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)

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

The dried roots of Scutellaria baicalensis (S. baicalensis) Georgi (common name: Huangqin in China) have been widely employed for many centuries in traditional Chinese herbal medicine as popular antibacterial and antiviral agents. They are effective against staphylococci, cholera, dysentery, pneumococci and influenza virus. Baicalein, one of the major flavonoids contained in the dried roots, possesses a multitude of pharmacological activities. The glycoside of baicalein, baicalin is a potent anti-inflammatory and anti-tumor agent. This review describes the biological properties of baicalein (Table 1), which are associated with the prevention and treatment of cardiovascular diseases. Baicalein is a potent free radical scavenger and xanthine oxidase inhibitor, thus improving endothelial function and conferring cardiovascular protective actions against oxidative stress-induced cell injury. Baicalein lowers blood pressure in renin-dependent hypertension and the in vivo hypotensive effect may be partly attributed to its inhibition of lipoxygenase, resulting in reduced biosynthesis and release of arachidonic acid-derived vasoconstrictor products. On the other hand, baicalein enhances vasoconstricting sensitivity to receptor-dependent agonists such as noradrenaline, phenylephrine, serotonin, U46619 and vasopressin in isolated rat arteries. The in vitro effect is likely caused by inhibition of an endothelial nitric oxide-dependent mechanism. The anti-thrombotic, anti-proliferative and anti-mitogenic effects of the roots of S. baicalensis and baicalein are also reported. Baicalein inhibits thrombin-induced production of plasminogen activator inhibitor-1, and interleukin-1beta- and tumor necrosis factor-alpha-induced adhesion molecule expression in cultured human umbilical vein endothelial cells. The pharmacological findings have highlighted the therapeutic potentials of using plant-derived baicalein and its analogs for the treatment of arteriosclerosis and hypertension.
Curr Drug Targets Cardiovasc Haematol Disord 2005 Apr
PMID:Biological properties of baicalein in cardiovascular system. 1585 50

Liver ischemia and subsequent reperfusion (IR) are associated with secondary, remote organ reperfusion injury attributable to oxidative stress mediators. Because N-acetyl-L-cysteine (NAC) was effective in attenuating lung reperfusion injury, its properties on aortic dysfunction were tested. Rat isolated perfused aortic rings (n = 8/group) were evaluated during and after exposure to liver postischemia perfusate. Aortic response to phenylephrine under these conditions was also assessed in the presence or absence of increasing concentrations of NAC. Aortic rings incubated with postischemia perfusates exhibited abnormally protracted contraction. Their response to phenylephrine was reduced to 18 +/- 7% and 65 +/- 11% of controls during and after the exposure, respectively, and their subsequent relaxation was irregular. NAC 0.25 mM best attenuated the IR-induced aortic tone impairments, 0.12 mM affected it slightly, and IR-NAC 0.5 mM and IR-NAC 0.74 mM solutions dilated the rings proportionately, abolishing reactions to both IR solutions and phenylephrine. Xanthine oxidase activity and reduced glutathione (GSH) level in all IR ring tissues were inversely proportionate, but not directly so. Thus, liver IR impaired aortic tone and its response to phenylephrine, even after removal of toxic elements. NAC concentrations directly and inversely correlated with xanthine oxidase activity but not with GSH level. It preserved aortic functions dose-specifically, mainly by oxidant quenching.
J Cardiovasc Pharmacol 2005 Jun
PMID:N-acetyl-L-cysteine mitigates aortic tone injury following liver ischemia-reperfusion. 1589 76

Increased production of reactive oxygen species (ROS) has been implicated in the pathogenesis of cardiovascular diseases. Enzymatic systems such as the mitochondrial respiratory chain, vascular NAD(P)H oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase (eNOS) produce superoxide anion (O2*-) in vascular cells. While some O2(*-) rapidly degrades by reacting with nitric oxide (NO*), the O2*- signal preserved by dismutation into hydrogen peroxide (H2O2) exerts prolonged signaling effects. This review focuses on patterns and mechanisms whereby H2O2 modulates different aspects of endothelial cell function including endothelial cell growth and proliferation, endothelial apoptosis, endothelium-dependent vasorelaxation, endothelial cytoskeletal reorganization and barrier dysfunction, endothelial inflammatory responses, and endothelium-regulated vascular remodeling. These modulations of endothelial cell function may at least partially underlie H2O2 contribution to the development of vascular disease.
Cardiovasc Res 2005 Oct 01
PMID:Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences. 1600 56

We investigated the structure-activity relationships regarding vascular and antioxidant activity of a range of synthetic flavonols and flavones with 3 or fewer hydroxyl (OH) or methoxyl substitutions. The relaxant responses and ability of the flavones/flavonols to inhibit phenylephrine (PE)- and Ca-induced contraction was determined in rat isolated thoracic aorta. The ability of these compounds to reduce the level of superoxide and preserve endothelium-dependent relaxation in the presence of oxidative stress was also examined. Four compounds impaired contraction to PE or Ca, in the potency order 3'-hydroxyflavonol>3',4'-dihydroxyflavonol>7,4'-dihydroxyflavonol>3',4'-dihydroxyflavone. Flavonol, 3',4'-dimethoxyflavonol, and flavone were significantly less active. The flavonoids caused concentration-dependent reductions in superoxide produced by rat aorta in the presence of NADPH. The most active compounds, 3',4'-dihydroxyflavonol and 7,4'-dihydroxyflavonol, preserved endothelium-dependent relaxation in the presence of oxidative stress caused by pyrogallol or xanthine/xanthine oxidase. The results indicate that the catechol group is not critical for vascular relaxant or antioxidant activity, but rather, the important determinants for higher vascular and antioxidant activity of these compounds are the presence of a C3 OH group and the total number of OH substituents, respectively. These results have allowed the identification of the structural characteristics that promote vascular and antioxidant activity of flavonols, which may lead to the development of agents useful in treatment of cardiovascular disease.
J Cardiovasc Pharmacol 2005 Sep
PMID:Vasorelaxant and antioxidant activity of flavonols and flavones: structure-activity relationships. 1611 35

