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 [3H]WEB-2086 from PAF receptors in rabbit platelet membranes (Ki = 0.6 nM) and inhibits PAF-induced increase in vascular permeability in rat trachea (100%), thymus (44%), seminal vesicles (100%) and stomach (54%) at a dose of 0.01 mg/kg i.v. Since PAF is thought to be an important mediator in endotoxic shock, the effect of pretreatment with UR-12670 on changes in vascular permeability, disseminated intravascular coagulation (DIC) and plasma biochemical parameters were determined in a rat model 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%, respectively) and seminal vesicles (81 and 100%), as assessed by the Evans blue extravasation method. Only lexipafant inhibited the increase in vascular permeability in the thymus (36%). Neither PAF antagonist was 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%, respectively) and the fibrinogen concentration decrease (53 and 31%), whereas the increase in prothrombin time was not affected. Increased plasma acid phosphatase (ACP, a lysosomal activation marker) and lactate dehydrogenase (LDH, a tissue damage marker) activity elicited by LPS was attenuated by pretreatment with 10 mg/kg i.v. of either UR-12670 or lexipafant (ACP: 55 and 48%; LDH: 50 and 33%). LPS-induced hyperglycemia (46 and 37%) and hyperlactacidemia (100% both) were also inhibited. UR-12670 protected against several shock symptoms, confirming the role of PAF in the pathogenesis of rodent endotoxemia.
Balsa
D
D
Department of Pharmacology, J.Uriach & Cia Laboratories, Barcelona, Spain.
Merlos
M
M
Giral
M
M
Ferrando
R
R
Garcia-Rafanell
J
J
Forn
J
J
D000135:Acid Phosphatase / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D005070:Evans Blue; D005119:Extravasation of Diagnostic and Therapeutic Materials; D007093:Imidazoles / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D019344:Lactic Acid / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D010314:Partial Thromboplastin Time; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011517:Prothrombin Time; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology
D001786:Blood Glucose; D007093:Imidazoles; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C097826:UR 12670; D019344:Lactic Acid; D005070:Evans Blue; D007770:L-Lactate Dehydrogenase; D000135:Acid Phosphatase