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PubMedDate not supplied

Vanadate interaction with the Na, K-ATPase. An assay of serum vanadate based on the displacement of (48V) vanadate from Na, K-ATPase.

Under optimum conditions for vanadate binding to Na, K-ATPase equilibrium binding date for a range of vanadate concentrations were compiled. Scatchard plots indicated an identical binding capacity for vanadate and ouabain with conventionally prepared Na, K-ATPase batches. A method for determination of vanadate in serum based upon the high affinity of vanadate for Na, K-ATPase is described. The method takes advantage of the shift in equilibrium binding of (48V) vanadate upon addition of an aliquot of vanadate-containing serum. It is shown that the interplay between vanadate and ouabain in vanadate-facilitated ouabain binding to Na, K-ATPase leads to an enzyme-vanadate-ouabain complex to which vanadate is rather firmly bound.

Animals↗

PubMed1980

Effects of vanadate in cultured rat heart muscle cells. Vanadate transport, intracellular binding and vanadate-induced changes in beating and in active cation flux.

Cultured rat heart muscle cells have been used to study uptake and intracellular binding of Na483VO4 (vanadate), as well as the influence of vanadate on beating and 86Rb+ uptake of these cells. 1. Vanadate is taken up into cultured rat heart muscle cells in an energy-independent manner by a saturable transport system (Km approximately 60 microM, V approximately 200 pmol per mg protein per min at 37 degrees C). Analysis of intracellular binding of vanadate reveals a curved Scatchard plot indicating more than one binding site. Maximal binding amounts to 3 . 10(9) molecules of vanadate per cell. 2. Vanadate exerts a positive chronotropic and inotropic effect and increases automaticity. First effects can be seen at 1 . 10(-7) M Na3VO4. Concentrations higher than 1. 10(-3) M induce toxic effects (arrhythmias, fibrillation and stand-still of the cell). 3. Vanadate-induced alterations of beating is paralleled by a vanadate-induced stimulation of (86Rb+ + K+) uptake into the cells of up to 75%. Maximal stimulation is obtained at concentrations of 1 . 10(-4)--1 . 10(-3) M vanadate. The stimulation is thought to be due to an increased activity of (Na+ + K+)-ATPase, since it can be inhibited by ouabain. This result is in contrast to in vitro experiments with purified membrane preparations of (Na+ + K+)-ATPase of different organs, where an inhibition of (Na+ + K+)-ATPase by vanadate has been found. 4. The results indicate a possible role of vanadate as an endogenous regulator of active cation flux in heart tissue.

Animals↗

PubMed1992

Vanadate stimulates system A amino acid transport activity in skeletal muscle. Evidence for the involvement of intracellular pH as a mediator of vanadate action.

Sodium orthovanadate caused a 2-fold stimulation of system A transport activity in soleus muscle, as assessed by the uptake of the nonmetabolizable analog 2-(methylamino)isobutyric acid (MeAIB). The effect of vanadate on system A was rapid, concentration-dependent and was characterized by an increased Vmax without modification of Km for MeAIB. Under these conditions, vanadate also activated 3-O-methylglucose uptake and lactate production. The effects of vanadate on muscle metabolism showed a complex interaction with the effects of insulin. Thus, the stimulatory effects of vanadate and insulin on MeAIB and 3-O-methylglucose uptake were not additive; however, the effects of insulin and vanadate on lactate production were additive. In spite of the lack of additivity, insulin- and vanadate-induced stimulation of system A differed in their sensitivity to gramicidin D, being the vanadate effect more susceptible to inhibition by gramicidin D than the insulin effect. System A transport activity shows a dependence on pH, and recent results suggest the presence of critical histidine residues on the A carrier that may be responsible for its pH dependence (Bertran, J., Roca, A., Pola, E., Testar, X., Zorzano, A. & Palacín, M. (1991) J. Biol. Chem. 266, 798-802). In this regard, a rise in extracellular pH led to a substantial activation of system A. Furthermore, lowering of muscle intracellular pH induced by ethylisopropylamiloride (EIPA), a specific inhibitor of sodium/proton exchange activity, led to inhibition of system A. This suggests that critical histidine residues are present in an intracellular localization on the A carrier. Furthermore, the rate of muscle glycolysis was also altered in response to a rise in extracellular pH or to EIPA treatment. Regarding the mechanisms involved in vanadate action, vanadate treatment in the incubated soleus muscle did not cause any significant stimulation of tyrosine kinase activity after partial purification of muscle insulin receptors. On the other hand, vanadate but not insulin caused a substantial increase in muscle intracellular pH as assessed by 5,5'-dimethyloxazolidine-2,4-dione equilibrium. This effect of vanadate on intracellular pH was not due to activation of the sodium/proton exchanger, since it was not blocked by EIPA. Based on these findings, we suggest that alkalinization of muscle intracellular pH might mediate the effects of vanadate on system A and on glycolysis.

