Allopurinol
Role of lipid peroxidation in gastric mucosal lesions induced by ischemia-reperfusion in the pylorus-ligated rat.

Tanaka J, Yuda Y.

Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan.

The peroxidation of lipids and changes in the activities of related enzymes, such as xanthine-xanthine oxidase (XOD), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) in the gastric mucosa were studied in rat model of ischemia-reperfusion with pylorus ligation. Myeloperoxidase (MPO), a marker enzyme of leucocytes, was also studied. Thiobarbituric acid reactive substances (TBA RS) in gastric mucosa were significantly increased by clamping the celiac artery for 30 min and reperfusion for 60 min after 3 h of pylorus ligation. XOD activity in gastric mucosa increased with the development of gastric mucosal injury. Allopurinol significantly suppressed XOD activity but did not inhibit mucosal injury or the increase in TBA RS. MPO activity in the gastric mucosa was significantly increased by gastric mucosal injury. Famotidine significantly inhibited the increase in MPO activity in gastric mucosa, while allopurinol did not. SOD and GSH-px activities in the gastric mucosa were decreased significantly by gastric mucosal injury. SOD activity was normal following treatment with famotidine and allopurinol. Moreover, GSH-px activity recovered to the normal level with famotidine and allopurinol treatment. These findings suggest that oxygen radicals and lipid peroxidation can cause gastric mucosal injury by ischemia-reperfusion in the pylorus-ligated rat. The generation of oxygen free radicals may be derived mainly from activated polymorphonuclear leukocytes (PMN), and the decrease in SOD and GSH-px activity in gastric mucosa seems to aggravate mucosal injury by free radicals and lipid peroxidation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8396487&dopt=Abstract allopurinol Zyloprim



Allopurinol
The effects of allopurinol and SOD on lipid peroxidation and energy metabolism in the liver after ischemia in an aerobic/anaerobic persufflation.

Minor T, Isselhard W, Yamamoto Y, Obara M, Saad S.

Institute for Experimental Medicine University of Cologne, Koln, Germany.

This study was aimed at examining the vulnerability of the liver to oxygen-free radicals upon reoxygenation after prolonged ischemia. Livers from male Wistar rats were first flushed with Ringer's and Euro-Collins solutions. After ischemic storage in Krebs-Henseleit solution at 37 degrees C for 60 min and in Euro-Collins solution at 4 degrees C for another 60 min, they were then persufflated with either gaseous O2 or N2 for 30 min at 37 degrees C, and rinsed again with Ringer's solution. Enzyme concentrations and calcium ion activities were measured in the effluent rinsing solution after passage through the liver. Treatment with superoxide dismutase (SOD) or allopurinol resulted in a significant reduction of tissue injury, determined by the enzyme loss, calcium uptake, and lipid peroxidation upon persufflation with O2. Allopurinol also improved the tissue levels of ATP and the sum of adenine nucleotides after aerobic persufflation, whereas SOD did not. Notwithstanding, neither treatment had any effect on anoxic persufflation with N2. Thus, we conclude that the postischemic liver is susceptible to oxygen-induced free radical injury and that allopurinol and SOD promote specific antioxidative protection of the liver, with the exclusion of side effects related to substrates or perfusion modalities.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8400677&dopt=Abstract allopurinol Zyloprim



Allopurinol
Modification of ischemia/reperfusion-induced ion shifts (Na+, K+, Ca2+ and Mg2+) by free radical scavengers in the rat retina.

Szabo ME, Droy-Lefaix MT, Doly M, Braquet P.

Institut Henri Beaufour, Paris, France.

We investigated the contribution of scavenging of oxygen free radicals to retinal ion contents during ischemia and reperfusion with the use of superoxide dismutase (SOD, Sigma), allopurinol (Sigma), EGB 761 (extract of Ginkgo biloba, Tanakan, IPSEN, Paris, France) and allopurinol plus EGB 761 in the rat. SOD (15,000 U/kg/day), allopurinol (50 mg/kg/day), EGB 761 (100 mg/kg/day) and allopurinol (50 mg/kg/day) plus EGB 761 (100 mg/kg/day) were administered for 10 days, respectively. Then, the eyes were subjected to 90 min of ischemia followed by 4 and 24 h of reperfusion, respectively. Retinal Na+, K+, Ca2+ and Mg2+ contents were measured by atomic absorption spectrophotometry after the washing out of blood and extracellular fluid from the vasculature. SOD, EGB 761 and the combination of EGB 761 with allopurinol significantly reduced the ischemia/reperfusion-induced Na+ and Ca2+ accumulation and K+ loss in ischemic/reperfused retinal tissue. Allopurinol alone failed to reduce the maldistribution of Na+, Ca2+ and K+ induced by ischemia/reperfusion in the retina. Neither intervention inhibited the cell Mg2+ loss which was observed during ischemia and reperfusion. Despite the responsible mechanisms remaining controversial, many studies confirmed that ischemia/reperfusion could trigger very sudden metabolic, electrophysiologic, morphologic and functional changes. There is general agreement that major ionic shifts are implicated; what triggers these changes is unclear, although many investigators believe that free radicals and oxidant stress may be important.(ABSTRACT TRUNCATED AT 250 WORDS)

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Allopurinol
Effect of allopurinol on myocardial recovery during reperfusion.

