Free radicals in diabetic endothelial cell dysfunction

Tesfamariam, Belay

doi:10.1016/0891-5849(94)90040-x

Cited by 374 publications

(221 citation statements)

References 65 publications

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“…Overall, the published evidence is congruent with our data, which extend the concept of a balance between hyperglycaemia and hyperinsulinaemia to the physiological domain, across glucose tolerance status and in different vascular districts. Among the numerous mechanisms through which in vitro hyperglycaemia impairs EDV, oxidative stress, both direct and indirect, appears to be the favoured one [42,43]. Our finding that oral glucose was associated with a small reduction in the antioxidant capacity of the plasma confirms what has been reported by other laboratories [44,45].…”

Section: Discussionsupporting

confidence: 90%

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

et al. 2008

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Aims/hypothesis Hyperglycaemia and hyperinsulinaemia have opposite effects on endothelium-dependent vasodilatation in microcirculation, but the net effect elicited by glucose ingestion and the separate influence of glucose tolerance are unknown. Methods In participants with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or diabetic glucose tolerance, multiple plasma markers of both oxidative stress and endothelial activation, and forearm vascular responses (plethysmography) to intra-arterial acetylcholine (ACh) and sodium nitroprusside (SNP) infusions were measured before and after glucose ingestion. In another IGT group, we evaluated the time-course of the skin vascular responses (laser Doppler) to ACh and SNP (by iontophoresis) 1, 2 and 3 h into the OGTT; the plasma glucose profile was then reproduced by means of a variable intravenous glucose infusion and the vascular measurements repeated. Results Following oral glucose, plasma antioxidants were reduced by 5% to 10% (p<0.01) in all patient groups. The response to acetylcholine was not affected by glucose ingestion in any group, while the response to SNP was attenuated, particularly in the IGT group. The ACh:SNP ratio was slightly improved therefore in all groups, even in diabetic participants, in whom it was impaired basally. A time-dependent improvement in ACh:SNP ratio was also observed in skin microcirculation following oral glucose; this improvement was blunted when matched hyperglycaemia was coupled with lower hyperinsulinaemia (intravenous glucose). Conclusions/interpretation Regardless of glucose tolerance, oral glucose does not impair endothelium-dependent vasodilatation either in resistance arteries or in the microcirculation, despite causing increased oxidative stress; the endogenous insulin response is probably responsible for countering any inhibitory effect on vascular function.

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Section: Discussionsupporting

confidence: 90%

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

et al. 2008

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“…Therefore, the oxidative stress in diabetic animals might be responsible for augbecause relaxation response to SNP was not significantly affected by L-arginine treatment in vivo. These mented contractility together with deficient endothelial activity (Chang et al, 1993;Tesfamariam, 1994). On the findings are consistent with previous results (Pieper and Peltier, 1995;Pieper and Dondlinger, 1997; other hand, in several studies, L-arginine in vitro has been shown to improve impairment in endothelium-1997).…”

Section: Discussionsupporting

confidence: 88%

The effects of chronic L-arginine treatment on vascular responsiveness of streptozotocin-diabetic rats

Özçeli̇kay

Tay

Dinçer

et al. 1999

General Pharmacology: The Vascular System

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In this study, the protective effects of L-arginine treatment in vivo on vascular reactivity of streptozotocin (STZ)-induced 12-week-old diabetic rats were examined. Loss of weight, polydipsia, polyphagia, hyperglycemia, hypoinsulinemia, and elevated levels of plasma cholesterol and triglyceride were observed in diabetic rats. L-arginine treatment (1 mg/mL in drinking water) did not significantly affect these metabolic and biochemical abnormalities. Plasma malondialdehyde (MDA) levels in untreated diabetic rats were also significantly higher than untreated controls. However, L-arginine treatment prevented the increase in MDA level of plasma of diabetic rats. Contractile responses, but not sensitivity to noradrenaline (NA), were significantly increased in diabetic rats compared to controls. Treatment of diabetic rats with L-arginine completely prevented the increase in NA responses. Relaxation response to acetylcholine (ACh), but not to sodium nitroprusside (SNP), in diabetic aorta has been found to be significantly decreased as compared with controls. However, there were no significant differences in pD 2 values of acetylcholine in either of the groups. L-arginine treatment increased the ACh responses to the control level. All effects of L-arginine on vascular reactivity were found to be specific for diabetic rats and not controls. These results suggest that functional abnormalities occurred in aorta from diabetic rat might at least in part result from L-arginine deficiency, and the lipid peroxidation-lowering effect of L-arginine may account for its protective effect on vascular reactivity of diabetic rats.

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“…NO reacts with superoxide radicals, thus lowering the effective NO available ; indeed, the superoxide scavenger superoxide dismutase increases the effectiveness of NO, and can, for example, promote vascular smooth muscle relaxation in itro [36]. The diabetic state is often associated with excessive superoxide radical production, leading to endothelial disfunction and macrovascular disease [37]. Indirect evidence suggesting excessive radical production associated with insulin-resistant skeletal muscle includes treatment of obese Zucker rats with the antioxidant lipoic acid, and this causes an improvement in insulin sensitivity [38].…”

Section: Discussionmentioning

confidence: 99%

Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle

Young

Leighton

1998

Biochemical Journal

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Nitric oxide activates guanylate cyclase to form cGMP, comprising a signalling system that is believed to be a distinct mechanism for increasing glucose transport and metabolism in skeletal muscle. The effects of a selective cGMP phosphodiesterase inhibitor, zaprinast, on basal glucose utilization was investigated in incubated rat soleus muscle preparations isolated from both insulin-sensitive (lean Zucker; Fa/?) and insulin-resistant (obese Zucker; fa/fa) rats. Zaprinast at 27 μM significantly increased cGMP levels in incubated soleus muscle isolated from lean, but not obese, Zucker rats. Muscles were incubated with 14C-labelled glucose and various concentrations of zaprinast (3, 27 and 243 μM). Zaprinast (at 27 and 243 μM) significantly increased rates of net and 14C-labelled lactate release and of glycogen synthesis in lean Zucker rat soleus muscle; glucose oxidation was also increased by 27 μM zaprinast. In addition, regardless of concentration, the phosphodiesterase inhibitor failed to increase any aspect of 14C-labelled glucose utilization in soleus muscles isolated from obese Zucker rats. The maximal activity of nitric oxide synthase (NOS) was significantly decreased in insulin-resistant obese Zucker muscles. Thus the lack of effect of zaprinast in insulin-resistant skeletal muscle is consistent with decreased NOS activity. To test whether there is a defect in insulin-resistant skeletal muscle for endogenous activation of guanylate cyclase, soleus muscles were isolated from both insulin-sensitive and insulin-resistant Zucker rats and incubated with various concentrations of the NO donor sodium nitroprusside (SNP; 0.1, 1, 5 and 15 mM). SNP significantly increased rates of net and 14C-labelled lactate release, as well as glucose oxidation in muscles isolated from both insulin-sensitive and insulin-resistant rats. A decreased response to SNP was observed in the dose-dependent generation of cGMP within isolated soleus muscles from insulin-resistant rats. A possible link between impaired NO/cGMP signalling and abnormal glucose utilization by skeletal muscle is discussed.

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Free radicals in diabetic endothelial cell dysfunction

Cited by 374 publications

References 65 publications

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

The effects of chronic L-arginine treatment on vascular responsiveness of streptozotocin-diabetic rats

Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle

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