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PubMed1988

Subchronic treatment with vanadate does not potentiate the toxicity of cardiac glycosides.

Since it has been claimed that vanadate is an endogenous regulator of Na/K-ATPase activity and that it potentiates the toxicity of cardiac glycosides, we were alarmed to discover that certain Finnish physicians were prescribing vanadate in combination with other trace minerals to elderly patients for many different chronic diseases (e.g., cancer, rheumatism). To study the interaction of vanadate and cardiac glycosides, we fed vanadate in the drinking water (25 micrograms/mL) to guinea pigs for 20 d, and studied either their sensitivity to the acute toxicity of the cardiac glycoside ouabain or whether the vanadate would influence the subacute toxicity of ouabain. Vanadate had no influence on the toxicity of ouabain either acute or subchronically administered, nor was there any sign of inhibition of Na/K-ATPase activity as measured by 86Rb-uptake into intact erythrocytes (RBCs), RBC content of sodium or potassium or Na/K-ATPase activity in RBC membranes prepared from the vanadate-treated guinea pigs. Vanadate had been absorbed in substantial quantities from the gastrointestinal tract, since serum, heart, liver, and especially kidney contained measurable amounts of vanadium in contrast to controls, but it is concluded that this vanadate is not in a biologically active form.

Animals↗
PubMed1998

The involvement of protein kinase C and tyrosine kinase in vanadate-induced contraction.

Gastric smooth muscle of cats was used to investigate the involvement of protein kinase in vanadate-induced contraction. Vanadate caused a contraction of cat gastric smooth muscle in a dose-dependent manner. Vanadate-induced contraction was totally inhibited by 2 mM EGTA and 1.5 mM LaCl3 and significantly inhibited by 10 microM verapamil and 1 microM nifedipine, suggesting that vanadate-induced contraction is dependent on the extracellular Ca2+ concentration. and the influx of extracellular Ca2+ was mediated through voltage-dependent Ca2+ channel. Both protein kinase C inhibitor and tyrosine kinase inhibitor significantly inhibited the vanadate-induced contraction and the combined inhibitory effect of two protein kinase inhibitors was greater than that of each one. But calmodulin antagonists did not have any influence on the vanadate-induced contraction. On the other hand, both forskolin (1 microM) and sodium nitroprusside (1 microM) significantly inhibited vanadate-induced contraction. Therefore, these results suggest that both protein kinase C and tyrosine kinase are involved in the vanadate-induced contraction which required the influx of extracellular Ca2+ in cat gastric smooth muscle, and that the contractile mechanism of vanadate may be different from that of agonist binding to its specific receptor.

Animals↗
PubMed2006

Low doses of vanadate and Trigonella synergistically regulate Na+/K + -ATPase activity and GLUT4 translocation in alloxan-diabetic rats.

Oral administration of vanadate to diabetic animals have been shown to stabilize the glucose homeostasis and restore altered metabolic pathways. However, vanadate exerts these effects at relatively high doses with several toxic effects. Low doses of vanadate are relatively safe but unable to elicit any antidiabetic effects. The present study explored the prospect of using low doses of vanadate with Trigonella foenum graecum, seed powder (TSP), another antidiabetic agent, and to evaluate their antidiabetic effect in diabetic rats. Alloxan diabetic rats were treated with insulin, vanadate, TSP and low doses of vanadate with TSP for three weeks. The effect of these antidiabetic compounds was examined on general physiological parameters, Na(+)/K(+) ATPase activity, membrane lipid peroxidation and membrane fluidity in liver, kidney and heart tissues. Expression of glucose transporter (GLUT4) protein was also examined by immunoblotting method in experimental rat heart after three weeks of diabetes induction. Diabetic rats showed high blood glucose levels. Activity of Na(+)/K(+) ATPase decreased in diabetic liver and heart. However, kidney showed a significant increase in Na(+)/K(+) ATPase activity. Diabetic rats exhibited an increased level of lipid peroxidation and decreased membrane fluidity. GLUT4 distribution was also significantly lowered in heart of alloxan diabetic rats. Treatment of diabetic rats with insulin, TSP, vanadate and a combined therapy of lower dose of vanadate with TSP revived normoglycemia and restored the altered level of Na(+)/K(+) ATPase, lipid peroxidation and membrane fluidity and also induced the redistribution of GLUT4 transporter. TSP treatment alone is partially effective in restoring the above diabetes-induced alterations. Combined therapy of vanadate and TSP was the most effective in normalization of altered membrane linked functions and GLUT4 distribution without any harmful side effect.

