Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

This study describes reduced motor nerve conduction velocity and increased resistance to hypoxia-induced conduction failure in sciatic nerves of rats after four weeks of streptozotocin-induced diabetes (both effects were significant at p less than 0.05). These changes occurred in the absence of any deficit in the steady-state ouabain-sensitive adenosine triphosphatase (ATPase) activity of sciatic nerve endoneurial homogenates. The addition of 10 nmol/l insulin to endoneurial homogenates from control animals resulted in a 34% increase in ouabain-sensitive ATPase activity and a 19% reduction in ouabain-insensitive ATPase activity (both p less than 0.01). This stimulation of ouabain-sensitive ATPase activity by insulin did not occur in homogenates from diabetic rats. Treating diabetic rats daily with the aldose reductase inhibitor, imirestat (1 mg/kg) improved nerve conduction velocity (p less than 0.05) but was without effect upon the resistance to hypoxic conduction blockade or the deficit in insulin-stimulated ouabain-sensitive ATPase activity. These data suggest that in streptozotocin-diabetic rats the functional disorders of reduced motor nerve conduction velocity and increased resistance to hypoxic conduction blockade do not share a common aetiology and that impaired nerve conduction is not related to reduced maximal potential ouabain-sensitive ATPase activity.
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PMID:Aldose reductase inhibition with imirestat-effects on impulse conduction and insulin-stimulation of Na+/K(+)-adenosine triphosphatase activity in sciatic nerves of streptozotocin-diabetic rats. 165 57

The role of sorbitol, myo-inositol, and Na+, K(+)-adenosine triphosphatase (ATPase) activity on motor nerve conduction velocity (MNCV) in streptozotocin (STZ)-diabetic rats was studied. Reduction of MNCV and Na+, K(+)-ATPase in caudal nerves appeared after 3 weeks of diabetes, and at this time treatment with aldose reductase inhibitor (ARI), ADN-138 and 1% myo-inositol supplement was begun. One percent myo-inositol supplement for 3 weeks resulted in a significant increase in myo-inositol levels in diabetic nerves, but left MNCV and sorbitol levels unchanged. In contrast, treatment with ADN-138 for 3 weeks reduced sorbitol levels in diabetic nerves and resulted in significant increases in MNCV and Na+, K(+)-ATPase in the nerves. Since ADN-138 did not restore myo-inositol levels, the increase in Na+, K(+)-ATPase levels by ADN-138 treatment was independent of myo-inositol levels. Also, nerve Na+ levels in ADN-138-treated rats were reduced and the ratio of K+ to Na+ was raised, while 1% myo-inositol supplement did not affect them. These results suggest that treatment with ADN-138 elevates MNCV through a series of processes: ARI----reduction of sorbitol level----increase in Na+, K(+)-ATPase activity----correction of K+, Na+ imbalance----increase in MNCV.
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PMID:Relation of Na+, K(+)-ATPase to delayed motor nerve conduction velocity: effect of aldose reductase inhibitor, ADN-138, on Na+, K(+)-ATPase activity. 216 92

This study measured the ouabain-sensitive and ouabain-resistant adenosine triphosphatase activity in homogenates of the sciatic nerves and of pooled fourth and fifth lumbar dorsal root ganglia from rats fed 20% galactose or made diabetic with streptozotocin for either 4 or 8 weeks. Diabetes caused reductions in both fractions of sciatic nerve adenosine triphosphatase activity. After 8 weeks the ouabain-sensitive fraction was 54% of control (p less than 0.05) and the ouabain-resistant fraction was 57% of control (p less than 0.05). Galactose feeding more than doubled the ouabain-sensitive adenosine triphosphatase activity in the sciatic nerve (225% of control after 4 weeks, 215% of control after 8 weeks of galactose feeding, both p less than 0.01) and produced a progressive increase in the ouabain-resistant fraction (119% of control at 4 weeks (p less than 0.05) and 176% of control at 8 weeks (p less than 0.01)). In a group of rats fed galactose for 5 days, sciatic nerve ouabain-sensitive adenosine triphosphatase activity was 165% of control. Treatment with the aldose-reductase inhibitors tolrestat, ponalrestat or sorbinil prevented accumulation of polyol and depletion of myo-inositol in the sciatic nerves, indicating effective inhibition of aldose reductase. These drugs prevented completely the effect of galactose on the sciatic nerve adenosine triphosphatase activity, but had no significant effect on the reduction in adenosine triphosphatase activity in the sciatic nerves of diabetic rats. In the dorsal root ganglia galactose feeding had no measurable effect on the adenosine triphosphatase activity. Diabetes caused a modest numerical reduction in the ouabain-sensitive activity only.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine triphosphatase in nerves and ganglia of rats with streptozotocin-induced diabetes or galactosaemia; effects of aldose reductase inhibition. 297 Sep 84

To explore metabolic changes associated with the sorbitol accumulation and myo-inositol depletion observed in glomeruli of rats with experimental diabetes, we examined total and ouabain-inhibited adenosine triphosphatase (ATPase) activity in glomeruli isolated from control and streptozocin (STZ)-diabetic rats. Glomerular Na/K-ATPase activity (ouabain-inhibited) was significantly reduced in diabetic animals, while total (composite) ATPase activity remained unchanged. Treatment with insulin partially restored the Na/K-ATPase activity. Administration of the aldose reductase inhibitor, sorbinil, which normalizes glomerular contents of both sorbitol and myo-inositol in diabetes, completely prevented the diminution of Na/K-ATPase activity. These results establish that glomerular Na/K-ATPase activity is reduced in acute experimental diabetes. The ability of sorbinil to prevent this decrease suggests that it is related to polyol accumulation and/or myoinositol depletion, although an effect of the drug unrelated to its aldose reductase inhibiting property has not been excluded. Since increased polyol pathway flux, decreased myo-inositol, and reduced Na/K-ATPase activity have also been described in peripheral nerve, another tissue in which typical diabetic complications characteristically occur, the consequences of these metabolic changes may be implicated in the pathogenesis of diabetic nephropathy.
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PMID:Reduced glomerular sodium/potassium adenosine triphosphatase activity in acute streptozocin diabetes and its prevention by oral sorbinil. 299 80