Amiloride↗

PubMed1994

Effects of chronic vanadate administration in the STZ-induced diabetic rat. The antihyperglycemic action of vanadate is attributable entirely to its suppression of feeding.

Vanadate treatment can lower glycemia in diabetic rats. This action is generally attributed to vanadate's insulinomimetic properties, but vanadate also inhibits feeding, which could lower blood glucose. We therefore assessed the contribution of hypophagia to vanadate's antihyperglycemic action in a 3-week study of streptozocin-induced (STZ) diabetic rats. Untreated diabetic rats (n = 8) ate 54% more food than nondiabetic control rats (P < 0.001). Diabetic rats given sodium metavanadate (0.5 mg in 0.5 ml of water by gavage twice daily; n = 8) had significantly lower food intakes (P < 0.001) than untreated diabetic rats. In vanadate-treated diabetic rats, blood glucose levels were significantly lower than in untreated diabetic rats (P < 0.001). Untreated diabetic rats pair-fed to the food intake of the vanadate-treated diabetic rats (n = 8) showed virtually identical blood glucose falls (P > 0.05 vs. vanadate-treated diabetic rats). Vanadate treatment did not affect plasma insulin concentrations in diabetic rats. In nondiabetic rats (n = 8), vanadate treatment significantly reduced food intake (P < 0.05) and also lowered plasma insulin concentrations (P < 0.05) without significantly affecting glycemia. To investigate the mechanism of vanadate's hypophagic effect, we also measured regional hypothalamic levels of neuropeptide Y (NPY), a potent central appetite stimulant that is thought to drive hyperphagia in STZ-induced diabetes. Hypothalamic NPY concentrations rise markedly in diabetes and are normalized by insulin replacement. Unlike insulin, vanadate treatment did not normalize regional hypothalamic NPY concentrations in diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2001

Enhanced sensitivity of insulin-resistant adipocytes to vanadate is associated with oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4).

Vanadate (sodium orthovanadate), an inhibitor of phosphotyrosine phosphatases (PTPs), mimics many of the metabolic actions of insulin in vitro and in vivo. The potential of vanadate to stimulate glucose transport independent of the early steps in insulin signaling prompted us to test its effectiveness in an in vitro model of insulin resistance. In primary rat adipocytes cultured for 18 h in the presence of high glucose (15 mm) and insulin (10(-7) m), sensitivity to insulin-stimulated glucose transport was decreased. In contrast, there was a paradoxical enhanced sensitivity to vanadate of the insulin-resistant cells (EC(50) for control, 325 +/- 7.5 microm; EC(50) for insulin-resistant, 171 +/- 32 microm; p < 0.002). Enhanced sensitivity was also present for vanadate stimulation of insulin receptor kinase activity and autophosphorylation and Akt/protein kinase B Ser-473 phosphorylation consistent with more effective PTP inhibition in the resistant cells. Investigation of this phenomenon revealed that 1) depletion of GSH with buthionine sulfoximine reproduced the enhanced sensitivity to vanadate while preincubation of resistant cells with N-acetylcysteine (NAC) prevented it, 2) intracellular GSH was decreased in resistant cells and normalized by NAC, 3) exposure to high glucose and insulin induced an increase in reactive oxygen species, which was prevented by NAC, 4) EPR (electron paramagnetic resonance) spectroscopy showed a decreased amount of vanadyl (+4) in resistant and buthionine sulfoximine-treated cells, which correlated with decreased GSH and increased vanadate sensitivity, while total vanadium uptake was not altered, and 5) inhibition of recombinant PTP1B in vitro was more sensitive to vanadate (+5) than vanadyl (+4). In conclusion, the paradoxical increased sensitivity to vanadate in hyperglycemia-induced insulin resistant adipocytes is due to oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4). Thus, sensitivity of PTP inhibition and glucose transport to vanadate is regulated by cellular redox state.

