Allopurinol and lodoxamide in complement-induced hepatic ischemia.
Intravascular complement activation with either zymosan or cobra venom factor (CVF) impairs hepatic blood flow. Oxygen radical scavengers given at the time of complement activation attenuate the resulting hepatic ischemia. It is not clear whether complement-stimulated phagocytes or transiently ischemic then reperfused endothelial and parenchymal cells generated the toxic oxygen radicals. In this study, a group of rats were given allopurinol (50 mg/kg/day postoperatively X 3 days plus 100 mg/kg iv at t = 0), a specific inhibitor of xanthine oxidase, prior to complement activation with CVF (20 units/kg iv at t = 30 and 60 min) to determine whether xanthine oxidase-derived oxygen radicals contributed significantly to the hepatic perfusion abnormalities. Additional rats received lodoxamide tromethamine (10 mg/kg iv bolus at t = 0 followed by 20 mg/kg/hr iv infusion), a novel and potent inhibitor of mast cell release and inhibitor of xanthine oxidase, prior to the same CVF challenge to determine whether mast cell mediators were involved in the flow disturbance. Thermodilution cardiac output, mean arterial pressure, heart rate, hematocrit, and effective hepatic blood flow (EHBF) by galactose clearance were determined at t = 2 hr. The percentage change in total hemolytic complement activity (% delta CH50) was determined between serum obtained prior to sacrifice and at t = 0. Systemic hemodynamics and HCT were for the most part unaffected regardless of pretreatment group or challenge with CVF or saline. CVF challenge produced a 25% reduction (P less than 0.05) in EHBF in vehicle-pretreated rats compared to saline challenge. Neither allopurinol nor lodoxamide tromethamine significantly improved EHBF when given prior to CVF challenge.(ABSTRACT TRUNCATED AT 250 WORDS)
Schirmer
W J
WJ
Department of Surgery, Veterans Administration Medical Center, Case Western Reserve University Hospitals, Cleveland, Ohio 44106.
Schirmer
J M
JM
Naff
G B
GB
Fry
D E
DE
D000493:Allopurinol / Q000494:pharmacology*; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D003167:Complement Activation; D003165:Complement System Proteins / Q000032:analysis / Q000502:physiology*; D004546:Elapid Venoms / Q000494:pharmacology; D006439:Hemodynamics; D007511:Ischemia / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology; D008102:Liver Circulation / Q000187:drug effects; D009570:Nitriles; D010072:Oxamic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D014325:Tromethamine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000596:Amino Acids; D004546:Elapid Venoms; D009570:Nitriles; D014325:Tromethamine; C022028:lodoxamide tromethamine; D000493:Allopurinol; D003165:Complement System Proteins; D010072:Oxamic Acid