Regulation of spontaneous EDRF release in diabetic rat aorta by oxygen free radicals

Langenstroer, Peter; Pieper, Galen M.

doi:10.1152/ajpheart.1992.263.1.h257

Cited by 117 publications

(114 citation statements)

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“…An enhancement of oxidative stress in diabetes [8,9], mainly by an increased generation of superoxide anions [11,36,42,45].is also widely accepted. In the experimental conditions of this study, the preincubation of isolated aortic and mesenteric vascular segments with SOD modify ACh-induced responses only in those groups in which endothelial dysfunction was 6 weeks of diabetes with aminoguanidine plus 3 week 8.05±0.14 (5) 6.85±0.17 a (5) of treatment with insulin pD 2 indicates the −log mol/l of the required concentration of sodium nitroprusside to reach the half-maximal relaxation.…”

Section: Discussionmentioning

confidence: 99%

Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature

et al. 2003

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Aims/hypothesis. In a model of streptozotocin-induced Type 1 diabetes mellitus in rats of 9 weeks duration, we analysed time associations between the development of hyperglycaemia, early and intermediate glycosylation Amadori adducts, or AGE compared with enhancement of oxidative stress and endothelial dysfunction.Methods. Endothelial function was tested at several stages of streptozotocin-induced diabetes and after treatment with insulin, resulting in different concentrations of blood glucose, glycosylated haemoglobin (an Amadori adduct), and AGE. Other animals were studied antagonising the formation of AGE with aminoguanidine. Results. Relaxation in response to acetylcholine (1 nmol/l to 10 µmol/l) was tested in isolated segments from aorta or mesenteric microvessels. Impairment of endothelium-dependent relaxations occurred after 2 weeks of untreated diabetes. Preincubation of vessels affected with 100 U/ml superoxide dismutase improved the relaxations to acetylcholine, along the time-course of the endothelial impairment. This indicates the participation of reactive oxygen species on diabetic endothelial dysfunction. The impairment of endothelium-dependent relaxations was recovered after 3 more weeks of insulin treatment. Aminoguanidine treatment did not modify this pattern of development. The time course of the rise and disappearance of endothelial dysfunction showed a higher correlation with glycosylated haemoglobin concentrations than with blood glucose or serum AGE. Conclusion/interpretation. Enhancement of early and intermediate Amadori adducts of protein glycosylation was the factor showing a better relation with the development of endothelium impairment. These results are consistent with a role for these products in the development of diabetic vasculopathy. [Diabetologia (2003) 46:556-566] Keywords Diabetes mellitus, endothelial dysfunction, nitric oxide, superoxide anions, hyperglycaemia, Amadori adducts, advanced glycosylation end-products. Endothelial dysfunction seems to be a key factor in the development of diabetic vascular complications. The impairment of endothelium-dependent vasodilatations is an early event occurring in diabetic patients [1,2,3] and animal diabetic models [4,5,6, 7]. Enhanced oxidative stress in diabetes mellitus has been also shown [8,9], which can be detected by peroxidation products [10] or by increased generation of reactive oxygen species (ROS), mainly superoxide anions [11]. Indeed, enhanced oxidative stress is proposed to be a major cause of diabetic endothelial dysfunction [12,13].There is also increasing evidence that diabetic endothelial dysfunction and oxidative stress are a conse-

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Section: Discussionmentioning

confidence: 99%

Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature

et al. 2003

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“…This could act in at least two ways; NO synthase requires NADPH as co-substrate and, probably more important, NADPH is necessary for glutathione reduction by glutathione reductase. The reduced form of glutathione is part of the endogenous scavenging mechanism limiting oxygen free radical activity, which would otherwise react with NO and prevent vasodilation [12]. Thus, the vascular effects of EPO and ARI treatments can be identified with increased prostacyclin and NO action respectively, although this may be an oversimplification since ARI treatment partially corrected reduced aorta prostacyclin output [29] and a deficit in the pressor response to arachidonic acid [30] in diabetic rats.…”

Section: Discussionmentioning

confidence: 99%

“…This defect may be bypassed by dietary supplementation with a y-linolenic acid-rich natural source such as evening primrose oil (EPO), thus restoring vasa nervorum prostacyclin synthesis [8] and preventing endoneurial blood flow and nerve conduction velocity (NCV) deficits [9][10][11][. The NO deficit is related to polyol pathway activity and increased oxygen free radical production, being prevented by aldose reductase inhibitor (ARI) treatment [7] and free radical scavengers [12], which also correct nerve blood flow and NCV abnormalities [13][14][15]. In non-diabetic rats, NCV reductions are found for chronic treatment with cyclo-oxygenase and NO synthase inhibitors [16].…”

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confidence: 99%

Interactions between essential fatty acid, prostanoid, polyol pathway and nitric oxide mechanisms in the neurovascular deficit of diabetic rats

