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 endo toxin (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 mu g/kg), spaced 24 h apart. SRI 63-675 significantl y lowered peak tumor necrosis factor levels after LPS challenge. Admin istration of SRI 63-675 around either the first (150 mg/kg) or second LPS dose (120 mg/kg), however, did not prevent coagulation. The unexpe cted high mortality after combined administration of SRI 63-675 and LP S precluded assessment of PAF inhibition around both LPS doses on coag ulation. 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 i ntrinsic toxic effect of SRI 63-675 cannot be ruled out, it is suggest ed that endotoxin may have primed the rabbit to the lethal, PAF-like, effects of SRI 63-675.