Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of a dietary supplement of an aldose reductase inhibitor (ponalrestat) or of myo-inositol on sodium transport into the rat brain and on concentrations of saccharide and polyols in cortical brain tissue and sciatic nerve was investigated in control rats and in streptozotocin-diabetic rats after a diabetes duration of 2 weeks. In untreated diabetes, the neocortical blood-brain barrier permeability for sodium decreased by 28% (3.4 +/- 0.4 vs 4.7 +/- 1.6 x 10(-5) ml/s g, mean +/- SD) as compared to controls. Levels of glucose, sorbitol and fructose increased in brain as well as in nerve tissues, whereas myo-inositol depletion was not demonstrable. Ponalrestat treatment of diabetic animals had no effect upon the decreased neocortical blood-brain barrier permeability to sodium (3.5 +/- 0.9 vs 4.7 +/- 1.1 x 10(-5) ml/s g) despite normalization of brain and nerve content of sorbitol and fructose. Myo-inositol supplementation of diabetic rats normalized sodium passage into the brain (4.2 +/- 1.1 vs 4.4 +/- 0.5 x 10(-5) ml/s g). Brain concentrations of monosaccharides and polyols were normalized as compared to the myo-inositol treated control group and nerve concentrations of glucose, sorbitol, and fructose were significantly increased. Myo-inositol treatment leads to a normalization of blood-brain barrier permeability; it is suggested that myo-inositol exerts a restituting effect upon Na+/K+-ATPase activity of the cerebral endothelial cells.
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PMID:Myo-inositol normalizes decreased sodium permeability of the blood-brain barrier in streptozotocin diabetes. 252 78

The progression of diabetic nephropathy can be arrested by an improvement in diabetic control. High glucose concentrations increase the flux through the aldose reductase pathway, and it has been proposed that this may contribute to renal damage. Aldose reductase is present in both the glomerulus and the renal tubule. Biochemical changes associated with increased sorbitol production have been demonstrated in animal models, including myo-inositol depletion, reduced Na+-K+ ATPase activity, and activation of the pentose phosphate and glucuronate-xylose pathways. Selective inhibition of aldose reductase reverses these biochemical changes and prevents some of the structural and functional abnormalities in diabetic rats. The potential beneficial effects of aldose reductase inhibitors on diabetic kidney disease in man are at present being investigated.
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PMID:Aldose reductase in the etiology of diabetic complications: 2. Nephropathy. 252 43

Elevated cellular sorbitol levels resulting from conversion of increased glucose by aldose reductase might deplete cellular myoinositol content, which could then lower inositol phosphates (InsPs) and diacylglycerol levels, key regulators of protein kinase C (PKC). Secondary to altered PKC activity, other cellular enzymes such as (Na,K)-ATPase could be affected. To test this hypothesis we examined the association between PKC activity, (Na,K)-ATPase activity, and sorbitol, myoinositol, and InsP levels in cultured bovine retinal capillary endothelial cells, a cell type prominently involved in diabetic retinopathy. Elevating glucose concentration in culture media from 100 to 400 mg/dl led to a 100% increase in sorbitol levels, which could be inhibited completely by sorbinil, an aldose reductase inhibitor. In contrast, no changes were observed in myoinositol or InsP levels. Subfractionated PKC activities showed a 100% increase in the membranous pool with a parallel decrease in the cytosolic fraction. Adding sorbinil did not affect PKC activity, whereas the PKC agonist, phorbol myristate acetate (PMA), stimulated translocation of PKC. Ouabain-inhibitable (Na,K)-ATPase activity was decreased 70% by elevated glucose levels. This decrease could be prevented by adding either PMA or sorbinil. Thus, in retinal capillary endothelial cells elevated glucose concentration can affect PKC and (Na,K)-ATPase activities, probably via different mechanisms.
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PMID:Differential regulation of protein kinase C and (Na,K)-adenosine triphosphatase activities by elevated glucose levels in retinal capillary endothelial cells. 839 Feb 75

We have found a defect in the ouabain-sensitive Na+, K+-ATPase (Na+ pump, EC 3.6.1.37) of erythrocytes from streptozocin diabetic rats. This defect was accompanied by an increase in cell volume and osmotic fragility and a decrease in the cytosolic K+/Na+ ratio. There was also a doubling in the time needed for diabetic erythrocytes to pass through 4.7-micron channels in a polycarbonate filter. Our data are consistent with a primary defect in the erythrocyte Na+ pump and secondary changes in cell volume, osmotic fragility, K+/Na+ ratio, and cell filterability. All were reversed or prevented in vivo by insulin or the aldose reductase inhibitor Sorbinil. Protein kinase C agonists (phorbol ester and diacylglycerol) and agonist precursor (myoinositol) reversed the Na+ pump lesion, suggesting that protein kinase C-dependent phosphorylation of the 100-kDa subunit regulates Na+ pump activity and that insulin can influence erythrocyte protein kinase C activity. Ouabain inhibition of the erythrocyte Na+ pump also produced increases in cell size and reductions in rates of filtration. Theoretical treatment of the volume changes also predicts reduction in filterability as a consequence of cell swelling. We suggest that enlarged erythrocytes could play a role in the evolution of the microvascular changes of diabetes mellitus.
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PMID:Reversible sodium pump defect and swelling in the diabetic rat erythrocyte: effects on filterability and implications for microangiopathy. 254 40

