Properties of ICI 128,436, a novel aldose reductase inhibitor, and its effects on diabetic complications in the rat

Stribling, Donald; Mirrlees, D.J.; Harrison, H E; Earl, Dudley C.N.

doi:10.1016/0026-0495(85)90223-9

Cited by 156 publications

(68 citation statements)

References 30 publications

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“…Tissue concentrations of sorbitol, fructose, glucose and myo-inositol were determined by capillary gas chromatography of trimethylsilyl ether derivatives [34].…”

Section: Methodsmentioning

confidence: 99%

Tissue ascorbic acid and polyol pathway metabolism in experimental diabetes

et al. 1998

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Abnormalities of collagen synthesis [1] and increased oxidative stress [2] have been implicated in the pathogenesis of diabetic microangiopathy. Since ascorbic acid (AA; vitamin C) is an essential cofactor for prolyl hydroxylase, a key enzyme in the biosynthesis of collagen and is also an important antioxidant [3], AA metabolism may link these processes.Decreased plasma AA concentrations and increased turnover of AA to the oxidised metabolite dehydroascorbic acid (DHAA) have been reported in diabetic subjects [4±10], particularly in patients with poor glycaemic control [11] and/or microangiopathy [12,13]. Although (i) leucocyte AA concentration is reduced following intravenous glucose [14], (ii) in vitro cell culture studies [15±18] demonstrate competitive cellular uptake of glucose and AA and (iii) in Diabetologia (1998) Summary Previous studies demonstrating reduced plasma concentrations of ascorbic acid (AA) in diabetes and interactions between this vitamin and biochemical mechanisms such as synthesis of structural proteins, oxidative stress, polyol pathway and nonenzymatic glycation of proteins suggest that disturbed AA metabolism may be important in the pathogenesis of diabetic microangiopathy. However, limited information is available on the concentration of AA in tissues which develop diabetic complications. This study demonstrates reduced renal but not sciatic nerve or plasma AA concentration in two animal models of insulin-dependent diabetes mellitus, namely the STZ-diabetic rat and the spontaneously diabetic BB rat. Decreased lens AA concentration was also observed in STZ-diabetic rats. Improvement of glycaemic control by insulin treatment (albeit insufficient to achieve normoglycaemia) partially corrected lens and renal AA concentration in STZ-diabetic rats. AA treatment increased kidney and lens AA concentrations of STZ-diabetic and non-diabetic rats and corrected the abnormalities observed for untreated diabetic rats. Sciatic nerve AA concentration was not increased by AA treatment in any group. Tissue ratios of dehydroascorbic acid (DHAA)/AA, one index of oxidative stress, were not different between the diabetic and non-diabetic groups and were unaltered by AA supplementation. AA treatment of STZ-diabetic rats had no effect on elevated tissue concentrations of glucose, sorbitol and fructose or reduced myo-inositol concentration. The effect of reduced tissue AA levels in diabetes on either collagen synthesis or ability to combat increased free radical production is not known. However, correction of abnormal kidney and lens AA concentrations in experimental diabetes by AA supplementation suggests that if AA does have a role in the development or progression of the renal and ocular complications of diabetes, this treatment could be beneficial. [Diabetologia (1998) 41: 516±523]

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“…Tissue concentrations of sorbitol, fructose, glucose and myo-inositol were determined by capillary gas chromatography of trimethylsilyl ether derivatives [34].…”

Section: Methodsmentioning

confidence: 99%

Tissue ascorbic acid and polyol pathway metabolism in experimental diabetes

et al. 1998

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“…They were frozen in liquid N2 and stored at -80 ~ until subsequent analysis. Nerve sugars and polyols were determined by gas chromatography of trimethylsilyl derivatives prepared from aqueous deproteinized extracts [26]. …”

