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)

Altered sorbitol and myo-inositol metabolism, (Na,K)-ATPase function, electrochemical sodium gradients, axonal swelling, and distortion and disruption of the node of Ranvier ("axo-glial dysjunction") directly implicate hyperglycemia in the pathogenesis of neuropathy in diabetic rats, but the relevance of this sequence to clinical neuropathy in heterogeneous groups of diabetic patients remains to be established. Fascicular sural nerve morphometry in 11 patients with neuropathy complicating insulin-dependent diabetes revealed a pattern of interrelated structural changes strikingly similar to that of the diabetic rat when compared to age-matched controls. 17 older non-insulin-dependent diabetic patients with comparable duration and severity of hyperglycemia and severity of neuropathy, displayed similar nerve fiber loss, paranodal demyelination, paranodal remyelination and segmental demyelination compared to age-matched controls, but axo-glial dysjunction was replaced by Wallerian degeneration as the primary manifestation of fiber damage, and fiber loss occurred in a spatial pattern consistent with an ischemic component. The mechanistic model developed from the diabetic rat does indeed appear to apply to human diabetic neuropathy, but superimposed hormonal, metabolic, vascular, and/or age-related effects alter the morphologic expression of the neuropathy in non-insulin dependent diabetes.
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PMID:Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy. 333 24

Endoneurial sodium, potassium adenosine triphosphatase (Na+,K+-ATPase) and Mg2+-ATPase activities were determined in routine sural nerve biopsies from patients being evaluated for peripheral neuropathy. A significant reduction of endoneurial Na+,K+-ATPase and Mg2+-ATPase activities was shown in six sural nerve biopsies from patients with Tangier disease complicated by mononeuropathy multiplex or progressive axonal neuropathy. Peripheral nerve ATPase activities did not correlate with myelinated or unmyelinated nerve fiber densities in these biopsies. Other peripheral neuronal disorders with reduced endoneurial Na+,K+-ATPase and Mg2+-ATPase activities included severe vasculitic neuropathy, diabetic neuropathy, tomaculous neuropathy, and motoneuron disease. Such reduced levels of ATPase activity in peripheral nerve may relate to altered endoneurial lipid metabolism and impaired axoplasmic flow.
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PMID:Endoneurial ATPase activity in Tangier disease and other peripheral neuropathies. 615 83

This study addressed the question as to whether the reduced activity of Na+,K(+)-ATPase reported to occur in diabetic nerves and to play a crucial role in the pathogenesis of diabetic neuropathy could be due to derangements in the axonal transport of the enzyme. A micromethod was developed to evaluate the ATPase accumulation in individual segments of ligated sciatic nerves from streptozotocin-induced diabetic rats. The results confirmed a approximately 40% decrease in the background activity, but showed that the enzyme was transported at similar rates in both anterograde and retrograde directions, suggesting that the decrease in its activity does not depend on an altered delivery along the axons.
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PMID:Defective activity of Na+,K(+)-ATPase in peripheral nerve of diabetic rats is independent of the axonal transport of the enzyme. 752 83

Two proposed mechanisms of diabetic neuropathy are microvascular ischaemia and a reduction in Na,K-ATPase activity. We evaluated the effect of cilostazol, a drug that is both a potent phosphodiesterase inhibitor that normalizes nerve Na,K-AT-Pase and a vasodilator, on nerve blood flow (NBF) to determine whether it would improve experimental diabetic neuropathy. We examined whether epineurally applied cilostazol acted as a vasodilator on the peripheral nerve of normal and diabetic rats, and whether feeding the rats a cilostazol-supplemented diet could improve diabetic neuropathy. Cilostazol increased nerve blood flow (NBF) in a dose-dependent fashion with an EC50 of 10(-5.74) mol/l. Cilostazol also normalized NBF in experimental diabetic neuropathy with a 10(-4) mol/l local application on the sciatic nerve. In diabetic neuropathy, a cilostazol-supplemented diet improved both NBF and nerve conduction in a dose- and time-dependent fashion. Potential mechanisms of action of cilostazol on the nerve include its effect on NBF, Na, K-ATPase, and restoration of the thromboxane:prostacyclin ratio. Cilostazol may have potential in the treatment of diabetic neuropathy.
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PMID:Effect of cilostazol on experimental diabetic neuropathy in the rat. 758 76