1996

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Summary Impaired c0-6 essential fatty acid metabolism and exaggerated polyol pathway flux contribute to the neurovascular abnormalities in streptozotocin-diabetic rats. The potential interactions between these mechanisms were examined by comparing the effects of threshold doses of aldose reductase inhibitors and evening primrose oil, alone and in combination, on neurovascular deficits. In addition, highdose aldose reductase inhibitor and evening primrose oil treatment effects were challenged by co-treatment with the cyclo-oxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, N%nitro-L-arginine. Eight weeks of diabetes caused an 18.9 % reduction in sciatic motor conduction velocity (p < 0.001). This was only modestly ameliorated by a 0.1% dietary supplement of evening primrose oil or the aldose reductase inhibitors ZD5522 (0.25 mg. kg -1. day ~) and WAY121509 (0.2 mg. kg -1. day -t) for the final 2 weeks. However, joint treatment with primrose oil and ZD5522 or WAY121509 caused marked 71.5 and 82.4 % corrections, respectively, of the conduction deficit. Sciatic nutritive blood flow was 43.1% reduced by diabetes (p < 0.001) and this was corrected by 67.8 % with joint ZD5522 and primrose oil treatment (p < 0.001). High-dose WAY121509 (10 rag. kg -1 9 day -1) and primrose oil (10 % dietary supplement) prevented sciatic conduction velocity and nutritive blood flow deficits in 1-month diabetic rats (p < 0.001). However, these effects were abolished by flurbiprofen (5 mg. kg -1. day -1) and NG-nitro-Larginine (10 mg. kg -1 9 day -1) co-treatment (p < 0.001). Thus, the data provide evidence for synergistic interactions between polyol pathway/nitric oxide and essential fatty acid/cyclo-oxygenase systems in the control of neurovascular function in diabetic rats, from which a potential therapeutic advantage could be derived. [Diabetologia (1996) 39: 172-182] Key words Neuropathy, nerve conduction, endoneurial blood flow, ischaemia, essential fatty acid, prostacyclin, aldose reductase, nitric oxide, vascular endothelium, diabetic rat.Impaired nutritive blood flow is the major factor contributing to early peripheral nerve dysfunction in experimental diabetes mellitus [1,2]. This is likely to be relevant to complications in patients, as direct and indirect investigations have provided strong evidence for nerve perfusion deficits associated with diabetic neuropathy [3]. In diabetic rats, neurovascular defects can be prevented or corrected by a number of therapeutic strategies that target the metabolic changes in diabetes or compensate for them by a direct vasodilator action on vasa nervorum [2]. Vascular endothelium appears particularly vulnerable to hyperglycaemia-driven metabolic changes in diabetes. Increased synthesis/action of angiotensin II [4] and endothelin 1 [5] promote vasa nervorum vasoconstriction. This is strongly exacerbated by deficits in prostacyclin synthesis [6] and nitric oxide (NO) release/action [7] which reduce local vasodilation. Prostacyclin changes appear to be caused by defecti...

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“…of superoxide anion radical (·O 2 ± ) which interacts to destroy NO activity [16±20] including the possibility of increased NO synthesis but that the actual NO bioactivity is masked by enhanced ·O 2 ± production [16,21].…”

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confidence: 99%

Long-term treatment in vivo with NOX-101, a scavenger of nitric oxide, prevents diabetes-induced endothelial dysfunction

1998

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Considerable evidence using experimental models [1±5] have shown that diabetes mellitus is an independent risk factor for the development of impaired endothelium-dependent relaxation ± that is, endothelial dysfunction. This defect has been confirmed in Type I (insulin-dependent) [6,7] and Type II (non-insulindependent) [8] diabetic patients. The factor(s) which contribute to endothelial dysfunction in diabetic patients is not known but data derived in experimental models have suggested several possibilities including: (a) concurrent release of an endothelium-derived constricting factor arising from the cyclooxygenase pathway [9,10] Summary Substantial evidence exists that diabetes results in impaired endothelial dysfunction suggesting diminished nitric oxide production from diabetic endothelium. It is not known what factors contribute to the development of this defect. In this study, we tested whether chronic treatment in vivo with NOX-101, a water-soluble nitric oxide scavenger, prevents endothelial dysfunction in diabetes. Sprague-Dawley rats were made diabetic by an intravenous injection of streptozotocin. A subgroup of control or diabetic animals received twice daily subcutaneous injections of 80 mg/kg NOX-101 beginning at 48 h after streptozotocin was injected and throughout 8 weeks of diabetes. Body weights and glucose concentrations were monitored weekly. At the end of 8 weeks, blood glucose and glycosylated haemoglobin was raised in diabetic rats but serum insulin concentrations were reduced. Treatment with NOX-101 did not alter glucose or insulin concentrations in control or diabetic rats; however, total glycosylated haemoglobin was partially reduced compared with untreated rats. In a subgroup of 2-week diabetic and age-matched rats fasted for 24 h, NOX-101 abolished total urinary nitrate plus nitrite (an index of nitric oxide production in vivo). In isolated tissue baths, relaxation to the endothelium-dependent vasodilator, acetylcholine, was impaired in diabetic aortic rings and relaxation to nitroglycerin was unaltered. Treatment of control rats with NOX-101 did not alter maximum relaxation to acetylcholine but shifted the response curve slightly to the right. In contrast in diabetic rats, NOX-101 prevented the impairment in endothelium-dependent relaxation but had no effect on relaxation induced by nitroglycerin. These data suggest the possibility that diabetes-induced endothelial dysfunction in diabetes results, in part, from a paradoxical increase in nitric oxide production during the course of the disease. This suggests a novel pathway of vascular complications. [Diabetologia (1998

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Regulation of spontaneous EDRF release in diabetic rat aorta by oxygen free radicals

Cited by 117 publications

References 0 publications

Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature

Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature

Interactions between essential fatty acid, prostanoid, polyol pathway and nitric oxide mechanisms in the neurovascular deficit of diabetic rats

Long-term treatment in vivo with NOX-101, a scavenger of nitric oxide, prevents diabetes-induced endothelial dysfunction

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