Molybdenum Deficiency and Tungstate Inhibition Studies

Higgins, Edwin S.; Richert, Dan A.; Westerfeld, W. W.

doi:10.1093/jn/59.4.539

Cited by 118 publications

(54 citation statements)

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“…Parallel decreases in myocardial XO activity, ventricular dysfunction, and H202 generation occurred in tungsten-or allopurinol-treated rats subjected to ischemia and then reperfusion. Tungsten is a relatively specific inhibitor that inactivates xanthine, aldehyde, and sulfite oxidases by interfering with their molybdenum-dependent active site (7)(8)(9). By comparison, allopurinol and its metabolite oxipurinol are potent, specific competitive inhibitors of XO (10), but not sulfite or aldehyde oxidases.…”

Section: Discussionmentioning

confidence: 99%

“…We tested this premise in simplified ("blood-free") isolated hearts using dimethylthiourea (DMTU), a highly permeant 02 metabolite scavenger, infused only during reperfusion (6). We also assessed the effect of inhibiting XO (by HPLC analysis) with tungsten (7)(8)(9) or allopurinol (10) on ventricular function after ischemia and reperfusion. In addition, we measured H202-dependent aminotriazole inactivation of myocardial catalase activity as an indicator of myocardial H202 production (1 1,12 (13).…”

Section: Introductionmentioning

confidence: 99%

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Xanthine oxidase produces hydrogen peroxide which contributes to reperfusion injury of ischemic, isolated, perfused rat hearts.

Brown¹,

Terada²,

Grosso³

et al. 1988

J. Clin. Invest.

129

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Three lines of investigation indicated that hydrogen peroxide (H202) from xanthine oxidase (XO) contributes to cardiac dysfunction during reperfusion after ischemia. First, addition of dimethylthiourea (DMTU), a highly permeant 02 metabolite scavenger (but not urea) simultaneously with reperfusion improved recovery of ventricular function as assessed by ventricular developed pressure (DP), contractility (+dP/dt), and relaxation rate (-dP/dt) in isolated Krebs-Henseleit-perfused rat hearts subjected to global normothermic ischemia. Second, hearts from rats fed tungsten or treated with allopurinol had negligible XO activities (< 0.5 mU/g wet myocardium compared with > 6.0 mU/g in control hearts) and increased ventricular function after ischemia and reperfusion. Third, myocardial H202-dependent inactivation of catalase occurred after reperfusion following ischemia, but not after ischemia without reperfusion or perfusion without ischemia. In contrast, myocardial catalase did not decrease during reperfusion of ischemic hearts treated with DMTU, tungsten, or allopurinol.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Xanthine oxidase produces hydrogen peroxide which contributes to reperfusion injury of ischemic, isolated, perfused rat hearts.

Brown¹,

Terada²,

Grosso³

et al. 1988

J. Clin. Invest.

129

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“…One might have expected that manganese would be displaced by some metal (other than manganese) because of such wellknown precedents as the displacement in the body of bromide by chloride (15), of molybdenum by tungsten (16) and of strontium by calcium (17). There exists, however, at least one metabolic difference between manganese and the elements listed above: the route of excretion.…”

Section: Discussionmentioning

confidence: 99%

The High Specificity of the Manganese Pathway Through the Body12

Cotzias¹,

Greenough²

1958

J. Clin. Invest.

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The accepted ideas about the physiological role of manganese have been derived predominantly from in vitro experiments. However, these are characterized by lack of specificity: Only a limited discrimination between manganese and some other metals is shown, for instance, in metal transport systems (1, 2), in enzyme activation (2-4) and in the preservation of mitochondria (5). The conclusions from these experiments were of interest because they threw new doubt on the functional specificity and even on the essentiality of manganese in the living organism. Thus it became necessary to ascertain whether manganese may be replaced in the intact animal as well. To investigate this, we have used a variation of the classical technique of flooding the organism with metals which we were led to believe would substitute for manganese. Surprisingly, these kindred metals were ineffective in eluting radiomanganese from the body: Only manganese compounds proved effective in that regard.The results suggest that there exists a segment in the pathway of manganese through the body, the properties of which permit the passage of that metal only. This paper deals with the implications of this finding both in reference to manganese as well as to the elements which have been thought not to possess such an in vivo specificity. MATERIALS AND METHODS Experiments with intact animalsAnimals. These Chicago, March, 1957. metal screening was used to prevent the animals from eating the bedding. Regardless of the type of bedding, the furs remained radiologically clean, as shown by the failure of VerseneQ and detergent baths to lower the total body radioactivity.Diets. Since the manganese turnover depends upon dietary intake, an effort was made to keep the manganese intake constant. In the bulk of the experiments, the same lot of Purina Fox chow was used (MnSO, reported by manufacturer as 0.02 per cent). As a "manganese free" diet, a vitamin B. deficient rat diet was used.3 To this a salt-vitamin fortification mixture' was added without supplementary manganese, unless otherwise stated.Stable metals and their salts. Rhenium dioxide was prepared by dissolving the metal in nitric acid and heating to dryness with anhydrous hydrazine HCl. The procedure was repeated twice with the precipitate. This was finally washed with water, ground into a fine suspension in normal saline and injected into the animals intraperitoneally. All the metals, oxides and salts 5 used in these experiments to challenge the isotope were injected with normal saline as the vehicle. In some experiments (see Table I) the sulfates or chlorides of the metals were dissolved with added equimolar amounts of sodium citrate (hereafter referred to simply as "citrate"). In those latter experiments the controls received equimoler sodium citrate instead of the routinely used saline injections. The doses of the challenging materials ranged from 1 X 10' to 1 X 10' mole of metal. These were given either as single or as daily injections for one week. SPECIFICITY OF THE MANGANESE PATHWAYIsotop...