Animals↗
PubMed1983

Detergent-induced distinctions between fluoride- and vanadate-stimulated adenylate cyclases and their responses to guanine nucleotides.

The influence of detergents on fluoride- and vanadate-stimulated adenylate cyclases was investigated with enzyme from liver and adipocyte plasma membranes. Stimulation of the adipocyte cyclase by Na3VO4 was maximal (sixfold) at 3 mM, was not additive with fluoride stimulation, and was readily reversed by washing of the membranes. Vanadate stimulation of the hepatic cyclase was specifically blocked by catechol, which had no effect on basal activity or on fluoride- or glucagon-stimulated activities. The hepatic enzyme, stimulated by fluoride ion, guanyl-5'-yl-(beta,gamma-imino)diphosphate (GPP(NH)P), or GPP(NH)P and glucagon, was inhibited by vanadate with 50% inhibition seen with 2 to 6 mM vanadate. The fluoride-activated adipocyte adenylate cyclase was inhibited by guanosine 5'-O-(3-thio-triphosphate) (GTP gamma S) more potently than by GPP(NH)P, with 50% inhibition being seen with 10 nM GTP gamma S or 100 nM GPP(NH)P. These nucleotides also inhibited the vanadate-stimulated enzyme, but with one-third the potency seen with the fluoride-activated cyclase. Dispersion of the adipocyte cyclase by Lubrol-PX into a 30,000g supernatant fraction caused no change in activation of the enzyme by fluoride, but reduced vanadate-stimulated activity 80%. By comparison, this treatment enhanced stimulation by GPP(NH)P twofold and by GTP gamma S threefold. More importantly, perhaps, the treatment with detergent blocked inhibition of the basal enzyme by GTP, blocked inhibition of fluoride- and vanadate-stimulated cyclases by GTP, GPP(NH)P, or GTP gamma S, and rendered vanadate-stimulated activity sensitive to enhancement by guanine nucleotides. The data indicate differences in the actions of vanadate and fluoride, made evident by the influence of guanine nucleotides and detergent treatment. The observations would be consistent with the idea that the effects of vandate may be due to the formation of GDP X V on the enzyme. The data strongly suggest that treatment of adenylate cyclase with Lubrol-PX causes a functional blockade in the guanine nucleotide-dependent inhibitory regulation (mediated by Ni), thereby allowing activation by the stimulatory guanine nucleotide-dependent regulatory component (Ns).

Adenylyl Cyclases↗
PubMed1983

The effects of several ligands on the potassium-vanadate interaction in the inhibition of the (Na+ + K+)-ATPase and the Na+, K+ pump.

Inhibition by vanadate of the K+-dependent p-nitrophenylphosphatase activity catalyzed by the (Na+ + K+)-ATPase partially purified from pig kidney showed competitive behavior with the substrate, K+ and Mg2+ acted as cofactors in promoting that inhibition. Ligands which inhibited the K+-dependent p-nitrophenyl phosphate hydrolysis (Na+, nucleotide polyphosphates, inorganic phosphate) protected against inhibition by vanadate. The magnitude of that protection was proportional to the inhibition produced in the absence of vanadate. In the presence of only p-nitrophenyl phosphate and Mg2+, or when the protective ligands were tested alone, the activation of p-nitrophenyl phosphate hydrolysis by K+ followed a sigmoid curve in the presence as well in the absence of vanadate. However, the combination of 100 mM NaCl and 3 mM ATP resulted in a biphasic effect of K+ on the p-nitrophenyl phosphate hydrolysis in the presence of vanadate. After an initial rise at low K+ concentration, the p-nitrophenylphosphatase activity declined at high K+ concentrations; this decline became more pronounced as the vanadate concentration was increased. This biphasic response was not seen when a nonphosphorylating ATP analog was combined with Na+ (which favors the nucleotide binding) or with inorganic phosphate (a requirement for K+ - K+ exchange). Experiments with inside-out resealed vesicles from human red cells showed that in the absence of Na+ plus ATP, K+ promoted vanadate inhibition of p-nitrophenylphosphatase activity in a nonbiphasic manner, acting at cytoplasmic sites. On the other hand, in the presence of Na+ plus ATP, the biphasic response of p-nitrophenyl phosphate hydrolysis is due to K+ acting on extracellular sites. In vanadate-poisoned intact red blood cells, the biphasic response of the ouabain-sensitive Rb+ influx as a function of the external Rb+ concentration failed to develop when there was no Na+ in the extracellular media. In addition, in the absence of extracellular Na+, external Rb+ did not influence the magnitude of inhibition. The present findings indicate that external K+ favors vanadate inhibition by displacing Na+ from unspecified extracellular membrane sites.

