EFFECTS OF UR-12633, A NEW ANTAGONIST OF PLATELET-ACTIVATING-FACTOR, IN RODENT MODELS OF ENDOTOXIC-SHOCK

1 The effects of the selective and potent novel platelet-activating fa ctor (PAF) antagonist, UR-12633 enylpropionyl)-4-(3-pyridylcyanomethyl )piperidine) on several markers of endotoxic shock syndrome were evalu ated in rats and mice. 2 UR-12633, administered 60 min after E. coli l ipopolysaccharide (LPS), reversed the LPS-induced sustained hypotensio n 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 inhi bited sustained hypotension. The immediate hypotension (within 1 min) caused by LPS was not prevented by either UR-12633 or WEB-2086. 3 Pret reatment with 10 mg kg(-1), i.v. of either UR-12633 or WEB-2086 inhibi ted the increase in disseminated intravascular coagulation markers, su ch as activated partial thromboplastin time (55 and 74% inhibition, re spectively), and prothrombin time (22 and 72% inhibition) and prevente d the decrease in plasma fibrinogen content (100 and 29% inhibition). 4 Increases in acid phosphatase (ACP) plasma activity, a marker of lys osomal activation, and in lactate dehydrogenase (LDH), a marker of tis sue 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, inhibit ed the LPS-induced increase in vascular permeability in rats, as shown by prevention of haemoconcentration and, to a lesser degree, the incr ease in Evans blue dye extravasation. 6 In a series of nine reference compounds and UR-12633, we found a high correlation (P < 0.001) betwee n PAF antagonist activity, measured as the inhibition of PAF-induced r abbit platelet aggregation or PAF-induced mortality in mice and the in hibition of LPS-induced mortality. 7 In spite of the multifactorial na ture of endotoxic shock, in which many mediators may be involved, the new potent PAF antagonist, UR-12633, proved effective in protecting ag ainst changes in most shock markers. These data strongly suggest a key role for PAF in the pathogenesis of endotoxic shock in rodents.