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)

PGE1 has been found to improve the symptoms of diabetic neuropathy. We considered that a PGI2 derivative may also have a similar action and therefore studied its effect in diabetic rats. Iloprost was administered intraperitoneally to streptozotocin-induced diabetic rats at a dose of 10 micrograms/kg/day for a month. The changes in nerve conduction velocity (NCV) were measured in the tail. One day after the last dose of iloprost, both sciatic nerves were removed from each rat, homogenized, and extracted with 6% TCA. The sorbitol and myo-inositol concentrations were determined by a combination of HPLC and an enzymatic method. Cyclic AMP (cAMP) levels were determined by RIA, and Na+, K+ ATPase activity was assessed by the enzyme cycling method of Greene and Lattimer. Iloprost was found to improve the NCV in the diabetic rats. The sorbitol content was not affected by iloprost, but the myo-inositol content was higher in the iloprost group than in the untreated group, although the difference was not statistically significant. The Na+, K+ ATPase activity and cAMP content were significantly higher in the iloprost group than in the untreated group. These findings suggest the possibility that the cAMP-dependent protein kinase (A-kinase) system has an important influence on improvement in Na+, K+ ATPase activity.
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PMID:Effect of a prostaglandin I2 derivative (iloprost) on peripheral neuropathy of diabetic rats. 128 52

In view of the possible implication of multifactorial mechanisms in the pathogenesis of diabetic neuropathy, the aldose reductase inhibitor (ARI), Statil, which ameliorates abnormal sorbitol or myo-inositol metabolism in diabetic nerves, and the prostaglandin E1 (PGE1) analogue, OP1206.alpha CD (OP), which improves diabetic vascular derangements, were administered simultaneously for 2 months to streptozocin (STZ)-induced diabetic rats with 5 months' duration of diabetes, and the effects on sciatic motor nerve conduction velocity (MNCV), Na(+)-K(+)-adenosine triphosphatase (ATPase) activity, and morphology of myelinated nerve fibers (MNF) were compared with the effects of a monotherapy with OP. The combination regimen ameliorated abnormal nerve sorbitol and myo-inositol levels and normalized decreased MNCV and enzyme activity. In contrast, neither sorbitol nor myo-inositol metabolism was ameliorated, and only insufficient improvement of MNCV and morphology of MNF was obtained with a monotherapy with OP. In addition, the combination therapy reversed both a decrease in the percent of large MNF and an increase in the percent of small MNF in diabetic rats, whereas a monotherapy with OP reversed only a decrease in the percent of large MNF. The results might suggest that a multiple-drug therapy with different mechanisms of action has greater effects on diabetic neuropathy than a single-drug therapy and is worthy of clinical consideration.
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PMID:A combination of the aldose reductase inhibitor, statil, and the prostaglandin E1 analogue, OP1206.alpha CD, completely improves sciatic motor nerve conduction velocity in streptozocin-induced chronically diabetic rats. 132 Jan 79

The effects of a new aldose reductase inhibitor (ARI), (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca rboxamide (SNK-860), on the slowing of motor nerve conduction velocity (MNCV) and metabolic abnormalities in sciatic nerve were investigated in acute streptozotocin (STZ)-induced diabetic rats. MNCV in the diabetic rats was significantly slower 2 weeks after STZ injection. In the following 2 weeks, treatment with SNK-860 improved MNCV in a dose-dependent manner. The efficacy of 1 mg/kg SNK-860 was equipotent to that of 20 mg/kg sorbinil. Four weeks after STZ injection, increases in sorbitol levels, decreases in myo-inositol levels, and reductions in Na+, K(+)-adenosine triphosphatase (ATPase) activity were observed in sciatic nerves of diabetic rats. Administration of SNK-860 for 14 days beginning 2 weeks after the induction of diabetes inhibited these metabolic abnormalities in a dose-dependent manner. SNK-860 restored all of these parameters to normal levels at a dose of 2 mg/kg. In addition, close correlations were observed between MNCV and sorbitol levels (r = -.95) and between MNCV and myo-inositol levels (r = .93) in the sciatic nerve; a close correlation was also observed between sorbitol and myo-inositol levels in the sciatic nerve (r = -.86). Therefore, it is suggested that the effect of SNK-860 on the slowing of MNCV results from normalizing the above-mentioned metabolic abnormalities in the sciatic nerve of diabetics. Thus, SNK-860 may be useful in the treatment of diabetic neuropathy.
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PMID:Effects of a new aldose reductase inhibitor, (2S, 4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca rboxamid e (SNK-860), on the slowing of motor nerve conduction velocity and metabolic abnormalities in the peripheral nerve in acute streptozotocin-induced diabetic rats. 132 19