Biological Transport, Active↗
PubMed1987

Vanadate inhibition of ATP-dependent H+ transport in membrane vesicles from turtle bladder epithelial cells.

The ATP-dependent proton transport into vesicles of a mixed membrane fraction obtained from turtle bladder epithelial cells consists of at least two kinetically defined moieties: one, which is maximally inhibited by 25% with nanomolar levels of vanadate, but not inhibited at all with equimolar levels of N-ethylmaleimide, and another, which is maximally inhibited by 70% with micromolar levels of N-ethylmaleimide and by 25% with equimolar levels of vanadate. In contrast to the transport function, the associated enzymatic function (the ouabain-resistant ATPase activity) in these membranes, not inhibited by nanomolar levels of vanadate or N-ethylmaleimide, is maximally inhibited by 40% with micromolar levels of vanadate and by 13% with equimolar levels of N-ethylmaleimide. Independent of these kinetic differences between the enzyme and the transport functions, membranes containing the N-ethylmaleimide-sensitive proton transport function are electrophoretically separable from those containing the vanadate-sensitive transport function. For example, the kinetically defined, vanadate-sensitive proton transport function is recovered exclusively and kinetically identified in one of four electrophoretic membrane fractions, EF-II; while the N-ethylmaleimide-sensitive function is recovered in EF-III as well as in EF-II. Membranes of EF-IV, maximally enriched in ouabain-resistant ATPase activity, possess no proton transport function at all, even in the absence of N-ethylmaleimide or vanadate. Additional data under in vivo as well as under in vitro conditions are required to prove that the vanadate-sensitive proton transport in these vesicles is an in vitro manifestation of the mechanism responsible for generating the vanadate-sensitive luminal acidification process under in vivo conditions in the intact turtle bladder.

Adenosine Triphosphate↗
PubMed1996

Vanadate inhibits vacuolar H(+)-ATPase-mediated proton transport in chicken kidney microsomes by an ADP-dependent mechanism.

Recent reports indicate that vacuolar-type proton ATPases from chicken osteoclasts (Chatterjee et al. (1992) Proc. Natl. Acad. Sci. USA 89, 6257-6261), yeast vacuoles and chromaffin granules (Beltran and Nelson (1992) Acta Physiol. Scand. Suppl. 607, 41-47) can be inhibited by vanadate, albeit at a concentration much higher than that required to inhibit P-type ATPases. We have characterized the mechanism by which vanadate inhibits vacuolar-type ATPase-mediated proton transport by chicken kidney microsomes. The initial rate of proton transport is somewhat less sensitive to vanadate than the total acidification, with IC50 values of 1.58 mM and 0.78 mM vanadate, respectively. The inhibition of both the initial rate and total acidification is noncompetitive with respect to ATP. The inhibition is abolished when ADP is removed by an ATP-regenerating system, and the addition of exogenous ADP increases the vanadate inhibition of proton transport in a synergistic manner, thus demonstrating that inhibition by vanadate is dependent on the presence of ADP and explaining the lower effect of vanadate on the initial rate of acidification. Phosphate protects proton transport activity from inhibition by vanadate. These effects of ADP and phosphate suggest that inhibition by vanadate may involve the formation of a complex with ADP at a nucleotide binding site, possibly at the catalytic site of the enzyme.

Adenosine Diphosphate↗
PubMed1982

Vanadate stimulates adenylate cyclase via the guanine nucleotide regulatory protein by a mechanism differing from that of fluoride.