Acetylcysteine↗

PubMed1998

The vanadate-tolerant yeast Hansenula polymorpha undergoes cellular reorganization during growth in, and recovery from, the presence of vanadate.

When present at intracellular concentrations above micromolar, vanadate becomes toxic to most organisms. However, the yeast Hansenula polymorpha is able to grow on vanadate concentrations in the millimolar range, showing at the same time modifications in cellular ultrastructure and polyphosphate metabolism. Here, the development of the ultrastructural changes, and of vacuolar and secretory activities, during exponential growth on vanadate and upon a return to vanadate-free conditions was investigated. External invertase secretion was inhibited by vanadate, as shown by a decrease in external invertase activity, an intracellular accumulation of small vesicles and a cytoplasmic accumulation of internal invertase. An aberrant appearance of the cell wall and defects in cellular surface growth, possibly linked to defects in secretion, were also observed. However, inhibition of the secretory pathway was not complete since the activity of another secreted enzyme, exoglucanase, increased in the presence of vanadate. Growth on vanadate was also accompanied by an enhancement of vacuolar proteolysis, as indicated by an increase in carboxypeptidase Y activity. However, these modifications were all reversible upon return to vanadate-free conditions, with the normalization process being complex and involving new and dramatic ultrastructural changes and activation of an autophagic mechanism. This mechanism is involved in the elimination/resorption of the observed vanadate-induced aberrant cell structures and/or sites involved in vanadate accumulation, a necessary prerequisite for restoration of conventional ultrastructure and metabolic functions.

Carboxypeptidases↗

PubMed1981

The effects of vanadate on calcium transport in dialyzed squid axons. Sidedness of vanadate-cation interactions.

(1) Vanadate (VO3-) fully inhibits the ATP-dependent uncoupled Ca efflux (Ca pump) in dialyzed squid axons. (2) Vanadate inhibits with high affinity. The mean apparent affinity (K 1/2) obtained was 7 microM. (3) Inhibition by vanadate is dependent on Cao. External Ca lead to a release of the inhibitory effect. (K 1/2 congruent to 3 mM). This antagonistic effect can be reverted by increasing the vanadate concentration. Internal K+ increases the affinity of the intracellular vanadate binding site. External K+ has no effect on the inhibition. (4) Vanadate has no effect on the Nao-dependent Ca efflux component (forward Na-Ca exchange) in the absence of ATP. In axons containing ATP vanadate modified this component.

Adenosine Triphosphate↗

PubMed2000

Vanadate and copper induce overlapping oxidative stress responses in the vanadate-tolerant yeast Hansenula polymorpha.

The mechanisms by which vanadate exerts a toxic effect on living organisms are not completely understood. This is principally due to the variety of intracellular targets of the metal and to the changes in the chemical form and oxidation states that vanadate can undergo, both in the external environment and intracellularly. In order to further elucidate the reasons for vanadate toxicity, and assuming that common detoxification mechanisms can be evoked by a general heavy metal response, we have compared some aspects of the cellular responses to vanadate and copper in the yeast Hansenula polymorpha. By means of 2D electrophoresis we show the existence of common determinants in the responses to vanadate- and copper-induced stresses. Moreover, we demonstrate that both metals induce significant increases in antioxidant enzyme levels, and that there are significant overlaps in the heavy metal and oxidative stress responses. Interestingly, vanadate induces an increase in catalase activity that is much higher than that seen with copper and, unlike copper, does not cause lipid peroxidation of cellular membranes. This suggests that H. polymorpha cells activate a further specific detoxification pathway against vanadate-induced oxidative insults.

