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The effect of nitric oxide synthase (NOS) inhibition on arterial glucose, free fatty acids (FFA) and lactate and their arterial-to-venous (a-v) differences and uptake/release during exercise.

The effect of nitric oxide synthase (NOS) inhibition on arterial glucose, free fatty acids (FFA) and lactate and their arterial-to-venous (a-v) differences and uptake/release during exercise.

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Background The role of nitric oxide in controlling substrate metabolism in humans is incompletely understood. Methods The present study examined the effect of nitric oxide blockade on glucose uptake, and free fatty acid and lactate exchange in skeletal muscle of eight healthy young males. Exchange was determined by measurements of muscle perfusion...

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... arterial concentrations of glucose and FFA were not affected by inhibition either at rest (Figure 1) or during exercise (Figure 2). Glucose uptake at rest was 0.40 ± 0.21 μmol/100 g/min and increased to 3.71 ± 2.53 μmol/ 100 g/min by acute one leg exercise (p < 0.01) (Figure 1). ...
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... uptake at rest was 0.40 ± 0.21 μmol/100 g/min and increased to 3.71 ± 2.53 μmol/ 100 g/min by acute one leg exercise (p < 0.01) (Figure 1). Inhibition of NOS did not affect glucose uptake at rest (Figure 1) or during exercise (Figure 2), although it re- duced (P < 0.05) resting muscle blood flow and increased (P < 0.05) oxygen extraction and uptake substantially ( Table 1). Inhibition of NOS altered the release of free fatty acids (FFA) at rest from a release of FFAs, to an up- take (P < 0.05) during NOS blockade (Figure 1). ...

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... nNOSμ is the main isoform expressed in skeletal muscle (210), is constitutively active, and muscle contraction causes a twofold increase in NO production (233). However, there is some disagreement in the field as to whether NOS inhibition decreases exercise-stimulated glucose uptake (27,143), as this is not universally observed (94,138). ...
Article
The skeletal muscle is the largest organ in the body, by mass. It is also the regulator of glucose homeostasis, responsible for 80% of postprandial glucose uptake from the circulation. Skeletal muscle is essential for metabolism, both for its role in glucose uptake and its importance in exercise and metabolic disease. In this article, we give an overview of the importance of skeletal muscle in metabolism, describing its role in glucose uptake and the diseases that are associated with skeletal muscle metabolic dysregulation. We focus on the role of skeletal muscle in peripheral insulin resistance and the potential for skeletal muscle-targeted therapeutics to combat insulin resistance and diabetes, as well as other metabolic diseases like aging and obesity. In particular, we outline the possibilities and pitfalls of the quest for exercise mimetics, which are intended to target the molecular mechanisms underlying the beneficial effects of exercise on metabolic disease. We also provide a description of the molecular mechanisms that regulate skeletal muscle glucose uptake, including a focus on the SNARE proteins, which are essential regulators of glucose transport into the skeletal muscle. © 2020 American Physiological Society. Compr Physiol 10:785-809, 2020.
... In addition, it has been reported to have an inhibitory effect on platelet aggregation and prevents the activation, adhesion and migration of leukocytes (Hegyi and Rakonczay, Jr. 2011). Studies have also documented the involvement of NO in glucose metabolism, especially as it affects skeletal muscle glucose uptake, with conflicting results (Bradley et al. 1999, Durham et al. 2003, Heinonen et al. 2013. Previous studies demonstrated that the administration of exogenous NO donors enhanced resting glucose uptake (Higaki et al. 2001, Durham et al. 2003. ...
... In agreement, the blockage of nitric oxide synthase (NOS) was demonstrated to decrease muscle glucose uptake during exercise in animals and humans (Balon and Nadler 1997, Bradley et al. 1999, Kingwell et al. 2002. However, some studies in animals and humans reported that the inhibition of NOS did not alter skeletal muscle glucose uptake during exercise (Inyard et al. 2007, Heinonen et al. 2013. ...
