Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Injury during reperfusion can partially offset the benefit of relief of ischemia in myocardial infarctions rapidly treated with thrombolytic drugs or angioplasty. We assessed whether bucillamine (N-[2-mercapto-2-methylpropionyl]-L-cysteine) is potentially useful to treat myocardial reperfusion injury. Bucillamine is a potent sulfhydryl donor not previously tested as a treatment of reperfusion injury. Cardiac myocytes were exposed to hydrogen peroxide or a xanthine/xanthine oxidase system resulting in injury-induced release of lactate dehydrogenase. Bucillamine (125-500 microM) prevented lactate dehydrogenase release in a concentration-dependent manner. Bucillamine, which has two donatable thiol groups, was twice as protective as N-2-mercaptopropionyl glycine, which contains a single donatable thiol group. Dogs were then exposed to 90 min of coronary artery occlusion and 48 h of reperfusion before sacrifice. Beginning at the onset of reperfusion, bucillamine, 11 or 22 mg/kg per hour, or vehicle (saline) was administered intravenously for 3 h. There was a dose-related response to bucillamine for infarct size, normalized for size of the region at risk and adjusted for collateral blood flow to the ischemic region. Infarct size was reduced by 41% in the group treated with bucillamine 22 mg/kg per hour, compared with the vehicle group. Bucillamine, probably through an antioxidant mechanism, reduced infarct size when administered during reperfusion.
J Cardiovasc Pharmacol 2001 Dec
PMID:Bucillamine prevents myocardial reperfusion injury. 1170 89

The cardioprotective properties of new pharmaceuticals such as carvedilol might be explained by enhanced mitochondrial protection. The aim of this work was to determine the role of carvedilol in the protection of heart mitochondria from oxidative damage induced by hypoxanthine/xanthine oxidase, a known source of oxidative stress in the vascular system. Carvedilol reduced oxidative-stress-induced mitochondrial injury, as seen by the delay in the loss of the mitochondrial transmembranar potential (Delta Psi), the decrease in mitochondrial swelling, and the increase in mitochondrial calcium uptake. Carvedilol improved the mitochondrial respiratory activity in state III and offered an overall protection in the respiratory control and in the P/O ratios in mitochondria under oxidative stress. The data indicated that carvedilol was able to partly protect heart mitochondria from oxidative stress-induced damage. Our results suggest that mitochondria can be important targets for some cardioprotective pharmaceuticals.
Cardiovasc Toxicol 2001
PMID:Carvedilol reduces mitochondrial damage induced by hypoxanthine/xanthine oxidase: relevance to hypoxia/reoxygenation injury. 1221 73

Oxidative stress occurs when the production of reactive oxygen species (ROS) exceeds the capacity of the cell to detoxify these potentially injurious oxidants using endogenous antioxidant defense systems. Conditions associated with oxidative stress include ischemia/reperfusion, hypercholesterolemia, diabetes, and hypertension. The adhesion of circulating blood cells (leukocytes, platelets) to vascular endothelium is a key element of the pro-inflammatory and prothrombogenic phenotype assumed by the vasculature in these and other disease states that are associated with an oxidative stress. There is a growing body of evidence that links the blood cell endothelial cell interactions in these conditions to the enhanced production of ROS. Potential enzymatic sources of ROS within the microcirculation include xanthine oxidase, NAD(P)H oxidase, and nitric oxide synthase. ROS can promote a pro-inflammatory/prothrombogenic phenotype within the microvasculature by a variety of mechanisms, including the inactivation of nitric oxide, the activation of redox-sensitive transcription factors (e.g., nuclear factor-kappaB) that govern the expression of endothelial cell adhesion molecules (e.g., P-selectin), and the activation of enzymes (e.g., phospholipase A(2)) that produce leukocyte-stimulating inflammatory mediators (e.g., platelet-activating factor). The extensively documented ability of different oxidant-ablating interventions to attenuate blood cell endothelial cell interactions underscores the importance of ROS in mediating the dysfunctional microvascular responses to oxidative stress.
Cardiovasc Toxicol 2002
PMID:Oxidative stress promotes blood cell-endothelial cell interactions in the microcirculation. 1266 63

Allopurinol, an inhibitor of xanthine oxidase, was shown to improve the regional ventricular function after coronary artery occlusion and reperfusion in animal models. The effects of oral administration of allopurinol on a transient increase in free radical generation after primary percutaneous transluminal coronary angioplasty (PTCA) in patients with acute myocardial infarction (AMI) and on their clinical outcomes were examined. Thirty-eight AMI patients undergoing primary PTCA were randomly assigned to control (group 1, n = 20) and allopurinol treatment groups (group 2, n = 18). Allopurinol (400 mg) was administered orally just after the admission (approximately 60 min before reperfusion). Free radical production was assessed by successive measurement of urinary excretion of 8-epi-prostaglandin F(2alpha) (PGF(2alpha)) after PTCA. Urinary 8-epi-PGF(2alpha) excretion was increased by twofold at 60-90 min after PTCA compared with the baseline value in group 1. This increase was completely inhibited in group 2. Plasma allopurinol concentration was 1,146 +/- 55 ng/ml in group 2 when reperfusion was achieved. Slow flow in the recanalized coronary artery after PTCA occurred less frequently in group 2 than in group 1. Cardiac index determined just after reperfusion and left ventricular ejection fraction at 6 months after PTCA were both significantly greater in group 2 than in group 1 although pulmonary capillary wedge pressure was similar in the two groups. In conclusion, allopurinol pretreatment is effective in inhibiting generation of oxygen-derived radicals during reperfusion therapy and the recovery of left ventricular function in humans.
J Cardiovasc Pharmacol 2003 May
PMID:Effect of allopurinol pretreatment on free radical generation after primary coronary angioplasty for acute myocardial infarction. 1271 99

