Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We tested the effect of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenosine (EHNA) on ischemia-reperfusion injury in isolated perfused rat heart. In the ischemia-reperfusion group (n = 10), ventricular fibrillation occurred within 3 min of reperfusion after the 40-min ischemic period. The incidence of ventricular fibrillation was 90% with a mean duration of 3.15 +/- 0.97 (SE) min. Resting tension increased significantly. By contrast, the incidence of ventricular fibrillation after reperfusion in the EHNA-treated (5 microM) group (n = 10) was 20% (P less than 0.01), and the duration was 0.30 +/- 0.21 min (P less than 0.01). Resting tension was significantly lower and around the normal level in the EHNA-treated group (P less than 0.01). Contraction amplitude and heart rate recovered to nearly normal compared with the ischemia-reperfusion group (P less than 0.01). Coronary flow was greater in the EHNA-treated group (P less than 0.01). It is concluded that EHNA protects the heart, possibly by accumulation of adenosine that benefits the hearts and by blocking the xanthine oxidase pathway for free radical generation.
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PMID:Protective effects of an adenosine deaminase inhibitor on ischemia-reperfusion injury in isolated perfused rat heart. 239 91

Because of the importance of adenosine deaminase (ADA) in brain function, a histochemical method for visualizing the enzyme in various areas of the human neuraxis was devised, using an MTT [3-(4,5-dimethyl-thiazolyl-2)-2,5-diphenyltetrazolium bromide] method and glutaraldehyde fixation. Controls consisted of preincubation without the substrate, incubation with omission successively of the substrate, MTT tetrazolium, purine nucleoside phosphorylase (PNP), xanthine oxidase (XO), NaCl, boiling for 20 min prior to fixation and incubation, and of incubation of sections with two powerful inhibitors of the enzyme, i.e., 2'-deoxycoformycin and EHNA [erythro-9-(2-hydroxy-3-nonyl)adenine.HCl]. The positive reaction consisted of the deposition of brownish-purple granules, as well as a diffuse nongranular reaction in the cytoplasm of neurons and glial cells, and in the interstitial spaces. Sections from 15 different areas in four brains were examined by this method. This is the first time that adenosine deaminase has been demonstrated histochemically in the nervous system of humans or of any other species.
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PMID:Histochemical demonstration of adenosine deaminase in the human neuraxis. Preliminary observations. 404 5

In the presence of its substrates hypoxanthine and xanthine, xanthine oxidase generates oxygen free radicals that cause postischemic injury. Recently, it has been demonstrated that the burst of xanthine oxidase-mediated free radical generation in the reperfused heart is triggered by a large increase in substrate formation, which occurs secondary to the degradation of adenine nucleotides during ischemia. It is not known, however, whether blocking this substrate formation is sufficient to prevent radical generation and functional injury. Therefore, studies were performed in isolated rat hearts in which xanthine oxidase substrate formation was blocked with the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), and measurements of contractile function and free radical generation were performed. Chromatographic measurements of the intracellular adenine nucleotide pool showed that preischemic administration of EHNA blocked postischemic hypoxanthine, xanthine, and inosine formation. Electron paramagnetic resonance spin trapping measurements of free radical generation showed that inhibition of adenosine deaminase with EHNA blocked free radical generation and that it also increased the recovery of contractile function by more than 2-fold. Exogenous infusion of hypoxanthine and xanthine totally reversed the protective effects of EHNA. These results demonstrate that blockade of xanthine oxidase substrate formation by adenosine deaminase inhibition can prevent free radical generation and contractile dysfunction in the postischemic heart.
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PMID:Adenosine deaminase inhibition prevents free radical-mediated injury in the postischemic heart. 862 67

