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.
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.
D000118:Acetylglucosaminidase / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004731:Endotoxins / Q000037:antagonists & inhibitors; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006867:Hydrolases / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D008247:Lysosomes / Q000201:enzymology; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains
D004731:Endotoxins; D005663:Furans; D010972:Platelet Activating Factor; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran; D006867:Hydrolases; D000118:Acetylglucosaminidase