Blood pressure, plasma NO(2) and NO(3) level, heart weight index, antioxidant enzyme activity, and vascular reactivity in rat intact aortic rings were assessed to investigate the effects of 8-week treatment with the hydroxy-methyl-glutaryl coenzyme A reductase inhibitor simvastatin (1 mg/kg per day) on endothelial dysfunction induced by chronic Nomega-nitro-l-arginine methyl ester (l-NAME 70 mg/kg per day). Results were compared with those obtained in rats receiving l-NAME, simvastatin or control animals. Coadministration of simvastatin did not restore l-NAME-increased blood pressure but normalized heart weight index (P < 0.05), endothelium-dependent relaxation to acetylcholine (P < 0.001), and plasma NO(2) and NO(3) concentration (P < 0.001) without affecting relaxation to sodium nitroprusside. Endothelium-dependent relaxation in these animals was abolished by acute incubation with l-NAME, unaffected by thromboxane synthetase inhibitor and TXA(2)/PGH(2) receptor antagonist, ridogrel, and decreased by indomethacin. Simvastatin treatment also increased plasma NO(2)+NO(3) without affecting endothelial function, heart weight index, and blood pressure of control rats. The presence of superoxide dismutase (SOD) and catalase improved endothelial relaxation only in l-NAME-treated rats, but O(2)- generated by hypoxanthine and xanthine oxidase inhibited the relaxant effect in both l-NAME and simvastatin plus l-NAME-treated rats. SOD activity was increased in all groups receiving simvastatin. Long-term treatment with simvastatin restored l-NAME-induced endothelial dysfunction, probably by preventing nitric oxide decrease. Other effects of simvastatin, including release of compensating vasodilatory cyclo-oxygenase products and increased SOD activity, could also be involved.
J Cardiovasc Pharmacol 2003 Aug
PMID:Effects of simvastatin on endothelial function after chronic inhibition of nitric oxide synthase by L-NAME. 1288 23

We hypothesized that 3',4'-dihydroxyflavonol (DiOHF) by scavenging superoxide anions (O2-*) would increase the bioavailability of NO and potentiate NO-mediated relaxation in the rat aorta. Furthermore we hypothesized that DiOHF, by its antioxidant activity, would preserve responses to acetylcholine (ACh) in the presence of O2-* generators in the aorta in vitro and after ischemia and reperfusion of the rat hindquarters vasculature in situ. Using lucigenin-enhanced chemiluminescence we demonstrated that DiOHF caused a concentration-dependent reduction in O2-* accumulation whether generated by xanthine/xanthine oxidase in a cell-free system or by rat isolated aorta in the presence of NADPH. DiOHF also prevented the inhibitory effects of xanthine/xanthine oxidase and pyrogallol on vasorelaxation to ACh and sodium nitroprusside (SNP) in the rat aorta in vitro, and attenuated the vascular dysfunction caused by 2 h ischemia and 2 h reperfusion (I/R) in the rat hindquarters. I/R significantly reduced the dilator responses to both ACh and SNP; however, this effect was attenuated when DiOHF was given before the onset of ischemia or reperfusion. In conclusion, DiOHF, by scavenging O2-*, increases the relaxant activity of ACh and SNP and reduces the degree of inhibition of xanthine/xanthine oxidase or pyrogallol on the response to ACh. DiOHF reduces the adverse effects of I/R on vascular function by increasing NO bioavailability suggesting that it may be useful in preventing reperfusion injury.
J Cardiovasc Pharmacol 2003 Dec
PMID:3', 4'-dihydroxyflavonol enhances nitric oxide bioavailability and improves vascular function after ischemia and reperfusion injury in the rat. 1463 94

High uric acid levels are associated with increased morbidity and mortality rates in cardiovascular disease. In this article we explore the relationship between cardiovascular disease and xanthine oxidase activity. We look at the evidence that uric acid and its production via the xanthine oxidase pathway, may directly contribute to this increased cardiovascular risk. We examine the relationship between uric acid and other established cardiovascular risk factors and look at the evidence that reducing uric acid production may have a beneficial impact on cardiovascular morbidity and mortality. We conclude that although there is currently insufficient evidence to recommend the routine use of xanthine oxidase inhibitors in those with cardiovascular disease and asymptomatic hyperuricemia, there is sufficient evidence to warrant a large scale morbidity and mortality trial.
Am J Cardiovasc Drugs 2003
PMID:Hyperuricemia and adverse outcomes in cardiovascular disease: potential for therapeutic intervention. 1472 64

