EFFECTS OF A NEW PLATELET-ACTIVATING-FACTOR ANTAGONIST, UR-12670, ON SEVERAL ENDOTOXIC-SHOCK MARKERS IN RATS

UR-12670 is a novel and potent PAF antagonist, eg., it displaces [H-3] WEB-2086 from PAF receptors in rabbit platelet membranes (Ki = 0.6 nM) and inhibits PAF-induced increase in vascular permeability in rat tra chea (100%), thymus (44%), seminal vesicles (100%) and stomach (54%) a t a dose of 0.01 mg/kg i.v. Since PAF is thought to be an important me diator in endotoxic shock, the effect of pretreatment with UR-12670 on changes in vascular permeability, disseminated intravascular coagulat ion (DIC) and plasma biochemical parameters were determined in a rat m odel of acute endotoxemia. UR-12670 and the reference PAF antagonist, lexipafant (10 mg/kg i.v.), strongly inhibited lipopolysaccharide (LPS , 25 mg/kg i.v.)-induced plasma leakage in the trachea (49 and 100%, r espectively) and seminal vesicles (81 and 100%), as assessed by the Ev ans blue extravasation method. Only lexipafant inhibited the increase in vascular permeability in the thymus (36%). Neither PAF antagonist w as effective in the stomach. Both UR-12670 and lexipafant at 10 mg/kg i.v. attenuated the LPS-induced variation of some DIC markers, such as activated partial thromboplastin time increase (56 and 58%, respectiv ely) and the fibrinogen concentration decrease (53 and 31%), whereas t he increase in prothrombin time was not affected. increased plasma aci d phosphatase (ACP, a lysosomal activation marker) and lactate dehydro genase (LDH, a tissue damage marker) activity elicited by IFS was atte nuated by pretreatment with 10 mg/kg i.v. of either UR-12670 dr lexipa fant (ACP: 55 and 48%; LDH: 50 and 33%). LPS-induced hyperglycemia (46 and 37%) and hyperlactacidemia (100% both) were also inhibited. UR-12 670 protected against several shock symptoms, confirming the role of P AF in the pathogenesis of rodent endotoxemia.