Catalase↗

PubMed1990

Plasma membrane-stimulated vanadate-dependent NADH oxidation is not the primary mediator of vanadate toxicity in Saccharomyces cerevisiae.

Interactions of oxyvanadium compounds with cellular metabolism have recently been demonstrated. Membrane-stimulated vanadate-dependent NADH oxidation has been hypothesized to involve the cellular accumulation of H2O2, which may cause the vanadate sensitivity of animals and microbes. This report shows that the vanadate-dependent NADH oxidation activity of the yeast plasma membrane requires oxygen and is present in vanadate-resistant mutants of Saccharomyces cerevisiae. In addition, the vanadate sensitivity of growth in S. cerevisiae is the same during aerobic and anaerobic growth. These results imply that neither plasma membrane-mediated vanadate-stimulated NADH oxidation, nor any other oxidative process, is the primary cause of vanadate sensitivity in yeast cells.

Aerobiosis↗

PubMed1986

Interaction of vanadate with phenol and tyrosine: implications for the effects of vanadate on systems regulated by tyrosine phosphorylation.

The interaction of vanadate with phenol and N-acetyltyrosine ethyl ester in aqueous solution has been studied by using 51V nuclear magnetic resonance spectroscopy. On the basis of these studies, it has been concluded that vanadate rapidly esterifies the hydroxyl group of the aromatic ring to yield a phenyl vanadate. For phenol, the equilibrium constant for this reaction in terms of the convention that the activity of liquid water is 1.0 is K1 = [phenyl vanadate]/[phenol][vanadate] = 0.97 +/- 0.02. This value is well over 4 orders of magnitude larger than estimates from the literature for the corresponding equilibrium constant for the esterification of phenol by phosphate. The equilibrium constant for esterification of the phenol moiety of N-acetyltyrosine ethyl ester is similar to that for esterification of phenol. The relevance of these observations to processes that are regulated by reversible phosphorylation/dephosphorylation of tyrosine residues is discussed, in particular the insulin-like effect of vanadate.

Hydrogen-Ion Concentration↗

PubMed1985

Interaction of inorganic vanadate with glucose-6-phosphate dehydrogenase. Nonenzymic formation of glucose 6-vanadate.

Inorganic vanadate (Vi) activates catalysis by glucose-6-phosphate dehydrogenase of the oxidation of glucose by NADP+. As the concentration of Glu-6-P dehydrogenase is increased, the rate of the vanadate-activated glucose oxidation becomes less sensitive to increases in enzyme concentration. The rate of glucose oxidation in the absence of Vi increases linearly with Glu-6-P dehydrogenase concentration. These results are interpreted in terms of nonenzymic formation of glucose 6-vanadate. At high enzyme concentration, vanadate ester formation becomes partially rate-limiting, and extrapolation to infinite Glu-6-P dehydrogenase concentration allows determination of the second order rate constant for formation of the ester. In separate experiments designed to test the proposed mechanism, it was found that Vi, at concentrations at which it strongly activates catalysis by Glu-6-P dehydrogenase of glucose oxidation, has no effect on the rates of oxidation of glucose 6-phosphate or 6-deoxyglucose catalyzed by Glu-6-P dehydrogenase. Sulfate, which is known to activate glucose oxidation and to inhibit glucose 6-phosphate oxidation, strongly activates 6-deoxyglucose oxidation. These experiments show that the 6-hydroxyl group of glucose is essential for the observed activation by Vi and are also consistent with the formation of glucose 6-vanadate. Also, the rate of the sulfate-activated glucose oxidation increases linearly with Glu-6-P dehydrogenase concentration. These results are consistent with the proposed mechanism for sulfate activation which involves sulfate binding to the enzyme (Anderson, W. B., Horne, R. N., and Nordlie, R. C. (1968) Biochemistry 7, 3997-4004). The second order rate constant calculated for formation of glucose 6-vanadate at pH 7.0 is 2.4 M-1 s-1. The corresponding values for glucose 6-phosphate and glucose 6-arsenate formation are approximately 9 X 10(-11) M-1 s-1 and 6.3 X 10(-6) M-1 s-1 (Lagunas, R. (1980) Arch. Biochem. Biophys. 205, 67-75).