Article
The inhibition of renin angiotensin system pathway has been largely documented to be effective in the control of cardiovascular events. The present study investigated the effect of angiotensin converting enzyme (ACE) inhibitor on fasting blood glucose level in hypertension induced by the inhibition of nitric oxide synthase (NOS) in male Wistar rats. Hypertension was induced by the inhibition of NOS using a non-selective NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). The blockade of NOS resulted in an increase in blood pressure, ACE, angiotensin II and endothelin-1 levels, and a decrease in fasting blood glucose and nitric oxide (NO) levels. The hypertensive rats treated with ACE inhibitor (ramipril) recorded a decrease in blood pressure, ACE, angiotensin II, endothelin-1, NO and fasting blood glucose levels, and an increase in prostacyclin level. In conclusion, ACE inhibitor potentiated the hypoglycaemic effect of NOS inhibitor and this effect is independent of NO and pancreatic insulin release.
... Hypoxic state associated with increased breathing intensity at the moment of transition to physical activity in tissue cells is one of the factors in formation of activated mitochondrion state [12]. Hypoxia initiates the formation of reactive oxygen forms with subsequent deployment of free-radical and peroxide reactions through moderate mobilization of endogenous fatty acids and stimulation of sympathoadrenal system [13]. The accumulation of endogenous oxygen in the process of free-radical reactions provides maintenance of intensive energy exchange and attraction of free-radical oxidation products to metabolic processes [14]. ...
Article
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Hemato-ophthalmic barrier is one of the mechanisms of body resistance. One of the complications of mechanical trauma of the eye and violation of the hemato-ophthalmic barrier is the emergence of oxidative stress on the background of the general inflammatory process. Normally, oxidative stress in the skeletal muscle tissue is not a damaging agent, but when intensified by other factors, it promotes pathological changes in the body. Objective: to study the dynamics of superoxiddismutase (SOD) activity in rat skeletal muscle tissue under oxidative stress caused by mechanical action on the hemato-ophthalmic barrier. Materials and methods: The study was carried out on pedigree matured male rats in the amount of 150 pieces. The activity of SOD in skeletal muscle tissue was studied before the experiment, as well as on the 1st, 3rd, 5th, 7th and 14th day of the experiment using the standard technique of V.S. Gurevich. The obtained digital material was subjected to statistical processing by means of non-parametric statistical analysis. Conclusion: SOD activity in rat skeletal muscle tissue under oxidative stress caused by mechanical action on hemato-ophthalmic barrier is most effectively stabilized in standard therapy of mechanical eye injury with the addition of quercetin in the form of injections.
... [21][22][23] Interestingly, this technique also controversially showed that nitric oxide synthase (NOS) inhibition increases the permeability of the capillaries to insulin, increasing the delivery of insulin to the skeletal muscle, and accelerating glucose lowering. 29 Local NOS inhibition had no effect on capillary blood flow during contraction, [30][31][32] while systemic 33 and local 34 NOS inhibition can block insulin-induced microvascular recruitment, suggesting a direct local effect on the microvasculature. NOS inhibition also suppressed muscle glucose uptake due to the reduction in perfusion during insulin exposure, 33 however, in exercise, impairments of glucose uptake by NOS inhibition occurred without changes in microvascular recruitment. ...
Article
The endocrine system relies on the vasculature for delivery of hormones throughout the body, and the capillary microvasculature is the site where the hormones cross from the blood into the target tissue. Once considered an inert wall, various studies have now highlighted the functions of the capillary endothelium to regulate transport and therefore affect or maintain the interstitial environment. The role of the capillary may be clear in areas where there is a continuous endothelium, yet there also appears to be a role of endothelial cells in tissues with a sinusoidal structure. Here we focused on the most common endocrine disorder, diabetes, and several of the target organs associated with the disease, including skeletal muscle, liver and pancreas. However, it is important to note that the ability of hormones to cross the endothelium to reach their target tissue is a component of all endocrine functions. It is also a consideration in organs throughout the body and may have greater impact for larger hormones with target tissues containing a continuous endothelium. We noted that the blood levels do not always equal interstitial levels, which is what the cells are exposed to, and discussed how this may change in diseases such as obesity and insulin resistance. The capillary endothelium is, therefore, an essential and understudied aspect of endocrinology and metabolism that can be altered in disease, which may be an appropriate target for treatment.