Previously, we have demonstrated the role of nucleoside transport and purine release in post-ischemic reperfusion injury (myocardial stunning) in several canine models of ischemia. Since rabbits are deficient of xanthine oxidase, it is not known whether selective blockade of purine release is beneficial in a rabbit model of coronary artery occlusion and reperfusion (stunning). Therefore, we determined the hemodynamic and metabolic correlates in response to myocardial stunning in the presence or absence of selective nucleoside transport blocker (p-nitrobenzylthioinosine, NBMPR) and adenosine deaminase inhibitor (erythro-9-(2-hydroxy-3-nonyl)adenine, EHNA). Sixty adult anaesthetized rabbits were surgically prepared for hemodynamic measurements. After stabilization period, the left anterior descending coronary artery was occluded for 15 min and reperfused for 30 min. Transmural myocardial biopsies were obtained from the ischemic LAD area and from the non-ischemic posterior (circumflex, CFX) segment of the myocardium. Rabbits (n = 60) were randomly assigned to either the control or the EHNA/NBMPR-treated group (n = 30 each). Each group was further divided to either functional or metabolic groups (n = 15 each subgroup). Each animal received intravenously 30 ml of either a vehicle solution or 100 M EHNA and 25 M NBMPR 10 min before ischemia. Although administration of EHNA/NBMPR did not affect the heart rate, it did cause mild hypotension (about 20-30%). Fifteen minutes of LAD occlusion resulted in significant ATP depletion and concomitant accumulation of nucleosides in both groups (p < 0.05 vs. baseline and non-ischemic CFX segment). AMP was higher in the LAD compared to the CFX segment. Significant accumulation of adenosine was observed in the treated group compared to the control group. It is concluded that EHNA/NBMPR induced site specific entrapment of adenosine of nucleoside transport in the rabbit heart, in vivo.
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PMID:Role of nucleoside transport and purine release in a rabbit model of myocardial stunning. 954 41

We investigated whether xanthine oxidase-derived superoxide radical generation could be modified by interfering with adenosine transport and metabolism in reducing myocardial injury during post-ischemic reperfusion. Isolated rat hearts perfused at constant pressure were subjected to 20 min of pretreatment with test agents, followed by 40 min global ischemia and 30 min reperfusion with or without test agents. In hearts treated with adenosine deaminase inhibitor, erythro 9-(2-hydroxy-3-nonyl) adenine (EHNA), alone or together with a selective nucleoside transport blocker, p-nitrobenzylthioinosine (NBMPR), the accumulated amount of O-2. was significantly reduced [10.2+/-0.97, 11.6+/-2.4, 8.1+/-0.51, respectively, v 31.6+/-2.1 (s. e.) nmol/wet g/30 min in ischemic control, P<0.01]. A positive correlation between O-2. and inosine release was observed in the initial 5 min of reperfusion in hearts treated with either EHNA or NBMPR ( r=0.475, P<0.05). Furthermore, the accumulated amount of LDH release showed positive correlation with that of O-2. among the same groups (r=0.474, P<0.05). Both EHNA and NBMPR had the cardioprotective effect on the recovery of left ventricular end-diastolic pressure (LVEDP), ATP repletion, and build up of endogenous adenosine. This study suggests that : (1) adenosine metabolism can be manipulated towards the formation of O-2. during reperfusion, and it has an important bearing on the cardiac recovery of ischemic myocardium, (2) the generation of O-2. is related to only inosine release during initial reperfusion.
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PMID:Modulation of adenosine effects in attenuation of ischemia and reperfusion injury in rat heart. 976 36

The effects on ATP breakdown of some modulators of adenosine transport or metabolism were studied in the rat colon muscularis mucosae, a tissue which contracts to ATP and is thought to contain P2Y1 receptors. The compounds tested were the xanthine oxidase inhibitor allopurinol, the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and the adenosine uptake blocker S-(4-nitrobenzyl)-6-thioinosine (NBTI). The degradation of adenosine 5'-triphosphate (ATP) (100 microM) and the appearance of metabolites was followed by high pressure liquid chromatography during incubation of isolated tissue preparations alone or in the presence of the drugs, following preincubation with the drugs for 1 h. In the absence of drugs ATP was rapidly degraded by the rat colon muscularis mucosae with a half-life of 6.1 +/- 0.7 min, the major breakdown product being inosine rather than adenosine. Allopurinol (1 microM) and NBTI (10 microM) had no effect on the rate of breakdown of ATP or on the pattern of metabolites produced. EHNA (1 or 10 microM) also had no effect on the half-life of ATP, but in the presence of EHNA (1 microM) the rate of production of inosine was significantly reduced and some adenosine was detected, while in the presence of 10 microm EHNA the production of inosine was abolished and adenosine became the final breakdown product. These results indicate that allopurinol (1 microM) and NBTI (10 microM) have no detectable effect on extracellular purine metabolism in this tissue, and that the build-up of adenosine produced by treatment with EHNA does not have a feedback effect on ATP breakdown.
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PMID:Effects of allopurinol, erythro-9-(2-hydroxy-3-nonyl)adenine and S-(4-nitrobenzyl)-6-thioinosine on the degradation of adenosine 5'-triphosphate in the rat colon muscularis mucosae. 1058 73