The guanidine compound ME10092 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine), which possesses a strong cardioprotective effect to ischemia-reperfusion, was assessed for different pharmacological actions that may underlie its cardioprotective effect. In the living rat ME10092 decreased the blood pressure and heart rate in a dose-dependent manner. We found ME10092 to bind to alpha 1- and alpha 2-adrenoreceptors with moderate affinity (Ki values 1-4 microM), and to block adrenaline-elicited contractile responses in isolated guinea pig aortas. Our results indicate that ME10092 possesses a certain anti-oxidant profile. Thus, in a competitive manner and with low affinity it inhibited the bovine milk xanthine oxidase enzyme, as well as NAD(P)H oxidase driven oxyradical formation in membrane fractions isolated from the rat brain. By using electron paramagnetic resonance we here show that, after its systemic administration, ME10092 modulates the nitric oxide (NO) content in several tissues of the rat in a time-dependent manner. However, in vitro ME10092 inhibited the activities of nitric oxide synthases nNOS and eNOS, but not that of iNOS. Our data give evidence that the cardioprotective effect of ME10092 could be mediated through pharmacological mechanisms that include some modulation of NO production, as well as possible inhibition of radical formation during ischemia-reperfusion.
J Cardiovasc Pharmacol 2004 Aug
PMID:Investigations on the pharmacology of the cardioprotective guanidine ME10092. 1524 98

We examined the effects of acute hyperglycemia on the function of rabbit cerebral arteries in vitro. It was hypothesized that increased formation of reactive oxygen species (ROS) could occur, which could explain how hyperglycemia aggravates certain pathologic situations such as cerebral ischemia. Three-millimeter basilar artery segments were incubated in either normoglycemic (NG, 5.5 mM D-glucose) or hyperglycemic (HG, 25 mM D-glucose) solution containing 3.10(-6) M indomethacin. After 90 minutes equilibration, a test (=T1) of relaxation to acetylcholine (Ach) at three concentrations was performed on histamine-precontracted segments. Three further identical tests were performed (T2-T4), after 30-minute rest periods. Ach responses in NG solution were stable, whereas those in HG solution, although greater at T1, fell progressively from one test to the next (P < 0.0001 versus NG), whereas nitroprusside responses did not change. In separate experiments, this time-dependent fall in Ach responses was significantly prevented by superoxide dismutase (SOD) plus catalase (P = 0.0003), but not by SOD alone. It was also significantly prevented by the NAD(P)H oxidase inhibitors diphenyleneiodonium (P = 0.020) and apocynin (P = 0.0179), but not by allopurinol (xanthine oxidase inhibitor). Control experiments with l-glucose ruled out a hyperosmotic or non-specific glucose effect. We conclude that, in HG solution in vitro, rapidly increasing ROS production largely derived from NAD(P)H oxidase reduced relaxation to acetylcholine. The rapidity of this effect suggests that the function of these arteries may be affected during brief periods of hyperglycemia in vivo.
J Cardiovasc Pharmacol 2004 Oct
PMID:Acetylcholine-induced relaxation of rabbit basilar artery in vitro is rapidly reduced by reactive oxygen species in acute hyperglycemia: role of NADPH oxidase. 1545 61

KATP channels are a complex of regulatory sulfonylurea receptor subunits and the pore-forming inward rectifiers such as Kir6.1. Using the whole-cell patch-clamp technique, we investigated the interaction of nicotine with the Kir6.1 subunit as well as the underlying mechanism. Stable expression of Kir6.1 in HEK-293 cells yielded a detectable inward rectifier KATP current. This inward current was significantly inhibited by PNU-37883A and by a specific anti-Kir6.1 antibody. Nicotine at 30 and 100 microM increased Kir6.1 currents by 42 +/- 11.8% and 26.2 +/- 14.6%, respectively (n = 4-6, P < 0.05). In contrast, nicotine at 1-3 mM inhibited Kir6.1 currents (P < 0.05). Nicotine at 100 microM increased the production of superoxide anion (O2) by 20.3 +/- 5.7%, whereas at 1 mM it significantly decreased the production of O2 by 37.7 +/- 4.3%. Coapplication of hypoxanthine (HX) and xanthine oxidase (XO) to the transfected HEK-293 cells resulted in a significant and reproducible increase in Kir6.1 currents (P < 0.05). The stimulatory effect of HX/XO on Kir6.1 current was abolished by tempol, a scavenger of O2. Tempol also abolished the stimulatory effect of 30 muM nicotine on Kir6.1 currents. In conclusion, nicotine stimulates Kir6.1 channel at least in part through the production of O2.
J Cardiovasc Pharmacol 2005 May
PMID:Mediation of the effect of nicotine on Kir6.1 channels by superoxide anion production. 1582 40


<< Previous 1 2 3 4 5 6 7 8 9 Next >>