Effects of L-652,731, a platelet-activating factor (PAF) receptor antagonist, on PAF- and complement-induced pulmonary hypertension in sheep.
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.
Smallbone
B W
BW
Department of Medicine, University of Western Ontario, London, Canada.
Taylor
N E
NE
McDonald
J W
JW
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D003167:Complement Activation; D003165:Complement System Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000209:etiology*; D000860:Hypoxia / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled; D012756:Sheep; D013931:Thromboxanes / Q000502:physiology; D015054:Zymosan / Q000494:pharmacology
D004731:Endotoxins; D005663:Furans; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013931:Thromboxanes; C039351:platelet activating factor receptor; D003165:Complement System Proteins; D015054:Zymosan; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran; D001241:Aspirin