pentostatin and Ischemia

Renal ischemia injures the renal tubular cell by disrupting the vital cellular metabolic machinery. Further cell damage is caused when the blood flow is restored by oxygen free radicals that are generated from xanthine oxidase. Oxygen radicals cause lipid peroxidation of cell and organelle membranes, disrupting the structural integrity and capacity for cell transport and energy metabolism. In the present study, the possible therapeutic usefulness of the adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF), during renal ischemia and reperfusion injury was investigated. The effects of DCF on renal malondialdehyde (MDA) and ATP levels were studied after 45 min ischemia and 15 min subsequent reperfusion in rat kidneys. MDA levels remained unchanged during ischemia, but increased after the subsequent reperfusion. DCF pretreatment (2.0 mg/kg i.m.) decreased MDA and increased ATP levels during the ischemia-reperfusion period. DCF exerts a dual protective action by facilitating purine salvage for ATP synthesis and inhibiting oxygen radical-induced lipid peroxidation. These results suggest that DCF therapy could be beneficial in the treatment of ischemia-reperfusion renal injuries.

Topics: Adenosine; Adenosine Deaminase Inhibitors; Adenosine Triphosphate; Animals; Antioxidants; Enzyme Inhibitors; Ischemia; Kidney; Lipid Peroxidation; Male; Malondialdehyde; Oxidative Stress; Pentostatin; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase

Little is known about the nature of biochemical disturbances during reperfusion after retinal ischemia. Previous studies have suggested that adenosine is responsible for regulation of retinal blood flow soon after ischemia has ended. Therefore, in this study we measured concentrations of adenosine and its metabolites in the rat retina/choroid after brief (10 min) or prolonged (60 min) periods of ischemia, and the functional consequences of inhibiting adenosine metabolism.. Ischemia was produced in anesthetized rats by ligation of the central retinal artery. The eyes were frozen in situ and purine nucleoside concentration was determined by high performance liquid chromatography. The functional effects of pre-ischemic inhibition of xanthine dehydrogenase/xanthine oxidase were assessed by measurement of the electroretinogram before, during, and up to 7 days following 60 min ischemia.. Changes in the concentrations of adenosine and its metabolites were significant early in the reperfusion period, and were greater in magnitude and occurred earlier in prolonged, compared to brief, ischemic periods. Concentrations of adenosine, inosine, and hypoxanthine remained elevated for 30 min following the end of 60 min ischemia, and xanthine concentration was significantly elevated until 60 min after the end of either 10 or 60 min of ischemia. The onset of its peak value after ischemia was delayed in comparison to that of adenosine. Ischemia-evoked increases in xanthine concentration were attenuated by inhibition of adenosine deaminase or xanthine oxidase/xanthine dehydrogenase. Pre-ischemic inhibition of xanthine oxidase/xanthine dehydrogenase by oxypurinol (40 or 80 mg/kg intraperitoneally [IP]) resulted in a significant improvement in recovery of the a and b waves of the electroretinogram in comparison to a saline-treated control group.. These results indicate that adenosine is a major component of the biochemical changes that occur after retinal ischemia. Long-lasting increases in xanthine concentration during reperfusion after ischemia could be a source of oxygen free radicals that may contribute to delayed injury of the retina, attempts to decrease xanthine concentration would ideally be initiated within one hour after the end of ischemia.

Topics: Adenosine; Animals; Choroid; Electroretinography; Enzyme Inhibitors; Ischemia; Osmolar Concentration; Oxypurinol; Pentostatin; Purines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Retina; Retinal Diseases

The concentrations of renal ATP have been measured by 31P-nuclear magnetic resonance (NMR) before, during, and after bilateral renal artery occlusion. Using in vivo NMR, the initial postischemic recovery of ATP increased with the magnitude of the residual nucleotide pool at the end of ischemia. ATP levels after 120 min of reflow correlated with functional recovery at 24 h. In the present study the effect of blocking the degradation of ATP during ischemia upon the postischemic restoration of ATP was investigated. Inhibition of adenosine deaminase by 80% with the tight-binding inhibitor 2'-deoxycoformycin led to a 20% increase in the residual adenine nucleotide pool. This increased the ATP initial recovery after 45 min of ischemia from 52% (in controls) to 62% (in the treated animals), as compared to the basal levels. The inhibition also caused an accelerated postischemic restoration of cellular ATP so that at 120 min it was 83% in treated rats vs. 63% in untreated animals. There was a corresponding improvement in the functional recovery from the insult (increase of 33% in inulin clearance 24 h after the injury). Inhibition of adenosine deaminase during ischemia results in a injury similar to that seen after a shorter period of insult.

Topics: Adenosine Deaminase Inhibitors; Adenosine Triphosphate; Animals; Coformycin; Inulin; Ischemia; Kidney; Magnetic Resonance Spectroscopy; Male; Nucleoside Deaminases; Pentostatin; Rats; Rats, Inbred Strains