Our previous studies have shown that the aldose reductase inhibitor (ARI), sorbinil, prevents galactose-induced alterations and cataracts in rat lenses. We have now used sorbinil as well as another ARI, Eisai compound E-0722, to determine their potency in inhibiting aldose reductase- and galactose-induced alterations in lens morphology and Na+-K+-ATPase activity. Young Sprague Dawley rats were fed Purina Rat Chow plus 50% galactose, with or without 15 mg sorbinil, 0.15, 0.5 or 1.0 mg of E-0722/kg body weight per day. Controls were given Purina Rat Chow with or without ARIs. Lenses were studied for up to 60 days following the initiation of the diet using morphological, cytochemical and biochemical approaches to assess any alterations in the lens. While galactose-induced damage and cataracts were delayed by low doses (0.15 mg and 0.5 mg) of E-0722, they were completely prevented by the administration of 15 mg of sorbinil or 1 mg of E-0722/kg body weight per day. This study further showed that just 1 mg of E-0722 was more effective in preventing cataracts than 15 mg sorbinil. Thus it appeared that E-0722 was a more potent inhibitor of aldose reductase than sorbinil.
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PMID:Aldose reductase inhibitors and prevention of galactose cataracts in rats. 254 46

Hyperglycaemia decreases (Na+, K+)-ATPase activity in specific tissues by a mechanism whose effects are prevented by aldose reductase inhibitors and by raising plasma myo-inositol. This mechanism was activated and studied in vitro in normal rabbit aortic intima-media. Raising medium glucose to 10 mmol/l for 60 min inhibited a major component of (Na+, K+)-ATPase-mediated 86Rb+/K+ uptake normally operative in resting aortic intima-media in medium containing normal plasma levels of glucose (5 mmol/l) and myo-inositol (70 mumol/l); 20 or 30 mmol/l glucose had no greater effect. This effect occurred under conditions in which the aortic intima-media's normal myo-inositol content is not detectably decreased. The inhibition was prevented by sorbinil (10 mumol/l) and by raising medium myo-inositol from 70 to 500 mumol/l, which had no effect on (Na+, K+)-ATPase activity when the medium glucose remained at 5 mmol/l. Raising medium glucose selectively inhibited a component of (Na+, K+)-ATPase activity that requires medium myo-inositol, because it is maintained by a regulatory system through rapid basal phosphatidylinositol turnover in a discrete pool, which is replenished by a fraction of basal de novo phosphatidylinositol synthesis that is selectively dependent on myo-inositol uptake. Medium myo-inositol at a normal plasma level became inadequate to maintain this fraction of basal de novo phosphatidylinositol synthesis [( 1,3-14C]glycerol incorporation) when the medium glucose was raised. When sorbinil was added raising medium glucose did not alter the ability of 70 mumol/l medium myoinositol to maintain the (Na+, K+)-ATPase activity that requires medium myo-inositol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of glucose-induced (Na+, K+)-ATPase inhibition in aortic wall of rabbits. 255 15

Our recent investigations have shown that the Eisai compound, E-0722, (2R-4S-6-fluoro-1-2-methylspirochroman 4,4'-imidazolidine 2,5'-dione) is a more potent aldose reductase inhibitor than Sorbinil (D-6-fluorospirochroman 4,4'-imidazolidine 2,5'-dione). In the previous studies these aldose reductase inhibitors were added to the 50% galactose diet fed to rats to determine their effect on galactose-induced alterations in the lens and the development of cataract. In this report we present our results on the effect of prefeeding the aldose reductase inhibitor, E-0722, on the alterations in rat lens following subsequent feeding of galactose. For this study, young Sprague Dawley rats were prefed either rat chow or rat chow plus 50% galactose containing 1mg/day/Kg body weight of E-0722 for 1 or 2 weeks. After this dietary regimen, the animals were transferred to diets containing 50% galactose for different periods. For controls, rats were fed either rat chow or 50% galactose without the prefeeding of E-0722. Our results obtained through gross observation of the lenses, light microscopic studies of lens sections and assay of Na+-K+-ATPase (NPPase) activity show that the prefeeding of E-0722 prior to galactose feeding delays galactose-induced alterations and the development of mature cataract.
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PMID:Prefeeding of aldose reductase inhibitor and galactose cataractogenesis. 255 45

The binding capacity of ouabain to erythrocyte Na,K-ATPase was determined to analyze alterations in this enzyme activity in non-insulin-dependent diabetic patients. A significant (p less than 0.001) reduction of the binding capacity of ouabain was found in erythrocytes obtained from the diabetic patients with polyneuropathy (0.51 +/- 0.02 pmol/10(9) erythrocytes, m +/- SE, n = 14) as compared with the patients without neuropathy (0.67 +/- 0.02, n = 14) or age-matched control subjects (0.71 +/- 0.04, n = 11). Accordingly, the effect of an aldose reductase inhibitor (ARI; Ponalrestat) on erythrocyte Na,K-ATPase activity was studied following two or three months oral administration in seven of the diabetic patients with polyneuropathy. After treatment with Ponalrestat the mean binding capacity of ouabain was significantly increased from 0.53 +/- 0.04 to 0.57 +/- 0.03 (p less than 0.05 by paired t-test). Furthermore, enzyme kinetics showed that in normal subjects the apparent Km and Vmax of erythrocyte membrane Na,K-ATPase were 0.51 +/- 0.07 mM (n = 5, m +/- SE) and 7.19 +/- 0.27 nmol Pi/mg protein/min (n = 5, m +/- SE), respectively. The Vmax with 3 mM ATP was significantly (p less than 0.05) decreased in the diabetic patients with polyneuropathy as compared with age-matched control subjects. However, the apparent Km did not change. Finally, the in vitro effect of Ponalrestat was examined in erythrocyte membrane fractions from the diabetic patients with polyneuropathy. The activity of erythrocyte membrane Na,K-ATPase was found to be directly stimulated about 1.2 fold by the addition of pharmacological doses of Ponalrestat (10(-10), 10(-8), 10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of aldose reductase inhibitor (Ponalrestat) on erythrocyte Na,K-ATPase activity in non-insulin-dependent diabetic patients with polyneuropathy. 256 96

A unifying metabolic hypothesis completely accounting for the development of one or more of the chronic complications of diabetes on the basis of a single aspect of disturbed glucose metabolism resulting from insulin deficiency and/or hyperglycemia has been sought by clinical and basic scientists for decades. A growing body of loosely related but internally consistent scientific data obtained from cultured cells, incubated tissue preparations, animal models, and man implicate sorbitol- and glucose-induced myo-inositol depletion and altered phosphoinositide metabolism in a series of secondary biochemical, functional, and architectural abnormalities in the PNS in diabetes. These early metabolically based functional and structural changes simulate those that characterize human diabetic neuropathy. Can abnormal phosphoinositide metabolism in diabetic nerve thereby by itself explain the development of chronic diabetic neuropathy with all of its clinical complexity and heterogeneity? Almost certainly not. Even if the entire contribution of hyperglycemia to the development of diabetic neuropathy were mediated by secondary abnormalities in phosphoinositide metabolism, other factors must also play a role. Witness the differences in the histopathological picture of neuropathy in patients with IDDM and NIDDM despite similar durations and severity of diabetes, the apparent influence of age and gender on the appearance of early neuropathy in patients with IDDM, and the association of alcohol consumption with diabetic neuropathy. While early metabolic and functional disturbances in diabetic nerve such as impaired (Na,K)-ATPase function and paranodal swelling are empirically attributable to abnormal myo-inositol and phosphoinositide metabolism, more advanced abnormalities such as axo-glial dysjunction may reflect superimposed independent biochemical and/or hormonal defects (although, as mentioned previously, aldose reductase inhibition decreases axo-glial dysjunction in diabetic humans). The PNS has only a limited repertoire of responses to a variety of insults, so that Wallerian degeneration, axonal atrophy, impaired axonal transport, and dystrophic changes in diabetic neuropathy may represent multiple factors. On the other hand, the increasingly recognized importance of the phosphoinositide cascade in neuromodulation may attribute a progressively wider range of disturbances in the diabetic PNS to myo-inositol depletion and associated defects in phosphoinositide metabolism. Thus, while all effects of aldose reductase inhibitors in the PNS of diabetic rats have been reproduced by myo-inositol supplementation when this alternative intervention has been tested, the exact role of phosphoinositide metabolism in most of these responses is not well understood.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pathogenesis of diabetic neuropathy: role of altered phosphoinositide metabolism. 256 4

Changes in tissue levels of sorbitol, myo-inositol, and Na+-K+-ATPase enzyme activity have been implicated in the development of diabetic complications in animal models of the disease and in humans. The ability of the aldose reductase inhibitor sorbinil to reverse the hyperglycemia-induced changes in these lenticular metabolite and enzyme-activity levels in the streptozocin-induced diabetic rat was examined to determine what, if any, relationship exists between these changes. Two weeks of untreated diabetes did not change ouabain-inhibitable ATPase enzyme activity assayed in lens homogenates but did result in a decrease in the Na+-K+-ATPase transport activity as measured by 86Rb uptake in the intact lens. This was accompanied by a 100-fold increase in the levels of sorbitol and significant decreases in the levels of myo-inositol, ATP, and glutathione in the lens. Whereas all of these changes could be reversed by sorbinil treatment, the dose required for restoration of the depleted myo-inositol level (ED50 greater than 20 mg.kg-1.day-1) was much higher than the dose required to reverse the other changes (ED50 range 2-5 mg.kg-1.day-1). These results suggest that the restoration of lenticular Na+ -K+ -ATPase activity is not secondary to a normalization of myo-inositol levels and may provide evidence that the two parameters are not strictly associated in diabetic tissues.
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PMID:Na+-K+-ATPase pumping activity is not directly linked to myo-inositol levels after sorbinil treatment in lenses of diabetic rats. 282 60


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