In-vivo nitric oxide synthesis is reduced in obese patients with metabolic syndrome

Siervo, Mario; Jackson, Sarah J.; Bluck, Les

doi:10.1097/hjh.0b013e3283487806

Cited by 39 publications

(45 citation statements)

References 51 publications

(71 reference statements)

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“…For example, it has been shown that serum nitrate and nitrite levels, an index of systemic NO bioavailability, were less in juvenile obese subjects with elevated systolic arterial pressure when compared with normal weight controls. 59 In vivo NO production, as measured by an oral nitrate test, 60 was also less in obese subjects with metabolic syndrome when compared with obese subjects without metabolic syndrome. 60 Consistent with this, we recently found that plasma nitrate and nitrite levels were less in obese hypertensive subjects when compared with their obese normotensive counterparts.…”

Section: Are No Bioavailability and L-argininementioning

confidence: 99%

“…59 In vivo NO production, as measured by an oral nitrate test, 60 was also less in obese subjects with metabolic syndrome when compared with obese subjects without metabolic syndrome. 60 Consistent with this, we recently found that plasma nitrate and nitrite levels were less in obese hypertensive subjects when compared with their obese normotensive counterparts. 5 Furthermore, it has been demonstrated that greater systolic arterial pressure is associated with reductions in NO synthesis in obese subjects.…”

Section: Are No Bioavailability and L-argininementioning

confidence: 99%

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Say NO to Obesity-Related Hypertension

2016

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O besity and its complications represent one of the major emerging challenges for the developed world. 1,2 Hypertension is a common sequelae of obesity, 3,4 and the obesity pandemic is estimated to contribute to 75% of cases of hypertension in men and 65% in women.1 Frequently, subjects with obesity are resistant to standard antihypertensive medication, 4 and poor understanding of the precise mechanisms underlying the link between obesity and hypertension has presented roadblocks for the development of new and effective therapy. 4 In this context, we recently found that obesity is associated with reduced nitric oxide (NO) bioavailability caused by impaired transport of its substrate l-arginine and that augmentation of endothelial l-arginine transport prevents experimental obesity-induced hypertension.5 Findings by others also provide clear evidence that endothelial dysfunction plays an important role in the pathogenesis of hypertension 6,7 including that associated with obesity. 8In the current review, we will discuss the role of the l-arginine-NO pathway in the long-term regulation of blood pressure, its complex inter-relationship with other key neurohormonal and biochemical determinants of arterial pressure, and the way in which this system becomes deranged in obesity-related hypertension. l-Arginine-NO PathwayNO is well recognized as a pivotal endogenous modulator of vascular tone and endothelial function.9 l-Arginine is the sole substrate for NO formation and transport of extracellular l-arginine via cationic amino acid transporter-1 (CAT1) is a rate limiting factor for endothelial NO synthase (eNOS)-dependent NO formation (Figure 1). [9][10][11] This occurs despite the fact that intracellular concentration of l-arginine far exceeds the Michaelis constant K m of eNOS for l-arginine, and this phenomenon is commonly referred to as the l-arginine paradox. 9 The precise factors underlying this paradox remain to be determined, but some of the proposed mechanisms include sequestration of intracellular l-arginine into pools that are not accessible to membrane-bound eNOS, the presence of endogenous eNOS inhibitors such as asymmetrical dimethylarginine and colocalization of CAT1, and eNOS within the plasma membrane of endothelial cells, which facilitates the use of extracellular l-arginine for eNOS-dependent NO formation.9-11 Regardless of the mechanism(s) involved, the presence of the l-arginine paradox creates a crucial role for l-arginine transporters in regulating NO bioavailability and consequently endothelial function. Does Endothelial Dysfunction Precede Hypertension in the Setting of Obesity?Although there is a plethora of data to support an association between endothelial dysfunction and hypertension, [12][13][14] the precise relationship between these 2 phenomena remains complex and undefined. Weisbrod et al 15 recently demonstrated that endothelial function as measured by aortic relaxation to acetylcholine ex vivo was impaired within 2 months of placing mice on a high fat, high sucrose diet. Howeve...

