Inhibitory Effect Of Allopurinol Research Articles

Allopurinol Prevents Nitroglycerin-induced Tolerance in Rat Thoracic Aorta

Xanthine oxidase is an important source of reactive oxygen species; so, it may play a role in the pathogenesis of endothelium dysfunction and its consequences. Allopurinol, a purine analog, is a famous xanthine oxidase inhibitor. This study aimed to investigate possible effects of allopurinol on nitroglycerin tolerance, vasoconstriction, and vasorelaxation in rat aortic ring. Using thoracic aortic rings obtained from male Wistar rats, the effect of allopurinol was examined on nitroglycerin-induced tolerance. In addition, changes of vasoconstriction (by using KCl and phenylephrine) and vasorelaxation (by using carbachol, sodium nitroprusside, and nitroglycerin) were also measured and compared between tissues treated with and without allopurinol. All 3 concentrations of allopurinol (50, 100, and 150 μM) significantly acted against the development of nitroglycerin-induced tolerance in comparison with controls. In terms of vasoconstriction and vasorelaxation, the effect of allopurinol was significant only on carbachol-induced (endothelium related) vasorelaxation in a dose-dependent manner. In conclusion, although allopurinol had no significant effect on the contractile response of the aorta, in accord with the previous data, it significantly intensified endothelium-dependent vasodilation. The inhibitory effect of allopurinol against the development of nitrate-induced tolerance may suggest its clinical benefit and is worth to be studied more extensively.

Xanthine oxidase inhibition attenuates skeletal muscle signaling following acute exercise but does not impair mitochondrial adaptations to endurance training

The aim of this research was to examine the impact of the xanthine oxidase (XO) inhibitor allopurinol on the skeletal muscle activation of cell signaling kinases' and adaptations to mitochondrial proteins and antioxidant enzymes following acute endurance exercise and endurance training. Male Sprague-Dawley rats performed either acute exercise (60 min of treadmill running, 27 m/min, 5% incline) or 6 wk of endurance training (5 days/wk) while receiving allopurinol or vehicle. Allopurinol treatment reduced XO activity to 5% of the basal levels (P < 0.05), with skeletal muscle uric acid levels being almost undetectable. Following acute exercise, skeletal muscle oxidized glutathione (GSSG) significantly increased in allopurinol- and vehicle-treated groups despite XO activity and uric acid levels being unaltered by acute exercise (P < 0.05). This suggests that the source of ROS was not from XO. Surprisingly, muscle GSSG levels were significantly increased following allopurinol treatment. Following acute exercise, allopurinol treatment prevented the increase in p38 MAPK and ERK phosphorylation and attenuated the increase in mitochondrial transcription factor A (mtTFA) mRNA (P < 0.05) but had no effect on the increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear respiratory factor-2, GLUT4, or superoxide dismutase mRNA. Allopurinol also had no impact on the endurance training-induced increases in PGC-1α, mtTFA, and mitochondrial proteins including cytochrome c, citrate synthase, and β-hydroxyacyl-CoA dehydrogenase. In conclusion, although allopurinol inhibits cell signaling pathways in response to acute exercise, the inhibitory effects of allopurinol appear unrelated to exercise-induced ROS production by XO. Allopurinol also has little effect on increases in mitochondrial proteins following endurance training.

Xanthine Oxidoreductase Is Involved in Macrophage Foam Cell Formation and Atherosclerosis Development

Hyperuricemia is common in patients with metabolic syndrome. We investigated the role of xanthine oxidoreductase (XOR) in atherosclerosis development, and the effects of the XOR inhibitor allopurinol on this process. Oral administration of allopurinol to ApoE knockout mice markedly ameliorated lipid accumulation and calcification in the aorta and aortic root. In addition, allopurinol treatment or siRNA-mediated gene knockdown of XOR suppressed transformation of J774.1 murine macrophage cells, treated with acetylated LDL or very low density lipoprotein (VLDL) into foam cells. This inhibitory effect of allopurinol was also observed in primary cultured human macrophages. In contrast, overexpression of XOR promoted transformation of J774.1 cells into foam cells. Interestingly, SR-A1, SR-B1, SR-B II, and VLDL receptors in J774.1 cells were reduced by XOR knockdown, and increased by XOR overexpression. Conversely, expressions of ABCA1 and ABCG1 were increased by XOR knockdown and suppressed by XOR overexpression. Finally, productions of inflammatory cytokines accompanied by foam cell formation were also reduced by allopurinol administration. These results strongly suggest XOR activity and/or its expression level to contribute to macrophage foam cell formation. Thus, XOR inhibitors may be useful for preventing atherosclerosis.

