1. The effects of the selective and potent novel
platelet-activating factor (PAF) antagonist,
UR-12633 (1-(3,3-diphenylpropionyl)-4-(3-pyridylcyanomethyl)piperidin e) on several markers of endotoxic
shock syndrome were evaluated in rats and mice. 2.
UR-12633, administered 60 min after E. coli
lipopolysaccharide (LPS), reversed the LPS-induced sustained
hypotension in rats at doses of 0.01 to 1 mg kg-1, i.v. The reference compound
WEB-2086 (1 mg kg-1) also reversed the LPS-
induced hypotension.
UR-12633 (1 mg kg-1), administered 10 min before LPS, almost fully inhibited sustained
hypotension. The immediate
hypotension (within 1 min) caused by LPS was not prevented by either
UR-12633 or
WEB-2086. 3. Pretreatment with 10 mg kg-1, i.v. of either
UR-12633 or
WEB-2086 inhibited the increase in
disseminated intravascular coagulation markers, such as activated partial thromboplastin time (55 and 74% inhibition, respectively), and prothrombin time (22 and 72% inhibition) and prevented the decrease in plasma
fibrinogen content (100 and 29% inhibition). 4. Increases in
acid phosphatase (ACP) plasma activity, a marker of lysosomal activation, and in
lactate dehydrogenase (
LDH), a marker of tissue damage, were inhibited by pretreatment with 10 mg kg-1, i.v. of either
UR-12633 or
WEB-2086 (100% and 69% inhibition, ACP; 62 and 48% inhibition, LDH). Hyperglycaemia (71 and 46%) and hyperlactacidaemia (92 and 56%) were also inhibited. 5.
UR-12633, but not
WEB-2086, inhibited the LPS-induced increase in vascular permeability in rats, as shown by prevention of haemoconcentration and, to a lesser degree, the increase in
Evans blue dye extravasation. 6. In a series of nine reference compounds and
UR-12633, we found a high correlation (P < 0.001) between PAF antagonist activity, measured as the inhibition of PAF-induced rabbit platelet aggregation or PAF-induced mortality in mice and the inhibition of LPS-induced mortality. 7. In spite of the multifactorial nature of endotoxic
shock, in which many mediators may be involved, the new potent PAF antagonist,
UR-12633, proved effective in protecting against changes in most
shock markers. These data strongly suggest a key role for PAF in the pathogenesis of endotoxic
shock in rodents.