Acute hyperglycemia depresses arteriolar  NO formation in skeletal muscle

Lash, J. M.; Nase, G. P.; Bohlen, H. G.

doi:10.1152/ajpheart.1999.277.4.h1513

Cited by 40 publications

(57 citation statements)

References 27 publications

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“…One of the major risks of obesity is that severe insulin resistance can allow occasional or sustained hyperglycemia, which are the hallmarks of type II or insulin-independent diabetes mellitus. In vivo studies in normal rats indicate that acute, Ն300 mg/dl D-glucose hyperglycemia was detrimental to the NO function of normal endothelial cells in intestinal, cerebral, and skeletal muscle vasculatures (5,16,20,22). In the present study, we found the same result in lean Zucker rats (see Figs.…”

Section: Discussionsupporting

confidence: 84%

“…In lean rats, 200 mg/dl D-glucose was benign, but 300 mg/dl D-glucose for ϳ30-60 min impaired endothelium-dependent NO vasodilation in normal cerebral, intestinal, and skeletal muscle vasculatures (5,16,20,22). We found that less NO was formed after these bouts of acute hyperglycemia as determined by both bioassay and direct measurement of arteriolar wall NO concentration ([NO]) (5,8,16,20). In addition, in vivo flow shear-dependent endothelial regulation, which is NO dependent in the rat intestinal arterioles, was suppressed during acute hyperglycemia (16).…”

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confidence: 99%

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Obesity lowers hyperglycemic threshold for impaired in vivo endothelial nitric oxide function

Bohlen

Nase

2002

American Journal of Physiology-Heart and Circulatory Physiology

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Obesity is a risk for type II diabetes mellitus and increased vascular resistance. Disturbances of nitric oxide (NO) physiology occur in both obese animals and humans. In obese Zucker rats, we determined whether a protein kinase C-βII (PKC-βII) mechanism may lower the resting NO concentration ([NO]) and predispose endothelial NO abnormalities at lower glucose concentrations than occur in lean rats. NO was measured with microelectrodes touching in vivo intestinal arterioles. At rest, the [NO] in obese Zucker rats was 60 nm less than normal or about a 15% decline. After local blockade of PKC-βII with LY-333531, the [NO] increased ∼90 nm in obese rats but did not change in lean rats. In lean rats, administration of 300 mg/dl d-glucose for 45 min depressed endothelium-dependent dilation; only 200 mg/dl was required in obese animals. These various observations indicate that resting [NO] is depressed in obese rats by a PKC-βII mechanism and the hyperglycemic threshold for endothelial NO suppression is reduced to 200 mg/dl d-glucose.

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Section: Discussionsupporting

confidence: 84%

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confidence: 99%

Obesity lowers hyperglycemic threshold for impaired in vivo endothelial nitric oxide function

Bohlen

Nase

2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…There is evidence for both an increase (10, 16, 31, 36) and a decrease (27,36) in the activity of the NO system in the diabetic state. Evidence for increased NO production under hyperglycemic conditions is shown, for example, by the increase in NO release in endothelial cells exposed to high glucose levels (9,16,18).…”

Section: Discussionmentioning

confidence: 99%

Hypertension inl-NAME-treated diabetic rats depends on an intact sympathetic nervous system

Fitzgerald

Brands

2002

American Journal of Physiology-Regulatory, Integrative and Comp

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Fitzgerald, Sharyn M., and Michael W. Brands. Hypertension in L-NAME-treated diabetic rats depends on an intact sympathetic nervous system. Am J Physiol Regulatory Integrative Comp Physiol 282: R1070-R1076, 2002. First published November 23, 2001 10.1152/ajpregu.00468. 2001.-We demonstrated previously that induction of diabetes in rats that were treated chronically with the nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) causes a severe, progressive increase in mean arterial pressure. This study tested the role of the sympathetic nervous system in that response. Rats were instrumented with chronic artery and vein catheters and assigned randomly to four diabetic groups pretreated with vehicle (D), L-NAME (DϩL), the ␣1-and ␤-adrenergic receptor antagonists terazosin and propranolol (DϩB), or L-NAME, terazosin, and propranolol (DϩLB). After baseline measurements were taken, rats were pretreated; 6 days later, streptozotocin was administered and 3 wk of diabetes ensued. DϩL rats had a marked, progressive increase in arterial pressure that by day 20 was ϳ60 mmHg greater than in D rats. The pressor response to L-NAME was significantly attenuated in diabetic rats cotreated with adrenergic blockers. During week 1 of diabetes, plasma renin activity (PRA) increased and then returned to control levels in D rats. PRA increased progressively in DϩL rats, and chronic adrenergic receptor blockade restored the biphasic renin response in DϩLB rats. These results suggest that the sympathetic nervous system may be involved in the hypertensive response to onset of diabetes in L-NAME-treated rats, possibly through control of renin secretion. nitric oxide; mean arterial pressure; glucose; angiotensin II; glomerular filtration rate; N G -nitro-L-arginine methyl ester DIABETES GENERALLY IS ASSOCIATED with an impairment in endothelial function (10,34,35,37,43). The long-term consequences of this impairment have not been well established, but it may play an important role in the accelerated atherosclerosis and increased prevalence of cardiovascular disease that is observed in diabetic populations (45a). Also unclear is what role the endothelium and its vasoactive hormones play in circulatory homeostasis early in diabetes before significant impairment develops (4,20,34,44). We demonstrated recently (15) that the induction of diabetes in the absence of a functional nitric oxide (NO) system causes a severe, progressive increase in mean arterial pressure (MAP). This finding suggests that there may be increased dependence on NO in the early stages of diabetes such that NO is essential to prevent hypertension from developing. This is consistent with reports (10, 31) that NO production is increased during the early stages of diabetes.The mechanism for this potentiating interaction on blood pressure between induction of diabetes and chronic NO synthesis inhibition is not known, but a role for the renin-angiotensin system was implicated by the finding of increased plasma renin activity (PRA) in the rats in our study ...

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“…Several studies have demonstrated that hyperglycemia/diabetes mellitus (DM) causes a loss of endothelium-derived NO in both animals (17)(18)(19) and humans (20), but the underlining mechanism is poorly understood. DM does not influence the overall eNOS protein level or its mRNA level (21).…”

Section: Endothelium-derived Nitric Oxide (No)mentioning

confidence: 99%

Protein Kinase A-dependent Translocation of Hsp90α Impairs Endothelial Nitric-oxide Synthase Activity in High Glucose and Diabetes

Lei

Venkatakrishnan

et al. 2007

Journal of Biological Chemistry

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Diabetes mellitus (DM) and high glucose (HG) are known to reduce the bioavailability of nitric oxide (NO) by modulating endothelial nitric-oxide synthase (eNOS) activity. eNOS is regulated by several mechanisms including its interaction with heat shock protein (Hsp) 90. We previously discovered that DM in vivo and HG in vitro induced the translocation of Hsp90␣ to the outside of aortic endothelial cells. In this report we tested the hypothesis that translocation of Hsp90␣ is responsible for the decline in NO production observed in HG-treated cells. We found that HG increased phosphorylation of Hsp90␣ in a cAMP-dependent protein kinase A-dependent manner, and that this event was required for translocation of Hsp90␣ in porcine aortic endothelial cells. Furthermore, preventing translocation of Hsp90␣ protected from the HG-induced decline in eNOS⅐Hsp90␣ complex and NO production. Notably, DM increased phosphorylation of Hsp90␣ and reduced its association with eNOS in the aortic endothelium of diabetic rats. These studies suggest that translocation of Hsp90␣ is a novel mechanism by which HG and DM impair eNOS activity and thereby reduce NO production. Endothelium-derived nitric oxide (NO)2 , a small, diffusible, lipophilic free radical gas, is a critical regulator of cardiovascular homeostasis (1, 2). Vascular NO dilates all types of blood vessels. It also inhibits platelet aggregation and adhesion, and leukocyte adhesion to the vessel wall (3-5). A deficiency of NO (decreased NO production, increased degradation of NO or decreased NO sensitivity) can promote atherogenesis (1, 6).Endothelial NO synthase (eNOS) is responsible for most of the vascular NO produced. A functional eNOS oxidizes its substrate L-arginine to L-citrulline and NO (4, 5). eNOS is highly regulated by post-translational modifications including myristoylation, palmitoylation, and phosphorylation (7-11). This enzyme is also tightly regulated by specific interactions with inhibitory and activating proteins such as caveolin-1 and Hsp90, respectively. The binding of heat shock protein 90 (Hsp90) to eNOS enhances eNOS activation, assists with the intracellular trafficking of eNOS, and helps activate eNOS by dissociating it from caveolin-1 (12, 13). Furthermore, Hsp90 provides a scaffold for eNOS and Akt, and thereby enhances eNOS activation (9, 14 -16).Several studies have demonstrated that hyperglycemia/diabetes mellitus (DM) causes a loss of endothelium-derived NO in both animals (17-19) and humans (20), but the underlining mechanism is poorly understood. DM does not influence the overall eNOS protein level or its mRNA level (21). One potential mechanism may be the reduced association of eNOS with Hsp90 (19).Hsp90 is an ATP-dependent chaperone that interacts with over 100 proteins (22,23), and has been implicated in many physiological and pathological processes (24 -27). DM induces an increase in the amount of Hsp90␣ at the luminal surface of the aorta, and this event could be mimicked by treating cultured vascular endothelial cells with high glucose ...

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Acute hyperglycemia depresses arteriolar NO formation in skeletal muscle

Cited by 40 publications

References 27 publications

Obesity lowers hyperglycemic threshold for impaired in vivo endothelial nitric oxide function

Obesity lowers hyperglycemic threshold for impaired in vivo endothelial nitric oxide function

Hypertension inl-NAME-treated diabetic rats depends on an intact sympathetic nervous system

Protein Kinase A-dependent Translocation of Hsp90α Impairs Endothelial Nitric-oxide Synthase Activity in High Glucose and Diabetes

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