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Section: Are No Bioavailability and L-argininementioning

confidence: 99%

Section: Are No Bioavailability and L-argininementioning

confidence: 99%

Say NO to Obesity-Related Hypertension

2016

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“…Twenty minutes after glucose administration, 201 mU of Human Actrapid insulin was given. A total of 30 blood samples were taken at )10, )5, )1, 1, 2, 3, 4, 5,6,8,10,13,15,20,25,30,35,40,50,60,70,80,90, 100, 120, 140, 160, 180, 210 and 240 min relative to the administration of glucose. Insulin sensitivity (Si) was characterised by the minimal model as defined by Bergman et al [12].…”

Section: Frequent Sampling Intravenous Glucose Tolerance Test (Fsivgtt)mentioning

confidence: 99%

“…All subsequent saliva samples were collected by the volunteer at home using pre-labelled containers. The protocol for the collection of saliva samples has been previously described [8]. The final saliva sample was collected 18 h after the meal on the following morning.…”

Section: Salivary Oral Nitrate Test (S-ont)mentioning

confidence: 99%

VEGF is indirectly associated with NO production and acutely increases in response to hyperglycaemia¹

Siervo

Tomatis

Stephan

et al. 2012

Eur J Clin Investigation

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Eur J Clin Invest 2012; 42 (9): 967–973 Abstract Background Increased levels of vascular endothelial growth factor (VEGF) have been observed in patients with metabolic syndrome (MetS). Nitric oxide (NO) formation is reduced in MetS, but its relationship to VEGF production remains poorly defined. We evaluated the association between VEGF/NO synthesis and insulin sensitivity in obese subjects and investigated the secretory response of VEGF to an acute elevation of glucose. Materials and methods Seven healthy normal‐weight subjects, seven obese subjects without MetS and seven obese subjects with MetS were recruited. Anthropometry, body composition and cardiometabolic functions (blood pressure, glucose, insulin, triglycerides, total cholesterol, HDL‐C and VEGF) were measured, and a novel stable isotope method was used to assess in vivo rates of NO production. A frequent sampling intravenous glucose tolerance test was performed to study the dynamics of VEGF release. Results Fasting VEGF levels were significantly higher in the two obese groups compared to the control group (P for trend = 0·02), but the difference was not significant after adjustment for age. Vascular endothelial growth factor levels were associated with systolic blood pressure (ρ = 0·54; P = 0·01) and NO production (ρ = −0·44; P = 0·04). Vascular endothelial growth factor levels increased in response to acute hyperglycaemia in normal‐weight and obese subjects (P < 0·001). Conclusions Vascular endothelial growth factor levels rapidly increase during hyperglycaemia and are inversely related to NO production at steady state. The potential link between the acute secretion of VEGF and atherosclerotic risk in subjects with poorly controlled glycaemia as well as the potential of lowering elevated VEGF levels by increasing NO production and/or availability warrants further investigation.

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“…41 Compounding these effects, obese individuals also have a decreased capacity for NO production. 42 NO and nitrate have well established vasodilatory properties. Therefore the increased activity of the XOR catalyzed nitrate-nitrite-NO pathway may function as an adaptive response to hypoxia in adipose tissue, especially in the setting of obesity, where it may have the tandem effect of dilating the blood vessels to improve tissue oxygenation and activating the browning process in adipocytes to reverse hypoxia-mediated pathological metabolic reprogramming (Fig.…”

mentioning

confidence: 99%

Does inorganic nitrate say NO to obesity by browning white adipose tissue?

Roberts

2015

Adipocyte

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In-vivo nitric oxide synthesis is reduced in obese patients with metabolic syndrome

Abstract: The advantages of the new saliva ONT method are its accuracy, sensitivity and lack of invasiveness, which could make it a reference method for the assessment of in-vivo rates of whole-body nitric oxide synthesis.

Cited by 39 publications

References 51 publications

Say NO to Obesity-Related Hypertension

Say NO to Obesity-Related Hypertension

VEGF is indirectly associated with NO production and acutely increases in response to hyperglycaemia¹

Does inorganic nitrate say NO to obesity by browning white adipose tissue?

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In-vivo nitric oxide synthesis is reduced in obese patients with metabolic syndrome

Abstract: The advantages of the new saliva ONT method are its accuracy, sensitivity and lack of invasiveness, which could make it a reference method for the assessment of in-vivo rates of whole-body nitric oxide synthesis.

Cited by 39 publications

References 51 publications

Say NO to Obesity-Related Hypertension

Say NO to Obesity-Related Hypertension

VEGF is indirectly associated with NO production and acutely increases in response to hyperglycaemia1

Does inorganic nitrate say NO to obesity by browning white adipose tissue?

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VEGF is indirectly associated with NO production and acutely increases in response to hyperglycaemia¹