Reversal by L-arginine of a dysfunctional arginine/nitric oxide pathway in the endothelium of the genetic diabetic BB rat

Pieper, Galen M.; Siebeneich, Wolfgang; Moore-Hilton, Gail; Roza, Allan M.

doi:10.1007/s001250050767

Cited by 68 publications

(40 citation statements)

References 17 publications

(30 reference statements)

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“…1,2 We and others have demonstrated that both aortic endothelial dysfunction and hypertension are present in type 2 spontaneously diabetic (db/db Ϫ/Ϫ ) mice and in fructose-fed insulinresistance mice. [3][4][5][6] Our recent observation that endothelial function and nitric oxide (NO) production are impaired in aortic strips from spontaneously type 2 diabetic GotoKakizaki rats seemed to conflict with our finding that the expressions of the mRNA and protein for endothelial NO synthase (eNOS) were increased in such aortas. 7 However, a possible explanation may be that in the intact cells, NO synthesis is regulated independently of changes in eNOS enzyme activity.…”

contrasting

confidence: 72%

“…This is consistent with previous observations of endothelial dysfunction in type 2 diabetic models. [3][4][5][6] Interestingly, the clonidine-induced relaxation and NO production were impaired, whereas ACh-induced responses were unchanged in the present type 2 diabetic aorta (at 12 weeks after nicotinamide-STZ). Possibly, this may be attributable to one agonist being an ␣ 2 -adrenoceptor agonist, whereas the other is a muscarine-receptor agonist.…”

Section: Discussionmentioning

confidence: 52%

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Impairment of PI3-K/Akt Pathway Underlies Attenuated Endothelial Function in Aorta of Type 2 Diabetic Mouse Model

et al. 2004

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Abstract-The phosphatidylinositol 3-kinase (PI3-K) pathway, which activates serine/threonine protein kinase Akt, enhances endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. We investigated the involvement of the PI3-K/Akt pathway in the relaxation responses to acetylcholine (ACh) and clonidine in a new type 2 diabetic model (streptozotocin plus nicotinamide-induced diabetic mice). Plasma glucose and insulin levels were significantly elevated in our model, and intravenous glucose tolerance tests revealed clear abnormalities in glucose tolerance and insulin responsiveness. Although in our model the ACh-induced relaxation and NO x Ϫ (NO 2 Ϫ ϩNO 3 Ϫ )/cGMP production were unchanged, the clonidine-induced and insulin-induced relaxations and NO x Ϫ /cGMP production were all greatly attenuated. In control mice, the clonidine-induced and insulin-induced relaxations were each abolished by LY294002 and by Wortmannin (inhibitors of PI3-K), and also by Akt-inhibitor treatment. The ACh-induced relaxation was unaffected by such treatments in either group of mice. The expression level of total Akt protein was significantly decreased in the diabetic mice aorta, but those for the p85 and p110␥ subunits of PI3-K were not. The clonidine-induced Ser-473 phosphorylation of Akt through PI3-K was significantly decreased in our model; however, that induced by ACh was not. These results suggest that relaxation responses and NO production mediated via the PI3-K/Akt pathway are decreased in this type 2 diabetic model. This may be a major cause of endothelial dysfunction (and the resulting hypertension) in type 2 diabetes. Key Words: diabetes mellitus Ⅲ hyperinsulinism Ⅲ aorta Ⅲ endothelium-derived relaxing factor Ⅲ nitric oxide N umerous epidemiological studies have indicated that the insulin resistance and hyperinsulinemia associated with type 2 diabetes make important contributions to the development of hypertension and cardiovascular diseases, and impaired endothelium-dependent vasodilation has been described in humans and in animal models of the disease. 1,2 We and others have demonstrated that both aortic endothelial dysfunction and hypertension are present in type 2 spontaneously diabetic (db/db Ϫ/Ϫ ) mice and in fructose-fed insulinresistance mice. [3][4][5][6] Our recent observation that endothelial function and nitric oxide (NO) production are impaired in aortic strips from spontaneously type 2 diabetic GotoKakizaki rats seemed to conflict with our finding that the expressions of the mRNA and protein for endothelial NO synthase (eNOS) were increased in such aortas. 7

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contrasting

confidence: 72%

Section: Discussionmentioning

confidence: 52%

Impairment of PI3-K/Akt Pathway Underlies Attenuated Endothelial Function in Aorta of Type 2 Diabetic Mouse Model

et al. 2004

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“…Interestingly, eNOS knockout mice exhibited accelerated diabetic nephropathy [79], supporting a role for deficient eNOS-derived NO production in the pathogenesis of diabetic nephropathy. Moreover, diabetic animals exhibited increased mRNA and protein for eNOS [80]. Whereas, other studies reported reduced cGMP formation.…”

Section: Animal Studiesmentioning

confidence: 79%

Oxidative Stress, Nitric Oxide, and Diabetes

Pitocco¹,

Zaccardi²,

Stasio³

et al. 2010

Rev Diabet Stud

282

194

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■ AbstractIn the recent decades, oxidative stress has become focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence from research on several diseases show that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on this research, the emerging concept is that oxidative stress is the "final common pathway", through which risk factors of several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell-cell homeostasis. In this review, we discuss the role of oxidative stress in the pathogenesis of insulin resistance and beta-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes, and in the pathogenesis of diabetic vascular complications, the leading cause of death in diabetic patients.

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“…The well-established tenet that acute hyperglycaemia impairs endothelial function is mainly based on in vitro studies using pharmacological (22 mmol/l or higher) concentrations of glucose [12,13] without insulin or on ex vivo studies using experimental animal models characterised by severe hyperglycaemia [14,15,37,38]. In humans, support for this notion derives mostly from studies using the OGTT as the stimulus, and flow-mediated dilatation of large arteries as the index of endothelial function [23][24][25].…”

Section: Discussionmentioning

confidence: 99%

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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Reversal by L-arginine of a dysfunctional arginine/nitric oxide pathway in the endothelium of the genetic diabetic BB rat

Cited by 68 publications

References 17 publications

Impairment of PI3-K/Akt Pathway Underlies Attenuated Endothelial Function in Aorta of Type 2 Diabetic Mouse Model

Impairment of PI3-K/Akt Pathway Underlies Attenuated Endothelial Function in Aorta of Type 2 Diabetic Mouse Model

Oxidative Stress, Nitric Oxide, and Diabetes

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

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