The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

Cameron, Norman E.; Dines, K. C.; Cotter, Mary A.

doi:10.1007/bf00399794

Cited by 67 publications

(24 citation statements)

References 64 publications

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“…This was repeated at another nerve site more than 4 mm proximal or distal. Mono-or bi-exponential curves were fitted to the data by regression analysis (Prism; Graphpad, San Diego, Calif., USA) [39]. The fitting procedure gave r 2 values within the range 0.997-1.000 for all individual curves in this study.…”

Section: Methodsmentioning

confidence: 94%

Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

et al. 1997

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Elevated polyol pathway activity has been implicated in the development of diabetic complications, including neuropathy [1]. In diabetic models, inhibitors of the first enzyme in the pathway, aldose reductase, prevent or correct nerve conduction velocity (NCV) and regeneration deficits [2][3][4][5][6][7][8][9][10][11][12][13]. Clinical trials of aldose reductase inhibitors (ARIs) have shown modest improvements in neurological symptoms, NCV, sensory measures, and an increase in nerve fibre regeneration [14-17] despite a less effective polyol pathway blockade than was found necessary for functional effects in animal studies [6,10,18].Several hypotheses have been advanced to explain the action of ARI. Some putative mechanisms are primarily dependent on the first half of the polyol pathway, conversion of glucose to sorbitol by aldose Diabetologia (1997) 40: 271-281 Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats Summary Aldose reductase inhibitors (ARIs) attenuate diabetic complications in several tissues, including lens, retina, kidney, blood vessels, striated muscle and peripheral nerve. However, it is unclear whether their action in diabetes mellitus depends directly on inhibiting the conversion of glucose to sorbitol by aldose reductase or indirectly by reducing the sorbitol available for subsequent metabolism to fructose by sorbitol dehydrogenase. To identify the polyol pathway step most relevant to complications, particularly neuropathy, we compared the biochemical effects of a sorbitol dehydrogenase inhibitor, WAY-135 706, (250 mg ⋅ kg −1 ⋅ day −1 ) and an ARI, WAY-121 509, (10 mg ⋅ kg −1 ⋅ day −1 ) on a variety of tissues, and their effects on nerve perfusion and conduction velocity. After 6 weeks of untreated streptozotocin diabetes, rats were treated for 2 weeks. Sorbitol was elevated 2.1-32.6-fold by diabetes in lens, retina, kidney, aorta, diaphragm, erythrocytes and sciatic nerve; this was further increased (1.6-8.2-fold) by WAY-135 706 whereas WAY-121 509 caused a marked reduction. Fructose 1.6-8.0-fold elevated by diabetes in tissues other than diaphragm, was reduced by WAY-135 706 and WAY-121 509, except in the kidney. Motor and sensory nerve conduction velocities were decreased by 20.2 and 13.9 %, respectively with diabetes. These deficits were corrected by WAY-121 509, but WAY-135 706 was completely ineffective. A 48.6 % diabetes-induced deficit in sciatic nutritive endoneurial blood flow was corrected by WAY-121 509, but was unaltered by WAY-135 706. Thus, despite profound sorbitol dehydrogenase inhibition, WAY-135 706 had no beneficial effect on nerve function. The data demonstrate that aldose reductase activity, the first step in the polyol pathway, makes a markedly greater contribution to the aetiology of diabetic neurovascular and neurological dysfunction than does the second step involving sorbitol dehydrogenase. [Diabetologia (1997) 40: ...

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Section: Methodsmentioning

confidence: 94%

Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

et al. 1997

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“…Nerve polyols nevertheless remain in the non-diabetic range, thus, a putative "pseudohypoxia" mechanism, based on changes in neuronal NADH/NAD ratio due to flux through the second half of the polyol pathway [41] is unlikely to cause the NCV reduction. Conversely, blood flow and NCV are restored by EPO and vasodilator treatments [2,4,5,19,39] although polyol pathway and pseudohypoxia mechanisms remain strongly activated. Thus, it must be concluded that pseudohypoxia does not contribute significantly to diabetic NCV changes and that neurovascular mechanisms predominate.…”

Section: Discussionmentioning

confidence: 99%

“…Endoneurial blood flow was measured in the contralateral limb by microelectrode polarography and hydrogen clearance as previously described [5,19]. Rats were given neuromuscular blockade using o-tubocurarine (Sigma, 2 mg. kg -~ via the carotid cannula) and artificially ventilated.…”

Section: Experimental Groups and Diabetes Inductionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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“…Sciatic axons in these rats are selectively susceptible to ischaemia induced by ET-1 due to more intense and prolonged vasoconstriction to the peptide [54]. Moreover, sciatic nerve motor conduction deficits in diabetic rats were corrected by an ET A antagonist, in association with increases in sciatic nutritive endoneurial blood flow [55]. Non-selective ET A /ET B blockade failed, however, to evoke similar actions [56], indicating that the addition of ET B blockade might blunt the beneficial effects of ET A antagonism.…”

Section: In Vivo Haemodynamic Studiesmentioning

confidence: 95%

Endothelin: emerging role in diabetic vascular complications

1999

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The endothelin (ET) family consists of three 21-amino acid peptides designated ET-1, 2]. The biological actions of the ETs are primarily mediated by two distinct, G-protein-coupled receptor subtypes designated ET A and ET B [2]. Endothelin A receptors have a higher affinity for ET-1 and ET-2 than ET-3 and the ET B receptor binds all three isoforms with equal affinity. Translation of preproET mRNA generates preproET, which is converted to big ET and finally cleaved by ET converting enzyme (ECE) to facilitate production of biologically active peptide. Endothelin-1 released by vascular endothelial cells exerts an autocrine influence by promoting vasodilatation, subsequent to activation of ET B receptors located on endothelial cells. It also exerts a paracrine effect on adjacent vascular smooth muscle cells (VSMC) in evoking vasoconstrictor and mitogenic actions by activation of both ET A and ET B receptors. The primary target of ET-1 is the vasculature where it evokes transient vasodilatation mediated by endothelial ET B receptors, followed by slow-onset and sustained contraction mediated by ET A and ET B receptors located on VSMC. The functional response to ET-1 varies throughout different tissues and vascular beds due to differences in distribution and expression of these two receptor subtypes. Endothelin-1 Diabetologia (1999) AbstractSince the discovery of endothelin-1 as the most potent endothelial-derived vasoconstrictor/mitogenic peptide a decade ago, considerable evidence has implicated this peptide in various cardiovascular disease states, including diabetes mellitus. Plasma and tissue concentrations of endothelin-1 as well as responses to the peptide are changed in various forms of the disease in humans and animals. Endothelin activity is also altered in atherosclerotic and ischaemic disease, nephropathy, retinopathy, erectile dysfunction, and neuropathy, many of the well-known complications of diabetes. Striking new evidence shows that antagonists of the endothelin system might beneficially affect and potentially overcome some of these complications. Despite this, lack of direct proof of causation makes this peptide's role in the disease uncertain. This review examines the current state of thought on the role of endothelin in diabetes and in the complications of the disease as well as the likely roles of altered metabolic variables in modulating endothelin-1 concentrations and its activity. It is concluded that although alterations in endothelin-1 release and action are clearly associated with the diabetic state, further studies using inhibitors of the endothelin system are warranted to determine its precise role in the complications of the disease. [Diabetologia (1999

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The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

Cited by 67 publications

References 64 publications

Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

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

Endothelin: emerging role in diabetic vascular complications

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