Inhibition of the platelet activating factor (PAF)-induced in vivo responses in rats by trans-2,5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (L-652,731), a PAF receptor antagonist.

Abstract

Trans-2,5-bis-(3,4,5-trimethoxyphenyl)tetrahydrofuran (L652, 731), a potent and specific receptor antagonist of platelet activating factor (PAF) (Hwang et al., J. Biol. Chem. 260: 15639-15645, 1985), potently inhibits several PAF-induced in vivo responses in rats. Intravenously and p.o. administered L-652,731 gave a dose-response inhibition of PAF-induced lysosomal hydrolase secretion and extravasation with ED50 values of 1 and 3 mg/kg, respectively. Inhibitions of 87% were achieved with 50 mg/kg p.o. After a single 5-mg/kg p.o. dose, L-652,731 achieved 50 to 60% inhibition of PAF-induced lysosomal hydrolase secretion and extravasation by 0.5 to 1.5 hr with near maximum inhibition lasting through 6 hr. A 20-mg/kg p.o. dose of L-652,731 inhibited PAF-induced leukopenia and neutropenia by 96 and 73%, respectively. The most substantial inhibitions of the extravasation and lysosomal hydrolase secretion induced by PAF or soluble immune complexes were achieved by p.o. L-652,731 (20 mg/kg) with moderate inhibition by dexamethasone and little or no inhibition by antagonists/inhibitors of histamine H1 or H2 or serotonin receptors or cyclooxygenase. Intravenous infusion of a 0.4 mg of L-652,731 bolus inhibited the hypotensive responses from subsequent PAF infusions by a maximum of 72% and with a half-life duration of action of 2.5 hr. Intravenous infusion of L-652,731 results in an immediate 87% reversal of the extreme hypotension induced by a previous endotoxin injection. Thus, with its good p.o. activity, long duration of action and specificity in inhibiting PAF-induced responses in vivo, L-652,731 is a very useful tool in determining the role of PAF in mediating different pathophysiological processes.

• Authors: M S Wu, T Biftu, T W Doebber
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 239 Issue 3 Pg. 841-5 (Dec 1986) ISSN: 0022-3565 [Print] United States
• PMID: 3795043 (Publication Type: Journal Article)

Chemical References

• Endotoxins
• Furans
• Platelet Activating Factor
• 2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran
• Hydrolases
• Acetylglucosaminidase

Topics

• Acetylglucosaminidase (metabolism)
• Animals
• Blood Pressure (drug effects)
• Endotoxins (antagonists & inhibitors)
• Female
• Furans (pharmacology)
• Hydrolases (metabolism)
• Leukopenia (chemically induced, prevention & control)
• Lysosomes (enzymology)
• Neutropenia (chemically induced, prevention & control)
• Platelet Activating Factor (antagonists & inhibitors)
• Rats
• Rats, Inbred Strains