Platelet activating factor (PAF) and tumor necrosis factor-alpha (TNF alpha) interactions in endotoxemic shock: studies with BN 50739, a novel PAF antagonist.
BN 50739, a new PAF receptor antagonist, was tested in vitro and in vivo for its capacity to block PAF, endotoxin and recombinant human tumor necrosis factor-alpha (rTNF)-mediated effects. In vitro, BN 50739 blocked PAF-induced platelet aggregation by 60 to 100% at 0.2-1 x 10(-7) M (P less than .002), respectively. In the conscious rat, pretreatment (30 min) with BN 50739 (n = 5-13) dose-dependently attenuated PAF-induced hypotension (-5 +/- 5 vs. - 43 +/- 2 mm Hg, P less than .01) and shortened the recovery time of mean arterial pressure (22 +/- 13 vs. 325 +/- 46 sec, P less than .01). BN 50739 (10 mg/kg i.p., n = 5-11) prevented endotoxin (14.4 mg/kg) induced-hemoconcentration (54 +/- 1 vs. 46 +/- 1%, P less than .01) and reduced 24-hr mortality (100 vs. 60%, P less than .05). Only partial protection was conveyed by BN 50739 against the hypotensive response to endotoxin (115 +/- 3 vs. 91 +/- 4 mm Hg, P less than .03). Also, BN 50739 attenuated the lipopolysaccharide-induced elevation of plasma thromboxane B2 (21.2 +/- 0.8 vs. 46.7 +/- 11.8 pg/100 microliters, P less than .01) and tumor necrosis factor-alpha (7523 +/- 3983 vs. 26,430 +/- 3541 U/ml, P less than .05), whereas leukopenia and thrombocytopenia remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Smithkline Beecham Laboratories, King of Prussia, Pennsylvania.
R
R
Rabinovici
T L
TL
Yue
M
M
Farhat
E F
EF
Smith
K M
KM
Esser
M
M
Slivjak
G
G
Feuerstein
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001773:Blood Cells / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D012772:Shock, Septic / Q000378:metabolism / Q000517:prevention & control*; D013931:Thromboxanes / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis* / Q000494:pharmacology
D001381:Azepines; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D013931:Thromboxanes; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C064509:BN 50739