A PAF receptor antagonist, BN 52021, attenuates thromboxane release and improves survival in lethal canine endotoxemia.
Platelet-activating (PAF) is a putative mediator in endotoxemia and sepsis. Administration of a PAF receptor antagonist prior to endotoxin improves survival in rats and attenuates the hypotension of endotoxemia. Both PAF and endotoxin stimulate eicosanoid production. We hypothesized that a PAF receptor antagonist, BN 52021, would alter the hemodynamic events, improve the survival and attenuate the eicosanoid release associated with endotoxemia in a resuscitated, but lethal, canine model. Male dogs were randomzied to two groups (n = 10 each). Group I received only E. coli endotoxin, 1 mg/kg IV, at time 0, while group II received BN 52021, 5 mg/kg IV, 30 min before and again 240 min after endotoxin treatment. During the 4-h study period, hemodynamics were measured and blood samples were taken at 0, 2, 60, 120, and 240 min. Survival was determined at 24, 48, and 72 h. All group I animals died before 24 h; all group II lived longer than 72 h (P less than 0.05). In group I, plasma TXB2 values increased from a baseline value of 0.26 +/- .04 ng/ml to 4.38 +/- 1.56 ng/ml at 120 min and then decreased to 2.64 +/- .96 ng/ml by 240 min. For group II, respective plasma TXB2 values were 0.35 +/- 0.13 ng/ml at baseline, 0.58 +/- 0.14 ng/ml at 120 min, and 0.39 +/- .09 ng/ml at 240 min. At the 120-min and 240-min time points, the groups differed at P less than 0.05. Heart rate tended to be less in group II, but MAP was unaffected. In group I, pH values were more acidotic than those observed in group II.
Moore
J M
JM
School of Medicine, Vanderbilt University, Nashville, Tennessee.
Earnest
M A
MA
DiSimone
A G
AG
Abumrad
N N
NN
Fletcher
J R
JR
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D015232:Dinoprostone / Q000097:blood; D004224:Diterpenes; D004285:Dogs; D004731:Endotoxins / Q000097:blood*; D004926:Escherichia coli; D046934:Ginkgolides; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled; D012772:Shock, Septic / Q000503:physiopathology*; D013929:Thromboxane B2 / Q000097:blood*
D004224:Diterpenes; D004731:Endotoxins; D046934:Ginkgolides; D007783:Lactones; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C045856:ginkgolide B; D015232:Dinoprostone