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

Abstract

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.

• Authors: B W Smallbone, N E Taylor, J W McDonald
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 242 Issue 3 Pg. 1035-40 (Sep 1987) ISSN: 0022-3565 [Print] United States
• PMID: 2821222 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endotoxins
• Furans
• Platelet Activating Factor
• Platelet Membrane Glycoproteins
• Receptors, Cell Surface
• Receptors, G-Protein-Coupled
• Thromboxanes
• platelet activating factor receptor
• Complement System Proteins
• Zymosan
• 2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran
• Aspirin

Topics

• Animals
• Aspirin (pharmacology)
• Complement Activation
• Complement System Proteins (physiology)
• Dose-Response Relationship, Drug
• Endotoxins (toxicity)
• Female
• Furans (pharmacology)
• Hypertension, Pulmonary (chemically induced, etiology)
• Hypoxia (chemically induced)
• Neutropenia (chemically induced)
• Platelet Activating Factor (antagonists & inhibitors)
• Platelet Membrane Glycoproteins
• Receptors, Cell Surface (drug effects)
• Receptors, G-Protein-Coupled
• Sheep
• Thromboxanes (physiology)
• Zymosan (pharmacology)