Vanadate stimulates adenylate cyclase activity in turkey erythrocyte membranes. The maximal stimulation is 7-fold over basal at 3 mM vanadate; higher concentrations are inhibitory. A suboptimal concentration of fluoride (1 mM) together with vanadate (3 mM) activates adenylate cyclase in a non-additive manner; cyclase activation by optimal fluoride (10 mM) is inhibited by vanadate (3 mM). There is no stimulation by vanadate of adenylate cyclase activity (measured either with Mg2+ or Mn2+) in CYC- S49 lymphoma cell membranes. Vanadate (3 mM) shows no effect on binding of Beta-adrenergic agonists or antagonists to the [3H] (-)-dihydroalprenolol binding site in turkey erythrocyte membranes. These results suggest that the effect of vanadate on Adenylate cyclase is mediated through the nucleotide regulatory protein and may act by a mechanism similar to fluoride. However, in cholera toxic-treated membranes as well as in GDP-beta-S plus isoproterenol-treated membranes, fluoride-stimulated adenylate cyclase activity is significantly reduced, but vanadate stimulation is not. Our results suggest that although the actions of vanadate and fluoride in adenylate cyclase may each involve the nucleotide regulatory unit, the exact mechanisms of activation by the two anions differ.

Adenylyl Cyclases↗
PubMed1990

Vanadate-induced inhibition of renin secretion is unrelated to inhibition Na,K-ATPase activity.

There is evidence that three inhibitors of Na,K-ATPase activity--ouabain, K-free extracellular fluid, and vanadate--inhibit renin secretion by increasing Ca2+ concentration in juxtaglomerular cells, but in the case of vanadate, it is uncertain whether the increase in Ca2+ is due to a decrease in Ca2+ efflux (inhibition of Ca-ATPase activity, or inhibition of Na,K-ATPase activity, followed by an increase in intracellular Na+ and a decrease in Na-Ca exchange) or to an increase in Ca2+ influx through potential operated Ca channels (inhibition of electrogenic Na,K transport, followed by membrane depolarization and activation of Ca channels). In the present experiments, the rat renal cortical slice preparation was used to compare and contrast the effects of ouabain, of K-free fluid, and of vanadate on renin secretion, in the absence and presence of methoxyverapamil, a Ca channel blocker. Basal renin secretory rate averaged 7.7 +/- 0.3 GU/g/60 min, and secretory rate was reduced to nearly zero by 1 mM ouabain, by K-free fluid, by 0.5 mM vanadate, and by K-depolarization (increasing extracellular K+ to 60 mM). Although 0.5 microM methoxyverapamil completely blocked the inhibitory effect of K-depolarization, it failed to antagonize the inhibitory effects of ouabain, of K-free fluid, and of vanadate. A concentration of methoxyverapamil two hundred times higher (100 microM) completely blocked the inhibitory effects of vanadate, but still failed to antagonize the effects of ouabain and of K-free fluid. Collectively, these observations demonstrate that vanadate-induced inhibition of renin secretion cannot be attributed entirely to Na,K-ATPase inhibition, since in the presence of methoxyverapamil, the effect of vanadate differed from the effects of either ouabain (a specific Na,K-ATPase inhibitor) or K-free fluid. Moreover, it cannot be attributed entirely to a depolarization-induced influx of Ca2+ through potential-operated Ca channels, since methoxyverapamil antagonized K-depolarization-induced inhibition of renin secretion much more effectively than it antagonized vanadate-induced inhibition.

Animals↗
PubMed1994

Effect of vanadate on reproductive efficiency in normal and streptozocin-treated diabetic rats.