The evidence of sorbitol excess in the crystalline lens of alloxan-diabetic rats has led to anticipate the role of the enzyme aldose-reductase in the pathogenesis of the diabetic cataract. In addition, a number of experimental works have more recently shown the involvement of myoinositol deficiency, which probably results from the sorbitol accumulation. These metabolic pathways are most likely implicated in the pathogenesis of diabetic neuropathy and perhaps additionally in that of microangiopathy. The synthesis of several aldose-reductase inhibitors (AR inhibitors) confirmed experimentally these hypothesis. By reducing the activity of the enzyme aldose-reductase, these substances suppress the adverse metabolic consequences of polyol accumulation, myositol deficiency and dysfunction of the Na+/K+ ATPase dependent sodium activity. Although different experimentations showed that the AR inhibitors could prevent in animals the development of experimental cataract as well as the early functional or later anatomic abnormalities of the diabetic retinopathy and nephropathy, the clinical trials did not clearly support these experimental results in humans. On the other hand, the AR inhibitors were proved to exhibit some efficacy in the early stage of diabetic neuropathy and in incipient nephropathy where they delay the development of albustix positive proteinuria. However, the benefit of an early treatment with AR inhibitors should be confirmed by long term prospective studies, which could also assess the safety of these drugs in chronic administration.
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PMID:[Role of polyols in the development of diabetic complications. Value of aldose-reductase inhibitors]. 141 Aug 79

The most common form of neuropathy associated with diabetes mellitus is distal symmetric sensorimotor polyneuropathy, often accompanied by autonomic neuropathy. This disorder is characterized by striking atrophy and loss of myelinated and unmyelinated fibers accompanied by Wallerian degeneration, segmental, and paranodal demyelination and blunted nerve fiber regeneration. In both humans and laboratory animals, this progressive nerve fiber damage and loss parallels the degree and/or duration of hyperglycemia. Several metabolic mechanisms have been proposed to explain the relationship between the extent and severity of hyperglycemia and the development of diabetic neuropathy. One mechanism, activation of the polyol pathway by glucose via AR, is a prominent metabolic feature of diabetic rat peripheral nerve, where it promotes sorbitol and fructose accumulation, myo-inositol depletion, and slowing of nerve conduction by alteration of neural Na(+)-K(+)-ATPase activity or perturbation of normal physiological osmoregulatory mechanisms. ARIs, which normalize nerve myo-inositol and nerve conduction slowing, are currently the focus of clinical trials. Other specific metabolic abnormalities that may play a role in the pathogenesis of diabetic neuropathy include abnormal lipid or amino acid metabolism, superoxide radical formation, protein glycation, or potential blunting of normal neurotrophic responses. Metabolic dysfunction in diabetic nerve is accompanied by vascular insufficiency and nerve hypoxia that may contribute to nerve fiber loss and damage. Although major questions about the pathogenesis of diabetic neuropathy remain unanswered and require further intense investigation, significant recent progress is pushing us into the future and likely constitutes only the first of many therapies directed against one or more elements of the complex pathogenetic process responsible for diabetic neuropathy.
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PMID:Complications: neuropathy, pathogenetic considerations. 146 45

An oral prostaglandin E1 (PGE1) analogue, OP-1206.alpha-CD, was given to rats with streptozocin (STZ)-induced diabetes to examine the therapeutic effects of OP-1206 on short-term and long-term diabetic neuropathy and its action mechanism with special reference to nerve Na(+)-K(+)-ATPase activity. In the short-term experiment, OP-1206 was administered daily to diabetic rats in 3- and 30-mg/kg doses for 4 wk from the day of STZ injection. In the long-term study, 10 micrograms/kg OP-1206 was also given daily for 8 wk from 7 mo after induction of diabetes. The compound improved decreased sciatic motor nerve conduction velocity in both short-term and long-term diabetic rats. The nerve Na(+)-K(+)-ATPase activity of diabetic rats, reduced by 40% compared with controls, was reversed to the level of controls in both experiments, whereas weight loss and hyperglycemia were unchanged, and neither nerve sorbitol accumulation nor myo-inositol depletion was corrected. In a morphometric analysis of myelinated nerve fibers (MNFs) in long-term diabetes, the mean diameter of the largest 10% of MNFs was significantly reduced in untreated diabetic compared with control rats, but OP-1206 completely reversed this reduction. The results suggest that OP-1206 ameliorates a decrease in nerve Na(+)-K(+)-ATPase activity without any effect on nerve myo-inositol level and that the compound may be not only a potent therapeutic agent for the treatment of diabetic neuropathy but also a useful research tool to investigate the mechanism of nerve Na(+)-K(+)-ATPase activity regulation.
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PMID:Amelioration of nerve Na(+)-K(+)-ATPase activity independently of myo-inositol level by PGE1 analogue OP-1206.alpha-CD in streptozocin-induced diabetic rats. 164 81

