Effects of a new platelet-activating factor antagonist, UR-12670, on several endotoxic shock markers in rats.

Abstract

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.

• Authors: D Balsa, M Merlos, M Giral, R Ferrando, J Garcia-Rafanell, J Forn
• Journal: Drugs under experimental and clinical research (Drugs Exp Clin Res) Vol. 23 Issue 5-6 Pg. 191-9 ( 1997) ISSN: 0378-6501 [Print] Switzerland
• PMID: 9515229 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Imidazoles
• Lipopolysaccharides
• Platelet Activating Factor
• Platelet Aggregation Inhibitors
• Pyridines
• UR 12670
• Lactic Acid
• Evans Blue
• L-Lactate Dehydrogenase
• Acid Phosphatase

Topics

• Acid Phosphatase (blood)
• Animals
• Blood Glucose (metabolism)
• Capillary Permeability (drug effects)
• Evans Blue
• Extravasation of Diagnostic and Therapeutic Materials
• Imidazoles (pharmacology)
• L-Lactate Dehydrogenase (blood)
• Lactic Acid (blood)
• Lipopolysaccharides (pharmacology)
• Male
• Partial Thromboplastin Time
• Platelet Activating Factor (antagonists & inhibitors)
• Platelet Aggregation Inhibitors (pharmacology)
• Prothrombin Time
• Pyridines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Shock, Septic (blood, drug therapy, physiopathology)