Effects of Allopurinol on Renal Stone Formation and Osteopontin Expression in a Rat Urolithiasis Model

Background: The inhibitory effect of allopurinol on calcium oxalate urolithiasis has been reported, but its effect on stone matrix proteins has not been studied in vivo. To clarify the effect of allopurinol on the matrix, we investigated its effect on the expression of osteopontin (OPN), which we previously identified as an important stone matrix protein. Methods: Control rats were not treated. Rats of the stone group were given ethylene glycol (EG) and vitamin D₃, while the allopurinol groups (low-dose group and high-dose group) were treated with allopurinol in addition to receiving EG and vitamin D₃. Results: The rate of renal stone formation was lower in the allopurinol groups than in the stone group. This was associated with a low expression of OPN mRNA in allopurinol-treated rats relative to that in the stone group. Conclusion: Allopurinol was effective in preventing calcium oxalate stone formation and reduced OPN expression in rats. Our results suggest that allopurinol prevents renal stone formation by acting against not only the control of oxalate but also OPN expression.

The effects of allopurinol on the ultrastructure of ischaemic and reperfused large intestine of sheep.

To test the possible inhibitory effect of allopurinol on reperfusion injury, caused by oxygen-derived free radicals, of sheep large intestine. An ultrastructural study on caecal tissues from control and treated groups. Fifty sheep in four ischaemic and reperfused (treatment) groups and one control group. Three of the treatment groups were subdivided for half to be injected with allopurinol and the other half with its solvent, potassium hydroxide (KOH). Ischaemia of the caecum was induced in the four treatment groups for 60 minutes by clamping the apex. Allopurinol and its KOH solvent were injected intravenously in three treatment groups prior to ischaemia. Samples were collected before and 1 hour after induction of ischaemia and 1 min, 1 h and 8 h after reperfusion. Tissues were processed and examined with an electron microscope. Untreated and solvent injected sheep showed minor ultrastructural changes following ischaemia. With reperfusion, there was severe mitochondrial, goblet cell and basement membrane damage. Tissues from allopurinol-treated sheep were preserved and appeared similar to tissues from the control group. Pre-treatment with allopurinol prevented damage to tissues whereas untreated or allopurinol solvent-treated showed severe damage following reperfusion. It is believed that allopurinol, an analogue of hypoxanthine and xanthine, prevents reperfusion injury by competitively binding with xanthine oxidase. This reduces or inhibits the xanthine oxidase mediated conversion of hypoxanthine to xanthine thereby preventing the formation of oxygen-derived free radicals.

The inhibitory effects of allopurinol on the production and cytotoxicity of tumor necrosis factor.

Allopurinol, a xanthine oxidase inhibitor, impaired the cytotoxic effect of human recombinant tumor necrosis factor (TNF) against WEHI cells. Actinomycin D abolished the inhibition of cytotoxicity by allopurinol. Allopurinol also exerted an inhibitory effect on the production of TNF by human mononuclear cells stimulated by either heat-killed Staphylococcus aureus or E. coli lipopolysaccharide. It is suggested that allopurinol inhibits TNF cytotoxicity by decreasing the level of oxygen free radicals generated (among other mechanisms) by the action of xanthine oxidase. Whatever the mechanism, the fact that allopurinol counteracts the toxicity of TNF can help towards an understanding of the complex nature of TNF toxicity.

Drug interaction between phenytoin and allopurinol.

The combination of phenytoin (DPH) and allopurinol is used for the treatment of a neurological disease. However, interactions between DHP and allopurinol and the mechanism are little known. The repeated dosing of allopurinol at higher doses (20 and 50 mg/kg) significantly retarded the elimination of DPH from the circulation and dramatically decreased the urinary excretion of p-hydroxyphenytoin (HPPH), a major metabolite of DPH. However, a single administration of allopurinol (10 or 50 mg/kg) did not give rise to these effects. Allopurinol did not affect the hepatic extraction of DPH and renal plasma flow rate. Allopurinol (50 mg/kg/d) dosed repeatedly could not inhibit the hepatic drug metabolizing enzyme activities. The in vitro hydroxylation of DPH was inhibited only slightly and the kinetic plots gave apparently non-competitive inhibition. The less inhibitory effect of allopurinol on the in vitro hydroxylation did not agree with the in vivo data. These results indicate that the inhibitory effect of allopurinol is not mediated by cytochrome P-450 dependent monooxygenase reactions.

Effects of allopurinol and oxipurinol on purine synthesis in cultured human cells.

In the present study we have examined the effects of allopurinol and oxipurinol on the de novo synthesis of purines in cultured human fibroblasts. Allopurinol inhibits de novo purine synthesis in the absence of xanthine oxidase. Inhibition at lower concentrations of the drug requires the presence of hypoxanthine-guanine phosphoribosyltransferase as it does in vivo. Although this suggests that the inhibitory effect of allopurinol at least at the lower concentrations tested is a consequence of its conversion to the ribonucleotide form in human cells, the nucleotide derivative could not be demonstrated. Several possible indirect consequences of such a conversion were also sought. There was no evidence that allopurinol was further utilized in the synthesis of nucleic acids in these cultured human cells and no effect of either allopurinol or oxipurinol on the long-term survival of human cells in vitro could be demonstrated. At higher concentrations, both allopurinol and oxipurinol inhibit the early steps of de novo purine synthesis in the absence of either xanthine oxidase or hypoxanthine-guanine phosphoribosyltransferase. This indicates that at higher drug concentrations, inhibition is occurring by some mechanism other than those previously postulated.