The effects of oral vanadate treatment on the reproductive efficiency of normal and diabetic female rats were studied. Vanadate treatment in a dose-dependent manner reduced both the conception rate and the ability to carry pregnancy to term compared with a control group. These effects were more severe in diabetic groups as compared with nondiabetic groups. At the 0.25 mg/mL vanadate dose, the conception rate was reduced by 13% and 33% for the nondiabetic group and the diabetic group, respectively. At the 0.50 mg/mL dose, this rate decreased by 20% and 47% for the nondiabetic and diabetic groups, respectively. With an identical oral vanadate regimen of 0.25 mg/mL, the ability to sustain pregnancy to term was reduced by 30% and 90% for the nondiabetic and diabetic groups, respectively, and by 84% and 100% for these groups at a dose of 0.50 mg/mL. Although the blood vanadate concentrations were an order of magnitude higher in diabetic animals treated with vanadate than in nondiabetic animals under an identical vanadate treatment, oral vanadate treatments had no measurable effects in ameliorating hyperglycemia in these diabetic pregnant animals. In conclusion, vanadate is ineffective in normalizing blood glucose in pregnant diabetic rats, and it impairs reproductive capacity and the ability to sustain pregnancy to term in both nondiabetic and diabetic animals.

Administration, Oral↗
PubMed1991

Vanadate inhibition of ATP and p-nitrophenyl phosphate hydrolysis in the fragmented sarcoplasmic reticulum.

The vanadate inhibition of the Ca(2+)-ATPase activity was analysed both in intact sarcoplasmic reticulum vesicles and in the presence of low concentrations of Tween 20, using ATP and p-nitrophenyl phosphate as substrates. The saturation of the internal low-affinity calcium-binding sites protects the enzyme against vanadate inhibition, because: (1) p-nitrophenyl phosphate hydrolysis is not inhibited by vanadate in intact vesicles, but inhibition developed after solubilization with detergents; (2) the vanadate inhibition of the p-nitrophenyl phosphate hydrolysis in solubilized preparations is prevented by free Ca2+ concentrations higher than 10(-3) M and vanadate competes with calcium (10(-5)-10(-3) M); and (3) the vanadate inhibition of ATP hydrolysis is decreased with an increase in vesicular Ca2+ concentration. The presence of magnesium ions is indispensable for the vanadate effect. The vanadate inhibition is non-competitive with respect to Mg-p-nitrophenyl phosphate and uncompetitive with respect to Mg-ATP. However, in the presence of dimethyl sulfoxide, which facilitates phosphorylation of the enzyme, the inhibition is converted to a competitive one with respect to a substrate. The results suggest, that in the process of enzyme operation vanadate interacts with the unliganded E form of Ca(2+)-ATPase, occupying probably an intermediate position between the E2 and E1 forms, with the formation of an E2 Van complex, that imposes the inhibition on the Ca(2+)-ATPase activity.

4-Nitrophenylphosphatase↗
PubMed1983

Vanadate and brain adenylate cyclase. Effect of spreading depression.

The effect of vanadate on the adenylate cyclase activity of rat cerebral cortex homogenates is described. In the absence of ethyleneglycol-bis-(beta-aminoethyl ether) N,N'-tetraacetic acid (EGTA), 10(-6)M vanadate inhibited enzyme activity by 23%, while 10 (-4) M and 10(-3) M stimulated the enzyme by 14 and 90%, respectively. In the presence of 0.2 mM EGTA, 10 (-6) M to 10(-3) M vanadate had only stimulating effects (18-450%). Additive effects of vanadate and noradrenaline on adenylate cyclase activity suggest different sites of action of these agents. Interaction of vanadate with both fluoride and guanyl-5'-yl imidodiphosphate had an apparently competitive character. Adenylate cyclase maximally stimulated by fluoride (10 mM) was inhibited by vanadate. This inhibitory effect was more pronounced in the absence of EGTA. Adenylate cyclase in the homogenates from the rat cerebral cortex in vivo invaded by spreading depression was slightly increased (up to 38%). This effect was abolished by low (10 (-7) M) vanadate. The results suggest that brain adenylate cyclase is stimulated by vanadate via the guanine nucleotide regulatory protein. The mechanism of vanadate's action, its modulation by calcium ions and the possible physiological role of these effects are discussed.

Adenylyl Cyclases↗
PubMed2003

New vanadate-induced Ca2+ pathway in human red cells.