... NO exerts other effects: it inhibits platelet aggregation (interestingly, activated-plateletderived substances increase the activity of eNOS, thus producing more NO) and the adhesion of leucocytes to the vascular wall by decreasing the expression of adhesion molecules on endothelial surface [90]. Moreover, it interferes with cellular metabolism [125] by modulating mitochondrial function, and oxygen metabolism [106,126]. As stated, NO forms ROS (ONOO − ) with increased levels of O 2− which, among others, impairs the mitochondrial respiratory chain [127]. ...
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... Nitric oxide synthase (NOS) activity and nitric oxide (NO) production are increased during electrical stimulations in muscle cells (34,42), muscle contractions, or exercise in rodents (14,15,31,32,36,38) and exercise in humans (28). Several studies have demonstrated that pharmacological inhibition of NOS attenuates the increase in skeletal muscle glucose uptake during contractile activity (1,3,14,24,31,32,37,38), although this is not a universal finding (7,10,12,13,39). Neuronal NOS (nNOS) is considered the predominant source of NO in contracting skeletal muscle (14,26) and is largely targeted to the mechanosensing dystrophin-glycoprotein complex at the sarcolemma (4). ...
Article
Skeletal muscle contraction increases glucose uptake via an insulin-independent mechanism. Signaling pathways arising from mechanical strain are activated during muscle contractions, and mechanical strain in the form of passive stretching stimulates glucose uptake. However, the exact mechanisms regulating stretch-stimulated glucose uptake are not known. Since nitric oxide synthase (NOS) has been implicated in the regulation of glucose uptake during ex vivo and in situ muscle contractions and during exercise, and NO is increased with stretch, we examined whether the increase in muscle glucose uptake during stretching involves NOS. We passively stretched isolated EDL muscles (15 min at ~100-130 mN) from control mice and mice lacking either neuronal NOSµ (nNOSµ) or endothelial NOS (eNOS) isoforms, as well as used pharmacological inhibitors of NOS. Stretch significantly increased muscle glucose uptake approximately 2-fold (P < 0.05), and this was unaffected by the presence of the NOS inhibitors NG-monomethyl-L-arginine (L-NMMA; 100 µM) or NG-nitro-L-arginine methyl ester (L-NAME; 100 µM). Similarly, stretch-stimulated glucose uptake was not attenuated by deletion of either eNOS or nNOSµ isoforms. Furthermore, stretching failed to increase skeletal muscle NOS enzymatic activity above resting levels. These data clearly demonstrate that stretch-stimulated skeletal muscle glucose uptake is not dependent on NOS.
... In addition to its direct positive effects on cardiac function, apelin has been shown to increase the release of nitric oxide, which has many important functions in peripheral vasculature (Heinonen et al., 2011(Heinonen et al., , 2013 and in the heart (Seddon et al., 2007;Simon et al., 2014). Consequently, apelin may be one of the key mediators regulating myocardial function and circulation, which are positively affected by regular physical activity (Heinonen et al., 2008(Heinonen et al., , 2014a. ...
Article
Background: Apelin is a hormone that regulates cardiovascular function, and its concentration is increased by hypoxia based on cell culture and animal studies. As it remains unknown as to whether hypoxia could affect apelin levels in humans, we investigated whether breathing normobaric hypoxic gas mixture increases the circulating apelin concentration in healthy male subjects. Methods: Ten healthy young men (age 29 ± 5 years, body mass index 24.7 ± 2.8 kg/m(2)) breathed normobaric hypoxic gas mixture (11% O2/89% N2) for 1 hour. Venous blood samples were obtained immediately before, and 2 and 24 hours after the start of the hypoxic exposure and analyzed for circulating apelin concentrations. Results: Arterial oxygen saturation decreased steadily from a baseline value of 99% ± 1% after the initiation hypoxia challenge and reached a steady-state level of 73% ± 6% within 20-30 minutes. Baseline apelin concentration was 3.3 ± 1.3 pmol/L and remained comparable (3.3 ± 1.4 pmol/L) to the baseline concentration at a 2-hour time point. However, apelin concentration at the 24-hour time point (5.5 ± 2.8 pmol/L) was significantly (by ∼67%) higher as compared with at both baseline and 2-hour time points (p < 0.05). Conclusion: In conclusion, in line with cell culture and animal studies, acute systemic hypoxia increases circulating apelin concentration also in humans.