Soncul H, Gokgoz L, Kalaycioglu S, Sinci V, Kaptanoglu M, Ersoz A.

Department of Thoracic and Cardiovascular Surgery, Gazi University Medical School, Ankara, Turkey.

A comparative study on isolated guinea pig hearts was carried out to determine the effect of allopurinol added to reperfusion solution on myocardial recovery after global ischaemia. After 20 min of normothermic ischaemia two groups of solutions (1-Krebs Solution 2-Krebs Solution + Allopurinol 1 mmol l-1) were used for reperfusion (10 animals in each group). Post-ischaemic myocardial functions (ventricular contractile force and heart work) and enzyme activities (CK-MB, LD) were compared with their preischemic values. Addition of allopurinol 1 mmol l-1 to reperfusion solution improved post-ischaemic myocardial functions and decreased myocardial injury.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8451598&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol transport in human erythrocytes.

Razavi M, Kraupp M, Marz R.

Institute of Medical Chemistry, University of Vienna, Austria.

The mechanism of allopurinol [4-hydroxypyrazolo(3,4-d)pyrimidine] transport into human erythrocytes was investigated with an inhibitor stop assay. Allopurinol transport could be resolved into two components: (1) a saturable system and (2) a non-saturable process, which most likely represents non-facilitated diffusion. Allopurinol transport had a Km of 268 mumol/L and a Vmax of 28 pmol/microL intracellular volume/sec; the non-saturable component was 0.0195/sec. Mutual inhibition studies showed that the competitive Ki values of hypoxanthine and adenine on allopurinol transport were 120 and 3 mumol/L, respectively. These Ki values as well as the IC50 values of 100-150 mumol/L for hypoxanthine and 3-10 mumol/L for adenine were similar to the corresponding transport Km values of these bases, which are 128 and 8 mumol/L, respectively. The Ki of allopurinol on hypoxanthine transport was 274 mumol/L and thus nearly identical to its Km. Thus in erythrocytes the uricostatic agent allopurinol is an alternative substrate for the purine transport system, but lacks the exceptional high affinity it has for xanthine oxidase. This could explain the paradoxical clinical side effect of allopurinol, namely that it can provoke an attack of gout. Theophylline, a methylated purine, inhibited allopurinol transport with an IC50 of 200-400 mumol/L. Oxypurinol [4,6-dihydroxypyrazolo(3,4-d)pyrimidine], the main metabolite of allopurinol, also inhibited allopurinol transport with an IC50 of 20-40 mumol/L. This is noteworthy, since allopurinol and oxypurinol do not share the same transport system in the kidney.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8452564&dopt=Abstract allopurinol Zyloprim



Allopurinol
The effect of supplementing hypothermic crystalloid cardioplegia with catalase plus allopurinol in the isolated rabbit heart.

Nishida K.

First Department of Surgery, Yamaguchi University School of Medicine, Japan.

The effect of adding allopurinol and catalase to hypothermic cardioplegia for ischemic-reperfusion injury was investigated in the isolated rabbit heart. Hearts were divided into two groups, namely: Group C (n = 7), which received a hypothermic crystalloid cardioplegic solution alone (4 degrees C), and group T (n = 7), which received the hypothermic cardioplegic solution with allopurinol (148 mumol/L)13 and catalase (37 nmol/L).12 The cardioplegic solution was infused continuously into the isolated hearts, which had been placed in ice-cold saline, during a 12 h preservation. Subsequently, the hearts were mounted on a noncirculating, nonpulsatile perfusion circuit using Krebs-Henseleit buffer solution at 37 degrees C for 1 h at a constant perfusion pressure of 75 mm Hg. The left ventricular developed pressure (LVDP), maximum rate of pressure change (max dp/dt), and percent recovery of coronary flow were higher, while the creatine phosphokinase concentration and left ventricular end diastolic pressure (LVEDP) were lower in group T. The tissue malondialdehyde concentration and water content were similar in both groups. Thus, cardiac function after a 12 h preservation was enhanced by the added combination of allopurinol and catalase to the cardioplegic solution, supporting its role in the prevention of free radical reperfusion injury in cardiac preservation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8461605&dopt=Abstract allopurinol Zyloprim