Section: Sciatic Nerve Polyol Pathway Metabolite and Myo-inositol Levelsmentioning

confidence: 99%

Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats

et al. 1994

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Summary Increased oxygen free radical activity, coupled with reduced protection against oxidative stress, could play a role in the aetiology of neurovascular abnormalities in experimental diabetes mellitus. To test this hypothesis, non-diabetic and streptozotocindiabetic rats were treated with the anti-oxidant probucol or the pro-oxidant primaquine. One-month diabetes caused 21.4 % and 13.6 % reduction in sciatic motor and saphenous sensory conduction velocity 07 < 0.001). These deficits were prevented by probucol treatment (/7<0.001). After 1-month untreated diabetes, conduction velocity deficits were reversed by a further month of probucol treatment (p < 0.001). For non-diabetic rats, primaquine treatment caused a 12.9% reduction in motor conduction velocity (p < 0.001), which was prevented by probucol treatment 07 < 0.001). Primaquine treatment did not affect diabetic rats. Sciatic nerve nutritive endoneurial blood flow, measured using microelectrode polarography and hydrogen clearance, was 48.0 % reduced by 2-month diabetes (p < 0.001). This was completely prevented by probucol treatment (p < 0.001). Primaquine treatment did not affect blood flow in diabetic rats. However, in non-diabetic rats it caused a 30.0 % reduction (p < 0.01) which was prevented by probucol treatment (p < 0.05). Sciatic endoneurial oxygen tensions were also measured by microelectrode polarography. Mean tension was 38.8 % reduced by diabetes 07 < 0.001). This was prevented by probucol treatment. Non-diabetic rats given primaquine treatment showed a 21.7 % reduction in endoneurial oxygen tension (p < 0.01). The data suggest that vascular-mediated nerve dysfunction in diabetes depends on oxidative stress, and that similar effects in non-diabetic rats may be produced by pro-oxidant treatment. This provides evidence for the potentially important role of oxygen free radical activity in diabetic neuropathy. [Diabetologia (1994) 37: 449-459] K~, ~tds Neuropathy, nerve conduction, endoneurial blood flow, hypoxia, oxidative stress, probucol, antioxidant, pro-oxidant, vascular endothelium, angiotensin converting enzyme, diabetic rat.Oxidative stress has been implicated in the aetiology of the complications [1, 2] of diabetes mellitus. The body's natural anti-oxidant defence mechanisms [3][4][5] are compromised and diabetes may cause lowering of

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“…Tissue concentrations of galactose, galactitol, xylose, xylitol, and myoinositol were measured by gas liquid chromatography using a modification of the method of Stribling et al ( 11). Briefly, tissue samples (< 200 mg) were homogenized in 1 ml 10 mM sodium phosphate buffer, pH 7.0, containing a-methylmannoside (0.02 mg ml-') as an internal standard and boiled for 25 min.…”

Section: Methodsmentioning

confidence: 99%

Effects of galactose feeding on aldose reductase gene expression.

Wu¹,

Lyons²,

A³

et al. 1993

J. Clin. Invest.

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Aldose reductase (AR) is implicated in the pathogenesis of the diabetic complications and osmotic cataract. AR has been identified as an osmoregulatory protein, at least in the renal medulla. An outstanding question relates to the response of AR gene expression to diet-induced galactosemia in extrarenal tissues. This paper shows that AR gene expression in different tissues is regulated by a complex multifactorial mechanism. Galactose feeding in the rat is associated with a complex and, on occasions, multiphasic pattern of changes in AR mRNA levels in kidney, testis, skeletal muscle, and brain. These changes are not in synchrony with the temporal sequence of changes in tissue galactitol, galactose, and myoinositol concentrations. Moreover, galactose feeding results in changes in tissue AR activities that are not related, temporally or quantitatively, to the alterations in tissue AR mRNA or galactitol levels. It is concluded that AR gene expression and tissue AR activities are regulated by mechanisms that are not purely dependent on nonspecific alterations in intracellular metabolite concentrations. This conclusion is supported by the finding that chronic xylose feeding, despite being associated with intracellular xylitol accumulation, does not result in alterations in AR mRNA levels, at least in the kidney. (J. Clin. Invest. 1993. 92:155-159.)

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Properties of ICI 128,436, a novel aldose reductase inhibitor, and its effects on diabetic complications in the rat

Cited by 156 publications

References 30 publications

Tissue ascorbic acid and polyol pathway metabolism in experimental diabetes

Tissue ascorbic acid and polyol pathway metabolism in experimental diabetes

Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats

Effects of galactose feeding on aldose reductase gene expression.

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