Mechanisms underlying attenuated contractile response of aortic rings to noradrenaline in fructose-fed mice

Kamata, Katsuo; Kanie, Noriyasu; Inose, Akemi

doi:10.1016/s0014-2999(01)01262-6

Cited by 25 publications

(23 citation statements)

References 37 publications

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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: 53%

“…Indeed, ␣ 2 -adrenoceptors are closely linked to GTP-binding protein, 19,20 whereas ACh receptors may not be linked to such a protein. 5,21 Many stimuli (including insulin, vascular endothelial growth factor, ␤-agonists, and shear-stress signals) regulate NO production by activating eNOS via Ser-1177 phosphorylation through the PI3-kinase/Akt pathway. 10,11,22 When a PI3-K or Akt inhibitor was added in our study, there was no significant difference in the ACh-induced relaxation or in NO x Ϫ /cGMP production, whereas the clonidine-induced and insulin-induced responses were completely abolished by each inhibitor in control aortas.…”

Section: Discussionmentioning

confidence: 99%

“…After a given mouse had been in a constant temperature box at 37°C for a few minutes (at 6 or 10 weeks after nicotinamide-STZ administration), its systolic blood pressure was measured by the tail-cuff method using a blood pressure analyzer (BP-98A; Softron). 5 Finally, mice were anesthetized with diethyl ether and euthanized by decapitation 12 weeks after treatment with nicotinamide-STZ or buffer. This study was conducted in accordance with the Guide for the Care and Use of Laboratory Animals adopted by the Committee on the Care and Use of Laboratory Animals of Hoshi University (which is accredited by the Ministry of Education, Science, Sports, and Culture, Japan).…”

Section: Animals and Experimental Designmentioning

confidence: 99%

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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: 53%

Section: Discussionmentioning

confidence: 99%

Section: Animals and Experimental Designmentioning

confidence: 99%

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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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“…In a type II model, the obese Zucker rat, the aorta has been reported to exhibit either increased endothelium-dependent relaxation (Sexl et al, 1995;Turner and White, 1996) or decreased reactivity (Walker et al, 1999). We and others have demonstrated that both aortic endothelial dysfunction and hypertension are present in type II spontaneously diabetic (db/db) mice and in fructose-fed insulin-resistant mice Kamata et al, 2001). However, our recent observation that both endothelial function and NO production are impaired in aortic strips from spontaneously type II diabetic Goto-Kakizaki rats seemed to conflict with our finding that the expressions of the mRNA and protein for endothelial NO synthase (eNOS) were increased in such aortae (Kobayashi et al, 2004a).…”

Section: Endothelium-dependent Relaxation In Diabetic Modelsmentioning

confidence: 97%

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

Kobayashi

Matsumoto

Kamata

2005

J Smooth Muscle Res

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Macro-and microvascular disease states currently represent the principal causes of morbidity and mortality in patients with type I or type II diabetes mellitus. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in various beds in different animal models of diabetes and in humans with type I or type II diabetes. Several mechanisms leading to endothelial dysfunction have been reported, including changes in substrate avail ability, impaired release of NO, and increased destruction of NO. The principal mediators of diabetes-associated endothelial dysfunction are (a) increases in oxidized low density lipoprotein, endothelin-1, angiotensin II, oxidative stress, and (b) decreases in the actions of insulin or growth factors in endothelial cells. An accumulating body of evidence indicates that abnormal regulation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway may be one of several factors contributing to vascular dysfunction in diabetes. The PI3-K pathway, which activates serine/threonine protein kinase Akt, enhances NO synthase phosphorylation and NO production. Several studies suggest that in diabetes the relative ineffectiveness of insulin and the hyperglycemia act together to reduce activity in the insulin-receptor substrates (IRS)/PI3-K/Akt pathway, resulting in impairments of both IRS/PI3-K/Akt-mediated endothelial function and NO production. This article summarizes the PI3-K/Akt pathway-mediated contraction and relaxation responses induced by various agents in the blood vessels of diabetic animals.

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Vitamin C improves basal metabolic rate and lipid profile in alloxan-induced diabetes mellitus in rats

et al. 2006

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Diabetes mellitus (DM)is a multi-factorial disease which is characterized by hyperglycaemia, lipoprotein abnormalities and oxidative stress. This study evaluated effect of oral vitamin C administration on basal metabolic rate and lipid profile of alloxan-induced diabetic rats. Vitamin C was administered at 200 mg/kg body wt. by gavage for four weeks to diabetic rats after which the resting metabolic rate and plasma lipid profile was determined. The results showed that vitamin C administration significantly (p less than 0.01) reduced the resting metabolic rate in diabetic rats; and also lowered plasma triglyceride, total cholesterol and low-density lipoprotein cholesterol. These results suggest that the administration of vitamin C in this model of established diabetes mellitus might be beneficial for the restoration of basal metabolic rate and improvement of lipid profile. This may at least in part reduce the risk of cardiovascular events seen in diabetes mellitus.

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Mechanisms underlying attenuated contractile response of aortic rings to noradrenaline in fructose-fed mice

Cited by 25 publications

References 37 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

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

Vitamin C improves basal metabolic rate and lipid profile in alloxan-induced diabetes mellitus in rats

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