... There are at least three isoenzymes of NOS: constitutive neuronal NOS (nNOS or NOS-1), inducible NOS (iNOS or NOS-2), and constitutive endothelial NOS (eNOS or NOS-3), located on different chromosomes and expressed in different cell lines [218]. eNOS has been described as a major regulator of adipose tissue metabolism and energy balance by affecting lipolysis [219]. The adipose tissue and skeletal muscle of obese humans and rodents have decreased eNOS [220][221][222]. ...
Article
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Background Despite the fact that insertions/deletions (INDELs) are the second most common type of genetic variations and variable number tandem repeats (VNTRs) represent a large portion of the human genome, they have received far less attention than single nucleotide polymorphisms (SNPs) and larger forms of structural variation like copy number variations (CNVs), especially in genome-wide association studies (GWAS) of complex diseases like polygenic obesity. This is exemplified by the vast amount of review papers on the role of SNPs and CNVs in obesity, its related traits (like anthropometric measurements, biochemical variables, and eating behavior), and its related complications (like hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance—collectively known as metabolic syndrome). Hence, this paper reviews the types of INDELs and VNTRs that have been studied for association with obesity and its related traits and complications. Main body of the abstract These INDELs and VNTRs could be found in the obesity loci or genes from the earliest GWAS and candidate gene association studies, like FTO, genes in the leptin–proopiomelanocortin pathway, and UCP2/3. Given the important role of the brain serotonergic and dopaminergic reward system in obesity susceptibility, the association of INDELs and VNTRs in these neurotransmitters’ metabolism and transport genes with obesity is also reviewed. Next, the role of INS VNTR in obesity and its related traits is questionable, since recent large-scale studies failed to replicate the earlier positive associations. As obesity results in chronic low-grade inflammation of the adipose tissue, the proinflammatory cytokine gene IL1RA and anti-inflammatory cytokine gene IL4 have VNTRs that are implicated in obesity. A systemic proinflammatory state in combination with activation of the renin–angiotensin system and decreased nitric oxide bioavailability as found in obesity leads to endothelial dysfunction. This explains why VNTR and INDEL in eNOS and ACE, respectively, could be predisposing factors of obesity. Finally, two novel genes, DOCK5 and PER3, which are involved in the regulation of the Akt/MAPK pathway and circadian rhythm, respectively, have VNTRs and INDEL that might be associated with obesity. Short conclusion In conclusion, INDELs and VNTRs could have important functional consequences in the pathophysiology of obesity, and research on them should be continued to facilitate obesity prediction, prevention, and treatment.
... Although single inhibition of NOS does not affect blood flow in exercising skeletal muscles in humans (Bradley et al. 1999;Frandsenn et al. 2001;Heinonen et al. 2011;Radegran and Saltin 1999), NO has been shown regulate glucose (Bradley et al. 1999;Kingwell et al. 2002) and free fatty acid uptake (Heinonen et al. 2013a), and even oxygen consumption in the resting state (Heinonen et al. 2011). Furthermore, the effects of NO are not limited to skeletal muscle, as it also regulates blood flow in subcutaneous adipose tissue (Heinonen et al. 2011) in addition adenosine formation, which also regulates adipose tissue blood flow (Heinonen et al. 2012a). ...