Both metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, nerve blood flow, and (Na+, K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. Nitric oxide may be the 'bridge' linking these divergent hypotheses of diabetic neuropathy. We propose a model for the pathogenesis of neuropathy invoking metabolic defects both at a vascular and neurochemical level. Early after the induction of experimental diabetes, metabolic defects may lead to a decrease in synthesis of nitric oxide in either the vascular endothelium or the sympathetic ganglia leading to decreased nerve blood flow. In addition, nitric oxide may be involved in more distal defects of somatic nerve metabolism which impair the activity of the nerve Na/K-ATPase by a mechanism involving phosphoinositide signaling and diacyl glycerol and may therefore affect nerve conduction velocity independently of ischaemia. Improved understanding of the effects of hyperglycaemia on nitric oxide metabolism, may provide important clues elucidating the mechanisms underlying the pathogenesis of diabetic neuropathy.
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PMID:Nitric oxide as a potential bridge between the metabolic and vascular hypotheses of diabetic neuropathy. 760 Jul 40

We have investigated the relationship between cAMP and sodium,potassium-ATPase (Na+,K(+)-ATPase) activity in the sciatic nerves of rats treated with cilostazol, a potent phosphodiesterase inhibitor; iloprost, a stable prostacyclin analog; or (Bu)2cAMP, a cAMP analog, which increase cAMP content by different mechanisms. In in vivo studies, administration of cilostazol (20 mg/kg BW.day), iloprost (4 micrograms/kg BW.day), or (Bu)2cAMP (4 mg/kg BW.day) for 4 weeks restored decreased cAMP content and Na+,K(+)-ATPase activity in the sciatic nerves of diabetic rats and further improved motor nerve conduction velocities without alteration of myo-inositol contents. There was a positive correlation between cAMP contents and Na+,K(+)-ATPase activities in the sciatic nerves. In in vitro experiments, cAMP accumulation and Na+,K(+)-ATPase activity in the desheathed sciatic nerve blocks obtained from both normal and diabetic rats were significantly increased by incubation with cilostazol, iloprost, or (Bu)2cAMP. In addition, cAMP accumulation and Na+,K(+)-ATPase activities in endoneurial preparations incubated in both normal and high glucose buffer were also significantly increased by cilostazol, iloprost, and (Bu)2cAMP. These results strongly suggest that there is a close relationship between cAMP content and Na+,K(+)-ATPase activity in rat sciatic nerves. Therefore, cAMP content may play an important role in the development of diabetic neuropathy by modulating Na+,K(+)-ATPase activity in the peripheral nerves.
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PMID:Cyclic adenosine 3',5'-monophosphate enhances sodium, potassium-adenosine triphosphatase activity in the sciatic nerve of streptozotocin-induced diabetic rats. 767 91

The complex interrelationships between metabolic factors (increased nerve glucose, fructose and sorbitol and decreased nerve myo-inositol levels) and ischaemic-hypoxic vascular factors [decreased nerve blood flow (NBF) and increased nerve vascular resistance (NVR)] in the pathogenesis of diabetic neuropathy are incompletely understood. This study evaluates, in mature animals, the time course and magnitude of changes in factors postulated to be of importance in the pathogenesis of experimental diabetic neuropathy (EDN). Hyperglycaemia was induced in mature 9-month-old male Sprague-Dawley rats with streptozocin (as in studies utilizing immature rats it has been difficult to separate effects which are due to the growth retardation and maturational delay induced by hyperglycaemia from those arising from diabetes per se). Groups of age-matched control and diabetic animals were compared 1, 2, 4, 8, 16 and 24 weeks after injection. In diabetic animals NBF was decreased and NVR was increased after 1 week (P < 0.05); sciatic nerve glucose, sorbitol and fructose levels were increased after 1 week (P < 0.05). These changes were maintained for the duration of the experiment. Sciatic and caudal nerve conduction velocities were significantly decreased after 16 weeks (P < 0.05), although trends were apparent after 4 weeks. Diabetic animals showed decreased sciatic nerve myo-inositol levels between 2 and 16 weeks (P < 0.05), but there was no significant difference at 24 weeks. There were no significant differences in sciatic nerve total (Na+K+)ATPase concentrations. Early and sustained alterations in vascular indices (NBF and NVR) support the postulate that ischaemic-hypoxic factors may play a role in the causation of EDN. The ischaemic-hypoxic postulates do not, however, diminish the obvious importance of the multitude of metabolic alterations which also occur very early after the onset of hyperglycaemia.
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PMID:Vascular and metabolic factors in the pathogenesis of experimental diabetic neuropathy in mature rats. 782 May 75