Glucose↗

PubMed1981

Inhibition of protein synthesis in cell cultures by vanadate and in brain homogenates of rats fed vanadate.

Following the observation of polysome disaggregation by vanadate, when Neuro-2a cells were incubated with vanadate, incorporation of 3H-leucine into protein was markedly inhibited. The inhibition of protein synthesis was dependent on vanadate concentration and on time of incubation. Inhibition of cell growth was also observed. Simultaneous measurements on vanadate-treated cells showed decreased Na,K-ATPase activity. Rats given sodium vanadate as their sole drinking fluid also showed an inhibition of brain protein synthesis (18 and 20% after 30 and 60 days, respectively, of treatment). Possible implications of the inhibition of Na,K-ATPase and of protein synthesis by vanadate are discussed.

Animals↗

PubMed1990

Role of glutathione in vanadate reduction in young and mature rats: evidence for direct participation of glutathione in vanadate inactivation.

The influence of renal glutathione content, modulated by the glutathione synthesis inhibitor buthionine sulphoximine or by glutathione infusion, on the polyuric and natriuretic effects of i.v. administered vanadate was investigated in 20- and 55-day-old rats. The modulation of renal glutathione content led to significant changes in urine volume and sodium excretion, independently of age. A decrease in the renal glutathione level led to intensification and prolongation of the diuretic effects of vanadate in 55-day-old animals. Treatment with glutathione abolished and treatment with buthionine sulphoximine increased the polyuric effect of vanadate. These observations indicate a role for renal glutathione in vanadate inactivation. Age-dependent differences in the polyuric and natriuretic effectiveness of vanadate are caused by differences in renal glutathione content during maturation of the kidney.

Aging↗

PubMed1992

Superoxide-independent reduction of vanadate by rat liver microsomes/NAD(P)H: vanadate reductase activity.

It has been reported that vanadate-stimulated oxidation of NAD(P)H by microsomal systems can proceed anaerobically, in contrast to the general notion that the oxidation proceeds exclusively by an O(2-)-dependent free radical chain mechanism. The current study indicates that microsomal systems are endowed with a vanadate-reductase property, involving a NAD(P)H-dependent electron transport cytochrome P450 system. Our ESR measurements demonstrated the formation of a vanadium(IV) species in a mixture containing vanadate, rat liver microsomes, and NAD(P)H. This vanadium(IV) species was identified as the vanadyl ion (VO2+) by comparison with the ESR spectrum of VOSO4. The initial rate of vanadium(IV) formation depends linearly on the concentration of microsomes. The Michaelis-Menten constants were found to be: km = 1.25 mM and Vmax = 0.066 mumol (min)-1 (mg microsomes)-1, respectively. Pretreatment of the microsomes with carbon monoxide or K3Fe(CN)6 reduced vanadium(IV) generation, suggesting that the NAD(P)H-dependent electron transport cytochrome P450 system plays a significant role in the microsomal reduction of vanadate. Measurements under argon or in the presence of superoxide dismutase caused only minor (less than 10%) reductions in vanadium(IV) generation. The VO2+ species was also detected in NAD(P)H oxidation by fructose plus vanadate, a reaction known to proceed via an O(2-)-mediated chain mechanism. However, the amount of vanadium(IV) generated by this reaction was an order of magnitude smaller than that by the microsomal system and was inhibitable by superoxide dismutase, affirming the conclusion that the microsomal/NAD(P)H system is endowed with the (O(2-)-independent) vanadium(V) reductase property.

