oxypurinol and 4-hydroxy-2-nonenal

We investigated the role of xanthine oxidase-derived oxygen radicals in the development of endothelin-1-induced gastric ulcer. Mucosal lipid peroxidation showed a peak 24 h after injection, while gastric mucosal haemodynamics were fully restored 26 h after endothelin-1 injection. Allopurinol and oxypurinol, but not superoxide dismutase or catalase, protected the gastric mucosa 24 h after endothelin-1 injection. Oxypurinol antagonized both the vasoconstrictor effect of endothelin-1 and the decrease in gastric ATP. All treatments on the second day after endothelin-1 injection significantly reduced gastric mucosal damage. Xanthine oxidase-derived oxygen radicals contributed largely to the exacerbation but they did not mediate the onset of endothelin-1-induced gastric ulcer. Pretreatment with probucol (500 mg/kg, p.o.) also protected the gastric mucosa from endothelin-1-induced mucosal injury by its antioxidant activity. Oxypurinol was gastroprotective through its vasoactive and energy saving actions. The haemodynamic background of endothelin-1-induced gastric ulcer consists of long lasting ischaemia and subsequent "reperfusion" which may be responsible for the late burst of oxygen radicals.

Topics: Adenosine Triphosphate; Aldehydes; Allopurinol; Animals; Catalase; Deferoxamine; Disease Progression; Endothelin-1; Gastric Mucosa; Male; Malondialdehyde; Oxypurinol; Peptic Ulcer; Probucol; Rats; Rats, Wistar; Regional Blood Flow; Superoxide Dismutase; Superoxides; Vasoconstriction; Xanthine Oxidase

The accumulation of the aldehydic lipid peroxidation product 4-hydroxynonenal and thiobarbituric acid-reactive substances was demonstrated during anoxia/reoxygenation of isolated rat hepatocytes. 4-Hydroxynonenal was detected as dinitrophenylhydrazone derivative by means of an isocratic HPLC separation. The highest 4-hydroxynonenal level was found 15 min after the beginning of reoxygenation. The concentration of 4-hydroxynonenal was compared with the thiobarbituric acid-reactive substances formation, the glutathione status, and the cell viability. Addition of the xanthine oxidase inhibitor oxypurinol decreased the aldehyde formation during the reoxygenation phase. The same suppression of oxidative load by 20 microM oxypurinol (inhibition of xanthine oxidase) and by 1 mM oxypurinol (inhibition of xanthine oxidase plus radical scavenging) leads to two conclusions: First, the purine degradation is the primary radical source of postanoxic hepatocytes; second, the inhibition of radical generation by xanthine oxidase is the main component of cell protecting by oxypurinol. On the other hand, oxypurinol addition did not accelerate the adenosine 5'-triphosphate (ATP) restoration.

Topics: Adenosine Triphosphate; Aldehydes; Animals; Cell Survival; Chromatography, High Pressure Liquid; Glutathione; Kinetics; Lipid Peroxidation; Liver; Male; Oxygen; Oxypurinol; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase