Attenuation of endothelium-dependent relaxation in aorta from diabetic rats

Oyama, Yohtaro; Kawasaki, Hisao; Hattori, Yoshiyuki; Kanno, Morio

doi:10.1016/0014-2999(86)90013-0

Cited by 338 publications

(196 citation statements)

References 9 publications

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“…Our success in this regard is evidenced in the present study by the ®nding that a relaxation of over 80% of the noradrenaline-induced contraction was induced by as little as 10 77 M ACh ( Figure 1a). The reduced endothelium-dependent relaxation seen in diabetic rats in the present study is in agreement with the results of numerous other studies on aortae from STZinduced diabetic rats (Oyama et al, 1986;Kamata et al, 1989;Poston & Taylor, 1995;Pieper, 1998;Kamata & Kobayashi, 1996;Kobayashi & Kamata, 1999a, b;Kobayashi et al, 2000;De Vriese et al, 2000;Hink et al, 2001).…”

Section: Discussionsupporting

confidence: 93%

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

Kanie

Kamata

2002

British J Pharmacology

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1 The biosynthesis of endothelin-1 is increased in the diabetic state. So this peptide may cause diabetic vascular complications. We tested this possibility by chronically administering J-104132, a potent orally active mixed antagonist of endothelin A and B (ET A /ET B ) receptors to streptozotocin (STZ)-induced diabetic rats and focusing on changes in endothelial function. 2 The acetylcholine (ACh)-induced endothelium-dependent relaxation was impaired in diabetic rats and this impairment was signi®cantly attenuated following chronic administration of J-104132 (10 mg kg 71 , p.o., daily for 4 weeks).3 In an in vitro experiment using aortae from diabetic rats, the ACh-induced relaxation was not changed by the presence of J-104132 (3610 79 M). 4 The expression levels of the mRNA for endothelial nitric oxide synthase was comparable among aortae from the three groups (control, diabetic and chronically J-104132-treated diabetic). 5 The amount of superoxide anion was signi®cantly greater in aortae from diabetic rats than in controls. Chronic J-104132 treatment signi®cantly decreased the level of superoxide anion in diabetic rats. 6 The expression of the p22phox mRNA for the NADH/NADPH oxidase subunit was signi®cantly increased in STZ-induced diabetic rats and this increase was completely prevented by chronic administration of J-104132. 7 These results suggest that in STZ-induced diabetic rats, ET-1 may be directly involved in impairing endothelium-dependent relaxation via increased superoxide-anion production.

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Section: Discussionsupporting

confidence: 93%

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

Kanie

Kamata

2002

British J Pharmacology

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“…Blood vessels from diabetic animals and humans exhibit attenuated endothelium-dependent relaxation in response to ACh [31]. Acetylcholine interacts with endothelial muscarinic M 3 receptors and causes NO release and vasodilatation [32].…”

Section: Discussionmentioning

confidence: 99%

Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice

et al. 2008

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Aims/hypothesis Exercise ameliorates oxidative stressmediated diabetic vascular endothelial dysfunction through poorly defined mechanisms. We hypothesised that, in addition to improving metabolic parameters, upregulation of antioxidants such as superoxide dismutase (SOD) mediates exercise-induced reductions of oxidative stress and increased nitric oxide (NO) bioavailability, and also restores vasodilatation. Methods Type 2 diabetic db/db and normoglycaemic wildtype mice were exercised at moderate intensity for 1 h a day for 7 weeks, leading to a 10% body weight loss. Sedentary animals or those undergoing a low-intensity exercise regimen causing non-significant weight loss were also used. We examined aortic endothelial cell function, NO bioavailability and various biomarkers of oxidative stress. Results Moderate-intensity exercise lowered body weight, increased mitochondrial manganese SOD (MnSOD) and both total and phosphorylated (Ser1177) endothelial nitric oxide synthase (eNOS) protein production; it also reduced wholebody (plasma 8-isoprostane) and tissue oxidative stress (nitrotyrosine immunostaining or protein carbonyl levels in the aorta). Low-intensity exercise did not alter body weight; however, it upregulated cytosolic Cu/Zn-SOD instead of MnSOD, and still demonstrated all the above benefits in the db/db aorta. Importantly, both exercise protocols improved endothelial-dependent vasodilatation and NO bioavailability without altering hyperglycaemic status in db/db mice. Conclusions/interpretation Exercise reverses diabetic vascular endothelial dysfunction independently of improvements in body weight or hyperglycaemia. Our data suggest that upregulation of eNOS and specific SOD isoforms could play important roles in improving NO bioavailability, as well as in reversing endothelial dysfunction in type 2 diabetes patients through lifestyle modifications in the management of diabetes.

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“…Impaired ACh-induced relaxation with normal responses to bradykinin has been reported in isolated resistance vessels from patients with type I diabetes (McNally et al, 1994), in the forearm circulation of type II diabetes patients (Gazis et al, 1999) and in mesenteric and hindlimb arteries of streptozotocin (STZ)-rats (Lash & Bohlen, 1991;Taylor et al, 1995), suggesting an abnormality at the level of the G-proteins. However, several other studies found equally suppressed responses to di erent endothelium-dependent agonists (Heygate et al, 1995;Fulton et al, 1996;Costa e Forti & Fonteles, 1998;Mayhan & Patel, 1995;1998;Mayhan, 1997) or impaired relaxation to the calcium-ionophore A23187 (Oyama et al, 1986;Durante et al, 1988;Cameron & Cotter, 1992;Fukao et al, 1997), making a disturbance of receptors or receptor-coupled mechanisms unlikely as a common mechanism of endothelial dysfunction.…”

Section: Mechanisms Of Impaired Endothelium-dependent Vasodilatation mentioning

confidence: 98%

Endothelial dysfunction in diabetes

Vriese

Verbeuren

Voorde

et al. 2000

British J Pharmacology

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769

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Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of di erent animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to di er according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.

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Attenuation of endothelium-dependent relaxation in aorta from diabetic rats

Cited by 338 publications

References 9 publications

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

Effects of chronic administration of the novel endothelin antagonist J‐104132 on endothelial dysfunction in streptozotocin‐induced diabetic rat

Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice

Endothelial dysfunction in diabetes

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