PAF. Infusions of 2 to 20 micrograms of PAF in 0.25% ovine serum albumin-saline produced pulmonary hypertension, hypoxia and dose-dependent thrombocytopenia, neutropenia and thromboxane synthesis. The effects of a 2 micrograms of PAF infusion were both qualitatively and quantitatively similar to those produced by a ZAP infusion. Pretreatment with aspirin (10 mg/kg) protected the sheep against the pulmonary vascular response to 20 micrograms of PAF and blocked completely the thromboxane synthesis. L-652,731 at a dose of 8 mg/kg blocked completely the neutropenia, thrombocytopenia, thromboxane synthesis, pulmonary hypertension and hypoxia induced by 5 micrograms of PAF, but this protective effect was not observed in animals infused with ZAP. These results indicate that PAF is probably not a mediator of the neutropenia, thromboxane-mediated pulmonary hypertension and hypoxia which result from the infusion of ZAP into sheep.