Anaerobiosis↗

PubMed2000

Vanadate reduction by molybdenum-free dissimilatory nitrate reductases from vanadate-reducing bacteria.

Molybdenum- and molybdenum cofactor-free nitrate reductases recently isolated by us from vanadate-reducing bacteria Pseudomonas isachenkovii are likely to mediate vanadate reduction. During anaerobic growth of P. isachenkovii on medium supplemented with nitrate and vanadate, vanadate dissimilation was followed by nitrate consumption, and this process was associated with some structural reorganizations of nitrate reductases. The homogeneous membrane-bound nitrate reductase of P. isachenkovii reduced vanadate with NADH as an electron donor.

Anaerobiosis↗

PubMed2005

Separation of (134)Cs and (152)Eu using inorganic ion exchangers, zirconium vanadate and ceric vanadate.

Two inorganic ion exchangers, zirconium vanadate and ceric vanadate were synthesized and applied to confine and separate (152)Eu and (134)Cs from a synthetic mixture. The percentages of adsorption of the two radionuclides were studied for the two ion exchangers at varying pH conditions. At pH 3, zirconium vanadate adsorbs both Eu and Cs and a column chromatographic separation was achieved using 0.1M EDTA as the eluant. The ceric vanadate ion exchanger showed an increased trend in adsorption for both the radionuclides with increase of pH value from 1 to 6. At pH 1, a column chromatographic separation of these radionuclides from a mixture was achieved, because at this pH only (134)Cs was adsorbed to ceric vanadate bed in the column.

Journal Article↗

PubMed1991

Effects of valinomycin on vanadate-sensitive and vanadate-resistant H+ transport in vesicles from turtle bladder epithelium: evidence for a K+/H+ exchanger.

The vanadate-sensitive component of the ATP-dependent H+ gradient formed in isolated vesicles from a urinary epithelium was abolished by valinomycin omission. This suggests that vanadate-sensitive H+ transport has an absolute requirement for intravesicular K+ and that the transport may be due to a K+/H+ exchanger. Sensitivity to the inhibitor SCH28080 supports this conclusion. On the other hand, valinomycin affects the initial velocity of vanadate-resistant transport without altering its maximum gradient. This is consistent with the development of a membrane potential consequent to electrogenic uniport H+ transport.

Adenosine Triphosphate↗

PubMed2002

Vanadate inhibits the ATPase activity and DNA binding capability of bacterial MutS. A structural model for the vanadate-MutS interaction at the Walker A motif.

MutS, a member of the ABC ATPases superfamily, is a mismatch DNA-binding protein constituent of the DNA post-replicative mismatch repair system (MMRS). In this work, it is shown that the ATPase activity of Pseudomonas aeruginosa and Escherichia coli MutS is inhibited by ortho- and decavanadate. Structural comparison of the region involved in the ATP binding of E.coli MutS with the corresponding region of other ABC ATPases inhibited by vanadate, including the myosin- orthovanadate-Mg complex, showed that they are highly similar. From these results it is proposed that the orthovanadate inhibition of MutS ATPase can take place by a similar mechanism to that described for other ATPases. Docking of decavanadate on the ATP-binding region of MutS showed that the energetically more favorable interaction of this compound would take place with the complex MutS- ADP-Mg, suggesting that the inhibitory effect could be produced by a steric impediment of the protein ATP/ADP exchange. Besides the effect observed on the ATPase activity, vanadate also affects the DNA-binding capability of the protein, and partially inhibits the oligomerization of MutS and the temperature-induced inactivation of the protein. From the results obtained, and considering that vanadate is an intracellular trace component, this compound could be considered as a new modulator of the MMRS.

Adenosine Diphosphate↗