Article
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Purpose: Animal studies suggest that the inhibition of nitric oxide synthase (NOS) affects blood flow differently in different skeletal muscles according to their muscle fibre type composition (oxidative vs glycolytic). Quadriceps femoris (QF) muscle consists of four different muscle parts: vastus intermedius (VI), rectus femoris (RF), vastus medialis (VM), and vastus lateralis (VL) of which VI is located deep within the muscle group and is generally regarded to consist mostly of oxidative muscle fibres. Methods: We studied the effect of NOS inhibition on blood flow in these four different muscles by positron emission tomography in eight young healthy men at rest and during one-leg dynamic exercise, with and without combined blockade with prostaglandins. Results: At rest blood flow in the VI (2.6 ± 1.1 ml/100 g/min) was significantly higher than in VL (1.9 ± 0.6 ml/100 g/min, p = 0.015) and RF (1.7 ± 0.6 ml/100 g/min, p = 0.0015), but comparable to VM (2.4 ± 1.1 ml/100 g/min). NOS inhibition alone or with prostaglandins reduced blood flow by almost 50% (p < 0.001), but decrements were similar in all four muscles (drug × muscle interaction, p = 0.43). During exercise blood flow was also the highest in VI (45.4 ± 5.5 ml/100 g/min) and higher compared to VL (35.0 ± 5.5 ml/100 g/min), RF (38.4 ± 7.4 ml/100 g/min), and VM (36.2 ± 6.8 ml/100 g/min). NOS inhibition alone did not reduce exercise hyperemia (p = 0.51), but combined NOS and prostaglandin inhibition reduced blood flow during exercise (p = 0.002), similarly in all muscles (drug × muscle interaction, p = 0.99). Conclusion: NOS inhibition, with or without prostaglandins inhibition, affects blood flow similarly in different human QF muscles both at rest and during low-to-moderate intensity exercise.
... As discussed, NO is considered a vasodilator; however, there are some inconsistencies with regards to its effects on metabolism. In resting muscle, inhibition of NO synthesis causes free fatty acid uptake, increased oxygen uptake, but not glucose uptake [68], and the authors proposed a possible contribution of an inhibitory effect of NO on mitochondrial respiration to explain their data; thus, the contribution of NO to basal metabolism may be slight. PET has been used to show that NO is involved in maintaining resting skeletal muscle blood flow, and suppresses resting muscle oxygen uptake, likely because NO competes with oxygen and inhibits mitochondrial respiration [19]; further studies demonstrated that NO may contribute to the regulation of free fatty acid metabolism at rest [68]. ...
... In resting muscle, inhibition of NO synthesis causes free fatty acid uptake, increased oxygen uptake, but not glucose uptake [68], and the authors proposed a possible contribution of an inhibitory effect of NO on mitochondrial respiration to explain their data; thus, the contribution of NO to basal metabolism may be slight. PET has been used to show that NO is involved in maintaining resting skeletal muscle blood flow, and suppresses resting muscle oxygen uptake, likely because NO competes with oxygen and inhibits mitochondrial respiration [19]; further studies demonstrated that NO may contribute to the regulation of free fatty acid metabolism at rest [68]. Thus, while NO is a known vasodilator, its role in metabolism is unclear. ...
Chapter
Skeletal muscle is a major metabolic organ that plays a critical role in regulating glucose homeostasis and lipid utilization. Impaired muscle metabolic response is evident in diseases such as diabetes, obesity and cardiovascular diseases, and is also often associated with microvascular dysfunction. Here, we investigate the changes that can occur in the muscle microvasculature and the profound impact they can have on metabolism. Under basal conditions, vasoactive compounds are able to affect metabolism in muscle by providing more glucose and oxygen to resting muscle. Insulin and exercise increase the perfusion of muscle, and thus provide more microvascular surface area, increasing the delivery of these metabolites to muscle. Endothelial dysfunction can therefore impair the delivery of oxygen, glucose and hormones to muscle, both through effects on blood flow distribution and the transport of these factors across the endothelium, leading to a decrease in oxygen consumption and glucose metabolism. Obesity and diabetes are associated with endothelial dysfunction and are accompanied by underlying changes in metabolism and reductions in insulin sensitivity. The muscle is a highly metabolic organ, and the vasculature is essential to maintain appropriate metabolic response; therefore, the muscle microcirculation may be a target for treating metabolic disease. Cathryn M Kolka (2016). The Skeletal Muscle Microvasculature and Its Effects on Metabolism, Microcirculation Revisited - From Molecules to Clinical Practice, Dr. Helena Lenasi (Ed.), InTech, Available from: http://www.intechopen.com/books/microcirculation-revisited-from-molecules-to-clinical-practice/the-skeletal-muscle-microvasculature-and-its-effects-on-metabolism