The plasma level of the uric acid is frequently elevated in heart failure, due to increased production and/or to reduced renal excretion of this antioxidant metabolite. The transformation of hypoxanthine to xanthine and the conversion of the latter into uric acid, which occur in purine catabolism, are catalysed by xanthine oxidoreductase. The constitutive xanthine dehydrogenase form of this enzyme generally uses NAD(+) as an electron acceptor, whereas the post-translational xanthine oxidase form uses molecular oxygen and yields four units of reactive oxygen species per unit of transformed substrate. Allopurinol and oxypurinol inhibit xanthine oxidoreductase and thus diminish the generation of reactive species and decrease plasma uric acid. In a recent study in patients with NHYA class II-III heart failure, add-on treatment with allopurinol 300 mg/day for 3 months lowered plasma uric acid but failed to improve laboratory exercise performance or the distance walked in 6 minutes. In another recent trial, which was carried out in patients with NHYA class III-IV heart failure, add-on treatment with oxypurinol 600 mg/day for 24 weeks decreased plasma uric acid concentration but did not change a composite of patient outcome and state. These results indicate that the reduction in plasma uric acid caused by allopurinol or oxypurinol does not benefit patients with heart failure. Moreover, the hypothesis that the diminution in the renal excretion of the antioxidant uric acid caused by diuretics may be salutary in cardiac failure is strengthened by the study results considered.
Cardiovasc Drugs Ther 2005 Oct
PMID:Allopurinol or oxypurinol in heart failure therapy - a promising new development or end of story? 1638 92

We have previously demonstrated that tumor necrosis factor alpha (TNFalpha), a cytokine known to be induced by ischemia, independently promotes preconditioning in part via ceramide generation. As reactive oxygen species (ROS) signaling is evoked by ischemic preconditioning, by TNFalpha and by ceramide we reasoned that ceramide-induced preconditioning is ROS-mediated. Fibroblastic L-cells were subjected to 8 hours simulated ischemia and were preconditioned by pretreatment with cell permeable c2 ceramide (1 microM) with or without the antioxidant N-mercaptopropionyl glycine (MPG; 1 mM). Pretreatment with ceramide reduced lactate dehydrogenase release at the end of the simulated ischemia but this cytoprotective effect was lost in the presence of MPG. Concurrent temporal ROS generation was measured using confocal microscopy on cells stained with dichlorofluorescein diacetate (DCF-DA). Ceramide increased ROS production after 30 minutes and this induction was decreased by MPG. Incubation of ceramide with cyclooxygenase-2 inhibitor, NS 398 (10 microM), or with a mitochondrial respiratory chain inhibitor, rotenone (10 microM) reduced the cytoprotective effect of ceramide in parallel with a partial diminution in ROS generation. In contrast, inhibition of other ROS-producing systems including nitric oxide synthase, xanthine oxidase, or NADPH oxidase failed to modulate ceramide-induced cytoprotection. Collectively, these data demonstrate that ceramide induces a cell survival program through ROS signaling activated, in part, via cyclooxygenase and the mitochondrial respiratory chain.
J Cardiovasc Pharmacol 2006 Jan
PMID:Ceramide attenuates hypoxic cell death via reactive oxygen species signaling. 1642 1

While timely reperfusion of acute ischemic myocardium is essential for myocardial salvage, reperfusion results in a unique form of myocardial damage. Functional alterations occur, including depressed contractile function and decreased coronary flow as well as altered vascular reactivity. Both myocardial stunning and infarction are seen. Over the last two decades, it has become increasingly clear that oxidant and oxygen radical formation is greatly increased in the post-ischemic heart and serves as a critical central mechanism of post-ischemic injury. This oxidant formation is generated through a series of interacting pathways in cardiac myocytes and endothelial cells and triggers subsequent leukocyte chemotaxis and inflammation. Nitric oxide (NO) production and NO levels are also greatly increased in ischemic and post-ischemic myocardium, and this occurs through NO synthase (NOS)-dependent NO formation and NOS-independent nitrite reduction. Recently, it has been shown that the pathways of oxygen radical and NO generation interact and can modulate each other. Under conditions of oxidant stress, NOS can switch from NO to oxygen radical generation. Under ischemic conditions, xanthine oxidase can reduce nitrite to generate NO. NO and peroxynitrite can inhibit pathways of oxygen radical generation, and, in turn, oxidants can inhibit NO synthesis from NOS. Ischemic preconditioning markedly decreases NO and oxidant generation, and this appears to be an important mechanism contributing to preconditioning-induced myocardial protection.
Cardiovasc Res 2006 May 01
PMID:The role of oxidants and free radicals in reperfusion injury. 1663 40


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