Dynein-mediated autophagosome (AP) trafficking was recently demonstrated to contribute to the formation of autophagolysosomes (APLs) and autophagic flux process in coronary arterial myocytes (CAMs). However, it remains unknown how the function of dynein as a motor protein for AP trafficking is regulated under physiological and pathological conditions. The present study tested whether the dynein-mediated autophagy maturation is regulated by a redox signalling associated with lysosomal Ca(2+) release machinery. In primary cultures of CAMs, reactive oxygen species (ROS) including H2 O2 and O2 (-.) (generated by xanthine/xanthine oxidase) significantly increased dynein ATPase activity and AP movement, which were accompanied by increased lysosomal fusion with AP and APL formation. Inhibition of dynein activity by (erythro-9-(2-hydroxy-3-nonyl)adenine) (EHNA) or disruption of the dynein complex by dynamitin (DCTN2) overexpression blocked ROS-induced dynein activation, AP movement and APL formation, and resulted in an accumulation of AP along with a failed breakdown of AP. Antagonism of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca(2+) signalling with NED-19 and PPADS abolished ROS-enhanced lysosomal Ca(2+) release and dynein activation in CAMs. In parallel, all these changes were also enhanced by overexpression of NADPH oxidase-1 (Nox1) gene in CAMs. Incubation with high glucose led to a marked O2 (-.) production compared with normoglycaemic CAMs, while Nox1 inhibitor ML117 abrogated this effect. Moreover, ML117 and NED-19 and PPADS significantly suppressed dynein activity and APL formation caused by high glucose. Taken together, these data suggest that ROS function as important players to regulate dynein-dependent AP trafficking leading to efficient autophagic maturation in CAMs.
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PMID:Enhancement of dynein-mediated autophagosome trafficking and autophagy maturation by ROS in mouse coronary arterial myocytes. 2491 85

We investigated whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuates arrhythmias through inhibiting nerve growth factor (NGF) expression in post-infarcted normoglycemic rats, focusing on adenosine and reactive oxygen species production. DPP-4 bound adenosine deaminase has been shown to catalyse extracellular adenosine to inosine. DPP-4 inhibitors increased adenosine levels by inhibiting the complex formation. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline or sitagliptin in in vivo and ex vivo studies. Post-infarction was associated with increased oxidative stress, as measured by myocardial superoxide, nitrotyrosine and dihydroethidium fluorescent staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham. Compared with vehicle, infarcted rats treated with sitagliptin significantly increased interstitial adenosine levels and attenuated oxidative stress. Sympathetic hyperinnervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Ex vivo studies showed a similar effect of erythro-9-(2-hydroxy-3-nonyl) adenine (an adenosine deaminase inhibitor) to sitagliptin on attenuated levels of superoxide and NGF. Furthermore, the beneficial effects of sitagliptin on superoxide anion production and NGF levels can be reversed by 8-cyclopentyl-1,3-dipropulxanthine (adenosine A1 receptor antagonist) and exogenous hypoxanthine. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation via adenosine A1 receptor and xanthine oxidase-dependent pathways, which converge through the attenuated formation of superoxide in the non-diabetic infarcted rats.
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PMID:Sitagliptin attenuates sympathetic innervation via modulating reactive oxygen species and interstitial adenosine in infarcted rat hearts. 2538 8