Demonstration of xanthine oxidase in human heart

Abadeh, Shahla; Case, Patrick; Harrison, Roger

doi:10.1042/bst020346s

Cited by 11 publications

(7 citation statements)

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“…XOR is widely distributed throughout the body, with the highest levels of expression in the liver (Linder et al, 1999). XOR is synthesized primarily in the liver and the lung, reflecting the high expression found within these tissues, with much lower levels of XOR expressed in most organs, including the brain, gut, heart, and in blood vessels (Abadeh et al, 1992(Abadeh et al, , 1993. XOR has been localized within the cytoplasm of numerous cell types (Jarasch et al, 1981(Jarasch et al, , 1986Moriwaki et al, 1993;Radi et al, 1997;Houston et al, 1999) but has also been localized bound to the outer surface of cells through binding to heparin sulfate glycosaminoglycans (GAGs).…”

Section: Molybdenum-containing Oxidase Enzymesmentioning

confidence: 99%

The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

et al. 2020

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Section: Molybdenum-containing Oxidase Enzymesmentioning

confidence: 99%

The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

et al. 2020

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“…Considerable evidence supports the concept that oxyradicals contribute to the pathogenesis of myocardial stunning in the dog (36) and that xanthine oxidase is an important source of reactive oxygen metabolites in this species (37). It is, however, controversial whether the human heart contains xanthine oxidase and, if so, how the levels of this enzyme compare to those found in the canine heart (38)(39)(40)(41)(42). Thus far, no report has suggested that oxyradicals contribute to stunning in large mammals that lack myocardial xanthine oxidase activity, and no information is available on the role of oxyradicals in conscious models other than the dog.…”

Section: Introductionmentioning

confidence: 95%

Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Sun¹,

Tang²,

Park³

et al. 1996

J. Clin. Invest.

223

137

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Conscious pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, for three consecutive days (days 1, 2, and 3). On day 1, pigs received an i.v. infusion of a combination of antioxidants (superoxide dismutase, catalase, and N -2 mercaptopropionyl glycine; group II, n ϭ 9), nisoldipine (group III, n ϭ 6), or vehicle (group I [controls], n ϭ 9). In the control group, systolic wall thickening (WTh) in the ischemic-reperfused region on day 1 remained significantly depressed for 4 h after the 10th reperfusion, indicating myocardial "stunning." On days 2 and 3, however, the recovery of WTh improved markedly, so that the total deficit of WTh decreased by 53% on day 2 and 56% on day 3 compared with day 1 ( P Ͻ 0.01), indicating the development of a powerful cardioprotective response (late preconditioning against stunning). In the antioxidant-treated group, the total deficit of WTh on day 1 was 54% less than in the control group ( P Ͻ 0.01). On day 2, the total deficit of WTh was 85% greater than that observed on day 1 and similar to that observed on day 1 in the control group. On day 3, the total deficit of WTh was 58% less than that noted on day 2 ( P Ͻ 0.01). In the nisoldipine-treated group, the total deficit of WTh on day 1 was 53% less than that noted in controls ( P Ͻ 0.01). On days 2 and 3, the total deficit of WTh was similar to the corresponding values in the control group. These results demonstrate that: ( a ) in the conscious pig, antioxidant therapy completely blocks the development of late preconditioning against stunning, indicating that the production of reactive oxygen species (ROS) on day 1 is the mechanism whereby ischemia induces the protective response observed on day 2; ( b ) antioxidant therapy markedly attenuates myocardial stunning on day 1, indicating that ROS play an important pathogenetic role in postischemic dysfunction in the porcine heart despite the lack of xanthine oxidase; ( c ) although the administration of a calcium-channel antagonist (nisoldipine) is as effective as antioxidant therapy in attenuating myocardial stunning on day 1, it has no effect on late preconditioning on day 2, indicating that the ability of antioxidants to block late preconditioning is not a nonspecific result of the mitigation of postischemic dysfunction on day 1. Generation of ROS during reperfusion is generally viewed as a deleterious process. Our finding that ROS contribute to the genesis of myocardial stunning but, at the same time, trigger the development of late preconditioning against stunning supports a complex pathophysiological paradigm, in which ROS play an immediate injurious role (as mediators of stunning) followed by a useful function (as mediators of subsequent preconditioning). (