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“…We inhibited XOD in two ways: 1) oxypurinol and 2) a tungsten diet. By placing rats on a diet that replaced molybdenum with tungsten as a coenzyme to XOD, XOD activity is inhibited, which blocks the production of superoxide and hydrogen peroxide in response to tissue ischemia and reperfusion (21,23). Additionally, we also used the superoxide dismutase mimetic tempol to catalyze the removal of superoxide anions.…”

Section: Postcapillary Venular Endothelial Cells Are Especially Suscementioning

confidence: 99%

“…The observed differences in magnitude of each treatment may be due to their distinct mechanisms of action. For example, the replacement of molybdenum with tungsten leads to the inhibition of XOD activity; however, the tungsten-enriched diet can also influence other molybdenum-dependent enzymes (21,23). Likewise, oxypurinol not only inhibits XOD, it may also directly scavenge ROS (9).…”

Section: Postcapillary Venular Endothelial Cells Are Especially Suscementioning

confidence: 99%

Ischemia-reperfusion injury in rats affects hydraulic conductivity in two phases that are temporally and mechanistically separate

Victorino¹,

Ramírez²,

Chong³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Victorino GP, Ramirez RM, Chong TJ, Curran B, Sadjadi J. Ischemia-reperfusion injury in rats affects hydraulic conductivity in two phases that are temporally and mechanistically separate. Am J Physiol Heart Circ Physiol 295: H2164 -H2171, 2008. First published September 12, 2008 doi:10.1152/ajpheart.00419.2008 injury is a major insult to postcapillary venules. We hypothesized that IR increases postcapillary venular hydraulic conductivity and that IR-mediated changes in hydraulic conductivity result from temporally and mechanistically separate processes. A microcannulation technique was used to determine hydraulic conductivity (Lp) in rat mesenteric postcapillary venules serially throughout ischemia (45 min) and reperfusion (5 h) induced by superior mesenteric artery occlusion and release. Mesenteric IR resulted in a biphasic increase in Lp. White blood cell (WBC) adhesion slowly increased with maximal adhesion corresponding to the second peak (P Ͻ 0.005). After IR, tissue was harvested for RT-PCR analysis of ICAM-1, E-selectin, and P-selectin mRNA. Intercellular adhesion molecule-1 (ICAM-1) mRNA in the gut showed the most significant upregulation. Quantitative real-time PCR revealed that ICAM-1 mRNA was upregulated 60-fold in the gut. An ICAM-1 antibody was therefore used to determine the effect of WBC adhesion on Lp during IR. ICAM-1 inhibition attenuated Lp during the first peak and completely blocked the second peak (P Ͻ 0.005). When rats were fed a tungsten diet to inhibit xanthine oxidase and then underwent IR, Lp was dramatically attenuated during the first peak and mildly decreased the second peak (P Ͻ 0.005). Inhibition of xanthine oxidase by oxypurinol decreased Lp during IR by over 60% (P Ͻ 0.002). Tempol, a superoxide dismutase mimetic, decreased Lp during IR by over 30% (P Ͻ 0.01). We conclude that IR induces a biphasic increase in postcapillary hydraulic conductivity. Reactive oxygen species impact both the first transient peak and the sustained second peak. However, the second peak is also dependent on WBC-endothelial cell adhesion. These serial measurements of postcapillary hydraulic conductivity may lead the way for optimal timing of pharmaceutical therapies in IR injury. microvascular permeability; reactive oxygen species; intercellular adhesion molecule-1

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Molybdenum Deficiency and Tungstate Inhibition Studies

Cited by 118 publications

References 0 publications

Xanthine oxidase produces hydrogen peroxide which contributes to reperfusion injury of ischemic, isolated, perfused rat hearts.

Xanthine oxidase produces hydrogen peroxide which contributes to reperfusion injury of ischemic, isolated, perfused rat hearts.

The High Specificity of the Manganese Pathway Through the Body12

Ischemia-reperfusion injury in rats affects hydraulic conductivity in two phases that are temporally and mechanistically separate

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