Vanadate is a commonly used Ca2+ pump blocker, exerting a substantial effect on Ca2+ extrusion at millimolar concentrations in human red cells. At such levels, vanadate also seems to open an L type-like Ca2+ channel in these cells (J Biol Chem 257 (1982) 7414; Gen Physiol Biophys 16 (1997) 359). Since neither a dose-dependence effect nor a metabolic requirement for the latter action could be found in the literature, we have addressed this matter in the present work. Accordingly, vanadate action on Ca2+ entry was systematically investigated in both young and old human red cells after metabolic depletion. Although vanadate enhanced Ca2+ entry indifferently in either cell type, a distinct over-all effect was paradoxically found depending on whether or not metabolic substrates that give rise to ATP were present. In ATP-depleted cells, unlike with ATP-containing cells, vanadate-stimulated Ca2+ entry was neither blocked by raising external K+ nor by adding voltage-dependent Ca2+ channel blockers (nifedipine, calciseptine, FTX3.3) or compounds affecting polyphosphoinositide metabolism (Li+, neomycin). Likewise, full substitution of external Na+ by other cations did not inhibit vanadate-enhanced Ca2+ entry. Regardless of the cell age, stimulation by vanadate depended strongly on internal Na+ (0-30 mM). Vanadate stimulation was significantly reduced (about 55%) by heparin (10 mg/ml) only in young cells and by ryanodine (about 35%, 250 microM) in old cells. The results suggest presence of a new vanadate-induced Ca2+ entry pathway in ATP-depleted cells.

Adenosine Triphosphate↗
PubMed2005

Modulation of glucose transporter (GLUT4) by vanadate and Trigonella in alloxan-diabetic rats.

Oral administration of vanadate is an effective treatment for diabetes in animal models. However, vanadate exerts these effects at high doses and several toxic effects are produced. Low doses of vanadate are relatively safe but are unable to elicit any antidiabetic effect. The present study explored the prospect of using low doses of vanadate in combination with Trigonella seed powder (TSP) to evaluate their antidiabetic effect in alloxan-diabetic rats. Alloxan-diabetic rats were treated with insulin, vanadate, TSP and vanadate and TSP in combination for 3 weeks. The effect of these antidiabetic compounds was examined on general physiological parameters and distribution of glucose transporter (GLUT4) in skeletal muscle by immunoblotting and immunohistochemistry. Treatment of alloxan-diabetic rats with insulin, vanadate, TSP and vanadate in combination with TSP revived normoglycemia and restored the disturbances in the distribution of GLUT4 in skeletal muscle. TSP treatment was only partially effective in the restoration of diabetic alterations. The treatment of diabetic rats with combined doses of vanadate and TSP was most effective in the normalization of plasma glucose levels and correction of altered GLUT4 distribution.

Alloxan↗
PubMed2002

Mechanisms of vanadate-induced cellular toxicity: role of cellular glutathione and NADPH.

Besides its insulin-mimetic effects, vanadate is also known to have a variety of physiological and pharmacological properties, varying from induction of cell growth to cell death and is also a modulator of the multidrug resistance phenotype. However, the mechanisms underlying these effects are still not understood. The present report analyzes the mechanisms of vanadate toxicity in two cell lines previously found to have different susceptibilities to this compound. It was shown that catalase and GSH reversed the sensitivity of a vanadate-sensitive cell line and NADPH sensitized vanadate-resistant cells. NADPH also increased the residues of P-Tyr and the induction of Ras protein expression in vanadate-resistant cells, while GSH avoided these effects in vanadate-sensitive cells. Thus, it seems that the effects of vanadate in signal transduction are dependent on NADPH and are related to cell death. Based on the effects observed in the present study it was suggested that once inside the cell, vanadate is reduced to vanadyl in a process dependent on NADPH. Vanadyl then may react with H2O2 generating primarily peroxovanadium species (PV) rather than following the Fenton reaction. The PV compounds formed would be responsible for P-Tyr increase, Ras induction, and cell death. The results obtained also point to vanadate as a possible chemotherapic in the use of multidrug-resistant tumors.

Animals↗
PubMed1998

Stimulatory effects of vanadate on amylase release from isolated rat pancreatic acini.