Streptozotocin (STZ)-induced diabetes in the rat causes a significant reduction in ouabain-sensitive Na,K-ATPase pumping activity measured by 86Rb+ influx, in sciatic endoneurium (by 54%) and dorsal root ganglia (by 22%). For endoneurium, the change is similar to that of ouabain-sensitive enzymatic Na,K-ATPase activity (42%), but in dorsal root ganglia, the decrease in enzymatic Na,K-ATPase activity was much greater. 86Rb+ efflux from dorsal root ganglia showed no difference between diabetic and control animals, confirming that the abnormal 86Rb+ influx reflects Na,K-ATPase function and not abnormal membrane permeability. The significance of these findings to pathogenetic mechanisms in diabetic neuropathy is discussed.
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PMID:Rubidium (86Rb+) influx into dorsal root ganglia and sciatic nerve endoneurium of control and streptozotocin-diabetic rats: comparison with enzymatic Na,K-ATPase activity. 165 45

The effects of alpha-receptor blockade on nerve conduction, hypoxic resistance, ouabain-sensitive Na(+)-K(+)-ATPase, nerve polyols, and capillary density were examined in streptozocin-induced diabetic (STZ-D) rats. Nondiabetic and untreated diabetic control groups were used. Diabetes duration was 2 mo. There were two treated diabetic groups. A "prevention" group received 5 mg/kg prazosin for 2 mo from the induction of diabetes. A "reversal" group was untreated for the 1st mo and was given prazosin for the subsequent month. Conduction was measured in motor nerves supplying tibialis anterior and gastrocnemius muscles and sensory saphenous nerve. Diabetes resulted in 15-29% reductions in conduction velocity (P less than 0.01). In the prevention group, conduction deficits were minimal compared with untreated diabetes (P less than 0.01). In the reversal group, motor conduction was also substantially improved, although sensory conduction was not significantly affected. In vitro measurement of sciatic nerve hypoxic resistance revealed a 49% increase in the time taken for compound action potential amplitude to reach half its initial value with diabetes (P less than 0.01). This was largely prevented by prazosin treatment (P less than 0.01), although treatment had a lesser effect in the reversal group. Treatment had no effect on nerve polyol levels or Na(+)-K(+)-ATPase activity. Functional improvements with prazosin were probably based on increased vasa nervorum perfusion. There was a 20% elevation of endoneurial capillary density (P less than 0.01) in both prevention and reversal groups. We conclude that vascular factors play an important role in the etiology of experimental diabetic neuropathy, and functional changes may be corrected by chronic vasodilator treatment.
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PMID:Effects of chronic alpha-adrenergic receptor blockade on peripheral nerve conduction, hypoxic resistance, polyols, Na(+)-K(+)-ATPase activity, and vascular supply in STZ-D rats. 166 93

Endoneurial hypoxia has been put forward as a factor contributing to diabetic neuropathy. The aim of this study was to determine whether alterations in motor nerve conduction velocity, Na+/K(+)-ATPase activity and substance P content of nerve and skin tissue, characteristic of the diabetic rat, could develop in non-diabetic animals subjected to a central hypoxaemia for five weeks. Compared to normoxic controls, five weeks of central hypoxaemia caused a fall in motor nerve conduction velocity of 30% (P less than 0.01), a decrease in sciatic nerve substance P content (68%; P less than 0.001) combined with elevated substance P content per unit area foot skin (44%; P less than 0.01). This pattern of change is qualitatively similar to that seen in diabetic rats. The Na+/K(+)-ATPase activity, however, was unaltered by the hypoxic environment. These findings support strongly a partial role for hypoxia in the pathogenesis of diabetic neuropathy.
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PMID:Central hypoxaemia in rats provokes neurological defects similar to those seen in experimental diabetes mellitus: evidence for a partial role of endoneurial hypoxia in diabetic neuropathy. 172 87

Diabetic neuropathy, a challenging contemporary problem, has a clinical prevalence of 60% problematic peripheral neuropathy occurs in about 20%. Recent concepts in aetiopathogenesis include the role of sorbitol excess and myoinositol depletion in causing deficient Na+/K+ ATPase activity. Sorbitol excess per se may result in intraneuronal oedema. Besides these metabolic hypotheses, theories on endoneurial microcapillary pathology and hypoxia have gained favour. Furthermore, a unifying concept of sorbitol excess with intraneuronal oedema leading to secondary vascular compromise has been suggested. A new research classification linking clinical and laboratory evaluation has been proposed which may serve to unify research results. Quantitative sensory testing, autonomic function testing and electrodiagnosis have been utilised to detect incipient diabetic neuropathy. The benefit of 'tight' glycaemic control has been objectively documented by using laboratory parameters. Oral myoinositol supplementation and gangliosides have produced marginal improvement. The role of intraneuronal oedema in the pathogenesis of diabetic neuropathy and its reversal by aldose reductase inhibitors holds out fresh promise for their use in prevention and treatment.
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PMID:Diabetic peripheral neuropathy. 130 35


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