Na+,K(+)-ATPase activity in nerve is reduced in rats with streptozotocin-induced diabetes; three different isoforms of the alpha (catalytic) subunit of the enzyme are present in nerve. Using western blot to determine subunit isoform polypeptide levels in sciatic nerve, we found a substantial reduction in alpha 1-isoform polypeptide (88% at 3 weeks, 94% at 8 weeks) after induction of diabetes by streptozotocin. Reductions in alpha 2 and alpha 3 polypeptide were smaller and not statistically significant. The reduction in amount of all three isoform polypeptides in the nerve of 3-week diabetic animals was corrected by administration of insulin. Accumulation of alpha 1 polypeptide at a nerve ligature indicated that rapid transport of that polypeptide in nerve occurs with normal kinetics. The results implicate a specific marked deficit in alpha 1, much more than alpha 2 or alpha 3, catalytic subunit isoform of Na+,K(+)-ATPase in the pathogenesis of diabetic neuropathy.
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PMID:Isoform specific reductions in Na+,K(+)-ATPase catalytic (alpha) subunits in the nerve of rats with streptozotocin-induced diabetes. 793 33

A decrease in Na/K-ATPase activity is probably involved in the pathogenesis of diabetic neuropathy. In human diabetes, Na/K-ATPase activity is almost always studied in red blood cells, readily accessible, and it could represent a marker of predisposition to diabetic neuropathy. But, we wanted to establish whether diabetes induced similar changes of Na/K-ATPase activity in erythrocytes, and in other tissues, especially the peripheral nerve and the kidney. So, we compared Na/K-ATPase activity measured in the erythrocyte, sciatic nerve and kidney of rats with streptozotocin-induced diabetes after 8 weeks (n = 9) and normal rats (n = 9). Na/K-ATPase activity was 39-44% lower in the RBC, sciatic nerve and kidney of diabetic rats compared to controls (RBC: 229 +/- 79 vs. 413 +/- 102 p < 0.05; sciatic nerve: 3250 +/- 692 vs. 5532 +/- 1260 p 0.05; kidney: 12920 +/- 4010 vs. 22410 +/- 5310 p < 0.05; results in nmol Pi.mg protein-1.h-1; mean +/- SD). A significant positive correlation was observed between Na/K-ATPase activities in the red blood cells and sciatic nerve (r = 0.81, p < 0.05) in the whole population of rats. This study shows that diabetes induces a parallel decrease in Na/K-ATPase activity in the red cell, sciatic nerve and kidney. The levels of this enzyme activity are significantly correlated in the red cell and sciatic nerve so that diabetes-induced changes of Na/K-ATPase activity in the erythrocyte seem to reflect those in the peripheral nerve.
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PMID:Effect of experimental diabetes on Na/K-ATPase activity in red blood cells, peripheral nerve and kidney. 800 15

Metabolic and vascular factors have been invoked in the pathogenesis of diabetic neuropathy but their interrelationships are poorly understood. Both aldose reductase inhibitors and vasodilators improve nerve conduction velocity, blood flow, and (Na+,K+)-ATPase activity in the streptozotocin diabetic rat, implying a metabolic-vascular interaction. NADPH is an obligate cofactor for both aldose reductase and nitric oxide synthase such that activation of aldose reductase by hyperglycemia could limit nitric oxide synthesis by cofactor competition, producing vasoconstriction, ischemia, and slowing of nerve conduction. In accordance with this construct, N-nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase reversed the increased nerve conduction velocity afforded by aldose reductase inhibitor treatment in the acutely diabetic rat without affecting the attendant correction of nerve sorbitol and myo-inositol. With prolonged administration, N-nitro-L-arginine methyl ester fully reproduced the nerve conduction slowing and (Na+,K+)-ATPase impairment characteristic of diabetes. Thus the aldose reductase-inhibitor-sensitive component of conduction slowing and the reduced (Na+,K+)-ATPase activity in the diabetic rat may reflect in part impaired nitric oxide activity, thus comprising a dual metabolic-ischemic pathogenesis.
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PMID:The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. 804 Mar 41


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