The effect of SRI 63-675, a competitive platelet-activating factor receptor-antagonist, in the generalized Shwartzman reaction.
Evidence indicates a role for platelet-activating factor (PAF) in endotoxin (LPS)-induced shock. To determine its involvement in LPS-induced intravascular coagulation, we assessed the efficacy of SRI 63-675, a specific PAF receptor antagonist, to prevent fibrin deposition in the various organs of New Zealand White rabbits 4 h after two intravenous doses of LPS (100 micrograms/kg), spaced 24 h apart. SRI 63-675 significantly lowered peak tumor necrosis factor levels after LPS challenge. Administration of SRI 63-675 around either the first (150 mg/kg) or second LPS dose (120 mg/kg), however, did not prevent coagulation. The unexpected high mortality after combined administration of SRI 63-675 and LPS precluded assessment of PAF inhibition around both LPS doses on coagulation. Sole administration of SRI 63-675 induced rapid and transient changes in peripheral blood cell counts, and blood pressure and heart rate suggestive of intrinsic PAF-like activity. Although some other intrinsic toxic effect of SRI 63-675 cannot be ruled out, it is suggested that endotoxin may have primed the rabbit to the lethal, PAF-like, effects of SRI 63-675.
Gans
R O
RO
Department of Pathology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo.
DiPirro
J C
JC
Ueda
Y
Y
Niesen
N
N
Lee
K H
KH
Brentjens
J R
JR
D000818:Animals; D001772:Blood Cell Count / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D006400:Hematocrit; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000627:therapeutic use* / Q000633:toxicity; D011817:Rabbits; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012790:Shwartzman Phenomenon / Q000378:metabolism / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011804:Quinolines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor; C053130:SRI 63-675