The effects of vanadate on exocrine pancreatic function were examined in isolated rat pancreatic acini. Vanadate caused a concentration-dependent stimulation of amylase release above a concentration of 1 mM. Co-incubation of vanadate with vasoactive intestinal polypeptide, 8-bromoadenosine 3':5'-cyclic monophosphate, and the Ca2+ ionophore A23187 produced a synergistic pattern of amylase release, whereas co-incubation with cholecystokinin octapeptide (CCK-8), carbamylcholine, and 12-O-tetradecanoylphorbol 13-acetate produced an additive effect. Vanadate alone had no influence on acinar cyclic AMP content, Ca2+ efflux, or intracellular Ca2+ concentration. However, preincubation with vanadate prevented the plateau phase of CCK-8-induced Ca2+ transient increase from returning to baseline. Moreover, depletion of the intracellular Ca2+ pool by pretreatment of acini with CCK-8 in Ca2+-free medium (plus ethyleneglycol bis[beta-aminoethylether]-N,N'-tetraacetic acid) had no effect on subsequent stimulation by vanadate, although it abolished the response to both CCK-8 and carbamylcholine stimulation. The protein kinase C (PKC) inhibitors staurosporine and calphostin C significantly inhibited vanadate-stimulated amylase release, whereas the protein tyrosine kinase inhibitor genistein had no inhibitory effect. Moreover, vanadate caused a significant translocation of PKC from cytosol to membrane fraction in pancreatic acinar cells. This translocation was inhibited significantly by staurosporine and calphostin C but not by genistein. These results suggest that vanadate acts directly on pancreatic acini and stimulates amylase release by activating PKC without an effect on Ca2+ mobilization, cyclic AMP, or protein tyrosine kinase.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Oxidizing effects of vanadate on calcium mobilization and amylase release in rat pancreatic acinar cells.

The effects of vanadate were examined by monitoring intracellular free calcium concentration ([Ca2+]i) and amylase secretion in collagenase-dispersed rat pancreatic acinar cells. Vanadate increased [Ca2+]i by mobilizing calcium from agonist-releasable intracellular calcium stores, since this increase was observed in the absence of extracellular calcium and vanadate failed to increase [Ca2+]i after treatment with thapsigargin in calcium-free medium. Moreover, pretreatment of acinar cells with vanadate prevented the cholecystokinin octapeptide (CCK-8)-induced signal of [Ca2+]i, whereas co-incubation with CCK-8 potentiated the plateau phase of calcium response to CCK-8 without modifying the transient calcium spike. The effects of vanadate on calcium mobilization were reversed by the presence of the sulfhydryl reducing agent dithiothreitol. Vanadate also activated the calcium influx, since an additional enhancement of calcium influx induced by thapsigargin-evoked intracellular store depletion was observed and vanadate reversed the inhibitory effect of lanthanum (an inhibitor of calcium entry) into acinar cells. In addition, vanadate evoked a concentration-dependent release of amylase from pancreatic acinar cells and moreover, reduced the secretory response to CCK-8. We conclude that, in pancreatic acinar cells, vanadate releases calcium from the agonist-releasable intracellular calcium pool and consequently induces amylase secretion. These effects are likely due to the oxidizing effects of this compound.

Amylases↗
PubMed1997

Vanadate stimulation of 2-deoxyglucose transport is not mediated by PI 3-kinase in human skeletal muscle.

Glucose transport in mammalian skeletal muscle is stimulated by insulin, hypoxia and tyrosine protein phosphatase inhibitors such as vanadate. However, it is unknown whether the vanadate signaling mechanism shares a common or separate pathway with insulin or hypoxia. Therefore, experiments were conducted on incubated human muscle strips to compare the effects of vanadate with insulin and hypoxia stimulated 2-deoxyglucose transport (2-DOG). We also used the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin to examine whether PI 3-kinase is a common step by which each stimulate glucose transport. Results demonstrate that whereas the effects of vanadate and hypoxia were additive with insulin stimulated glucose transport, the effect of vanadate plus hypoxia was not. In addition, wortmannin significantly (P < 0.05) reduced insulin but not vanadate or hypoxia stimulated 2-DOG transport. Moreover, PI 3-kinase activity was significantly elevated (P < 0.05) in the presence of insulin but not vanadate. In conclusion, these data suggest that vanadate and hypoxia stimulate glucose transport via a similar signaling pathway which is distinct from insulin and that the vanadate signaling pathway is not mediated by PI 3-kinase in human skeletal muscle.

Analysis of Variance↗