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“…19,21 Human heart has long been thought to exhibit very low, if any, XO activity, 38,39 but more recent studies have demonstrated substantial quantities of the enzyme. [40][41][42] The possibility that expression of the enzyme is increased in heart failure is particularly relevant and is substantiated by the observation of hyperuricemia in patients with decompensated valvular heart disease. 43 Of course, the quantity of XO will be irrelevant if the mechanism of sensitization turns out to be a direct effect unrelated to inhibition of the enzyme.…”

Section: Implications For Therapeuticsmentioning

confidence: 99%

Novel Myofilament Ca ²⁺ -Sensitizing Property of Xanthine Oxidase Inhibitors

Pérez¹,

Gao²,

Marbán³

1998

Circulation Research

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Abstract-Antioxidants are known to mitigate the cardiac contractile dysfunction that follows brief periods of ischemia ("myocardial stunning"). Stunning decreases contractility at the level of the contractile proteins; therefore, we asked whether antioxidant treatment preserves myofilament Ca 2ϩ responsiveness after global ischemia and reflow. Right ventricular trabeculae were dissected from rat hearts subjected either to 20 minutes ischemia and reperfusion in the absence of drugs (stunned group) or to the same protocol in the presence of allopurinol, an inhibitor of xanthine oxidase (XO), and mercaptopropionylglycine (MPG), a hydroxyl radical scavenger (antioxidant group). At 20 minutes of reflow, isovolumic developed pressure recovered completely in the antioxidant group, but in the stunned group it recovered by only 57%. [Ca 2ϩ ] i and contractile force measurements in trabeculae revealed the expected depression of myofilament function in the stunned group, with no change in Ca 2ϩ transients relative to nonischemic controls. In contrast, Ca 2ϩ transients were smaller, but force was greater, in the antioxidant group relative to both the stunned group and to nonischemic controls. Steady-state [Ca 2ϩ ] i -force relationships revealed a striking increase of maximal force and a modest shift of activation to a lower range of [Ca 2ϩ ] i . The increase in maximal force was reproduced by allopurinolϩMPG or by allopurinol alone under nonischemic conditions and also by oxypurinol (100 mol/L), a potent inhibitor of XO. We conclude that allopurinol and oxypurinol sensitize the cardiac myofilaments to Ca Key Words: allopurinol Ⅲ excitation-contraction coupling Ⅲ ischemia Ⅲ reperfusion Ⅲ stunning I t is generally accepted that the generation of oxygenderived free radicals (OFRs) during reperfusion after brief ischemia leads to the reversible postischemic myocardial dysfunction known as "stunning."1 Several lines of investigation have demonstrated that preventing OFR accumulation by antioxidant treatment strongly attenuates stunning (see Reference 1 for review). Conversely, exposure of heart muscle to exogenously generated free radicals reproduces many (but not all) of the phenotypic features of stunned myocardium.2 The fundamental injury produced by excitation-contraction coupling in stunned myocardium is a decrease of myofilament responsiveness to Ca 2ϩ (References 3 to 6). Therefore, we sought to determine whether antioxidant treatment prevents stunning by preservation of myofilament Ca 2ϩ responsiveness after global ischemia and reflow. In the present study, we used a combination of allopurinol, a xanthine oxidase (XO) inhibitor, and N-2-mercaptopropionylglycine (MPG), a scavenger of hydroxyl anions, to avoid OFR accumulation during ischemia/reperfusion in the rat myocardium. These drugs confer powerful protection against myocardial stunning, 7-9 a finding that we confirmed. Characterization of excitation/contraction coupling revealed not only a striking preservation of the myofilament responsiveness to Ca 2ϩ but als...

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Demonstration of xanthine oxidase in human heart

Cited by 11 publications

References 0 publications

The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Novel Myofilament Ca ²⁺ -Sensitizing Property of Xanthine Oxidase Inhibitors

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Demonstration of xanthine oxidase in human heart

Cited by 11 publications

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The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway

Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Novel Myofilament Ca 2+ -Sensitizing Property of Xanthine Oxidase Inhibitors

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Novel Myofilament Ca ²⁺ -Sensitizing Property of Xanthine Oxidase Inhibitors