To explore a possible link between diabetic nephropathy and the enhanced activity of the polyol pathway known to occur in diabetes, we examined several pertinent metabolic parameters in glomeruli isolated from control and streptozotocin-diabetic rats and assessed whether changes observed in diabetic glomeruli could be prevented by the oral administration of the aldose reductase inhibitor sorbinil. We found that glomerular polyol content is significantly increased in diabetes, whereas glomerular myo-inositol content is significantly reduced. The sorbitol accumulation and myo-inositol depletion were both completely prevented by sorbinil, which was given throughout the duration of diabetes. Activity of the membrane-bound sodium/potassium adenosine triphosphatase (Na-K-ATPase) was decreased in diabetic samples; this change was also completely prevented by sorbinil. Erythrocyte deformability is another factor that has been implicated in the pathogenesis of microangiopathic complications. The ability of red blood cells to undergo an adaptation in shape that permits passage through the smallest vessels is impaired in diabetes. Using blood from control, diabetic, and sorbinil-treated diabetic rats, we found that erythrocyte deformability was decreased in diabetic samples and that sorbinil treatment significantly improved this parameter. Thus, if the glomerular consequences of sorbitol accumulation, myo-inositol depletion, reduced Na-K-ATPase activity, and decreased erythrocyte deformability are pathogenetically implicated in diabetic nephropathy, the ability of sorbinil to impact on these changes suggests that it could favorably impact on the nephropathic process.
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PMID:Aldose reductase, glomerular metabolism, and diabetic nephropathy. 300 26

Slowing of nerve conduction, a hallmark of both experimental and human diabetic neuropathy, is improved or corrected by aldose reductase inhibitors such as sorbinil. Animal experiments suggest that a myo-inositol-related defect in nerve sodium-potassium adenosine triphosphatase (ATPase) is responsible for the acute reversible slowing of nerve conduction in diabetes mellitus. This myo-inositol-related defect is at present viewed as a cyclic metabolic defect. Aldose reductase inhibitors have been shown to restore to normal both the myo-inositol content and the sodium-potassium ATPase activity of nerve. This suggests that the acute effects of aldose-reductase inhibitors on nerve conduction in both diabetic animals and human patients may be modified by the correction of an underlying myo-inositol-related defect of nerve sodium-potassium ATPase. Furthermore, this myo-inositol-related defect may contribute to other biochemical, functional and structural abnormalities of diabetic peripheral neuropathy.
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PMID:Sorbitol, myo-inositol and sodium-potassium ATPase in diabetic peripheral nerve. 302 50

Vascular endothelial cells, which are polyfunctional, play an important role in the pathogenesis of diabetic complications. The increase in vascular permeability, ie, regulated by vascular endothelial cells, has been reported in patients with diabetes mellitus complicated by angiopathy. To determine the role of hyperglycemia in endothelial cell permeability, we examined the effect of high concentrations of glucose on the permeability of cultured bovine aortic endothelial cells. The permeations of albumin and fluorescein-labeled dextran (FD) across endothelial cell monolayers were increased when cultured with a high concentration of glucose (400 mg/dL). This increased permeation of albumin but not FD was temperature-dependent and was partially reduced by adding 100 mumol/L ponalrestat (ICI 128,436, Statil; ICI, Cheshire, UK), which is an aldose reductase inhibitor. Stimulation or inhibition of Na,K-adenosine triphosphatase (ATPase) in bovine aortic endothelial cells failed to alter their permeability. These findings suggest that high concentrations of glucose enhance transendothelial permeability of albumin in part by activating the polyol pathway, but independently of Na,K-ATPase activity.
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PMID:Increased transendothelial permeation of albumin by high glucose concentration. 754 Feb 48

Aldose reductase is a rate limiting enzyme in the polyol pathway associated with the conversion of glucose to sorbitol. The enzyme is located in the eye (cornea, retina, lens), kidney, myelin sheath, and also in other tissues less involved in diabetic complications. Experiments in diabetic animals have implicated sorbitol accumulation in the lens to the development of cataracts. The use of inhibitors of aldose reductase in animal studies has demonstrated that diabetic complications such as cataracts, nephropathy, and slowing of nerve conduction can be ameliorated. While an osmotic effect can explain the physical changes in the lens leading to cataract formation, the effect of sorbitol accumulation in other tissues and the resulting diabetic complications has been linked to the depletion of myoinositol content resulting in a derangement of sodium-potassium adenosine triphosphatase activity. Since glucose and other hexoses are poor substrates for aldose reductase, it is only in hyperglycemia when the enzyme hexokinase is saturated that aldose reductase is activated, leading to accumulation of sorbitol. The kinetics of inhibition of aldose reductase by a variety of inhibitors has been delineated. The dose required varies from inhibitor to inhibitor and is consistent with their inhibition constants. Toxicity is a consideration in the use of some of the inhibitors, as was demonstrated with sorbinil which caused hypersensitivity reactions in 10 percent of patients. Other inhibitors such as tolerant have shown efficacy and are under clinical investigation. Interpretation of results obtained with aldose reductase inhibitor therapy in human subjects suggest that these inhibitors are effective at early stages of diabetic complications.
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PMID:Aldose reductase and its inhibition in the control of diabetic complications. 845 42


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