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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.
Source publication
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...
Contexts in source publication
Context 1
... 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). ...Context 2
... 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). ...Citations
... However, the reports of its role in glucose metabolism are incongruent. Some research on both humans and animals claimed that blocking NOS during exercise had no effect on the uptake of glucose by the skeletal muscle [19,20]. In contrast, Higaki et al. [21] and Durham et al. [22] reported that nitric oxide plays a role in the uptake of glucose by skeletal muscle. ...
... The disparity in the studies above might be due to the type of exercise model used in these studies. For instance, in the Bradley et al. [24] study, the subjects were engaged in cycling exercise, while Heinonen et al. [20] positioned the right legs of the subjects in an inhouse-designed leg exercise dynamometer. Negating the studies above, other studies reported that inhibition of NOS reduces blood glucose level and administration of nitric oxide donor increases blood glucose concentration [28][29][30]. ...
... Total antioxidant capacity was evaluated by dissolving 0.2g of APB in 1 mL of distilled water. 0.1 mL of APB and different concentrations of ascorbic acid solution (20,40,60,80, and 100 μg/mL), which act as the standard, were measured into separate test tubes. Then 1mL of the reagent solution (0.6 M sulfuric acid, 28mM sodium phosphate, and 4mM ammonium molybdate) was added to each of them. ...
There is evidence that nitric oxide (NO) modulates the metabolism of glucose and lipid, and some antihypertensive medications have been shown to affect glucose and lipid metabolism. Peristrophe bivalvis is a medicinal plant that has been shown to have antihypertensive properties. The study investigated the effect of aqueous extract of Peristrophe bivalvis leaf (APB) on fasting blood glucose level (FBG) and lipid profile in rats pretreated with nitro-L-arginine methyl ester (L-NAME). Male Wistar rats (150–170 g, n=30) were randomly divided into two groups: control (CT, n=5) and L-NAME pretreated (n=25). CT received 5 mL/kg of distilled water [DW]) while L-NAME pretreated group received 60 mg/kg of L-NAME (L-NAME60) for eight weeks. After eight weeks, the L-NAME pretreated group was randomly subdivided into L-NAME group (LN), L-NAME recovery group (LRE), L-NAME ramipril group (LRA), and L-NAME APB group (LAPB). The groups received L-NAME60+DW, DW, L-NAME60+10 mg/kg ramipril, and L-NAME60+APB (200 mg/kg), respectively, for five weeks. Serum NO, lipid profile, cyclic guanosine monophosphate (cGMP), and insulin were measured by spectrophotometry, assay kits, and ELISA, respectively. Data were analysed using ANOVA at p < 0.05. At the eighth week, a fall in FBG and an increase in triglyceride, total cholesterol, and low-density lipoprotein cholesterol were recorded in L8 compared to CT. The same effects were also noticed in the thirteenth week in LN. However, FBG was significantly increased and lipid levels were decreased in LAPB compared to LN. A significant increase was observed in cGMP level in LAPB compared to LN. The study showed that APB corrected the hyperlipidemia and hypoglycemia caused by L-NAME, and this effect might be via the activation of cGMP.
... Pharmacological inhibition of NOS inhibits exercise-mediated glucose transport in human [168,169] and rodent [167,170] skeletal muscles. However, other studies show that NOS inhibitors do not affect exercise-mediated glucose transport [171,172]. The discrepancy in the literature could be due to the intensity of the exercise, as studies suggest that glucose uptake at rest and low-moderate intensity are not nitric oxide mediated [171,173], while it is for high intensity exercise [168,169]. ...
... However, other studies show that NOS inhibitors do not affect exercise-mediated glucose transport [171,172]. The discrepancy in the literature could be due to the intensity of the exercise, as studies suggest that glucose uptake at rest and low-moderate intensity are not nitric oxide mediated [171,173], while it is for high intensity exercise [168,169]. ...
Insulin signaling plays a key role in glucose uptake, glycogen synthesis, and protein and lipid synthesis. In insulin-resistant states like obesity and type 2 diabetes mellitus, these processes are dysregulated. Regular physical exercise is a potential therapeutic strategy against insulin resistance, as an acute bout of exercise increases glucose disposal during the activity and for hours into recovery. Chronic exercise increases the activation of proteins involved in insulin signaling and increases glucose transport, even in insulin resistant states. Here, we will focus on the effect of acute exercise on insulin signaling and protein kinase B (Akt) pathways. Activation of proximal proteins involved in insulin signaling (insulin receptor, insulin receptor substrate-1 (IRS-1), phosphoinoside-3 kinase (PI3K)) are unchanged in response to acute exercise/contraction, while activation of Akt and of its substrates, TBC1 domain family 1 (TBC1D1), and TBC domain family 4 (TBC1D4) increases in response to such exercise/contraction. A wide array of Akt substrates is also regulated by exercise. Additionally, AMP-activated protein kinase (AMPK) seems to be a main mediator of the benefits of exercise on skeletal muscle. Questions persist on how mTORC1 and AMPK, two opposing regulators, are both upregulated after an acute bout of exercise.
... 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). ...
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. ...
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]. ...
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. ...
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]. ...
... 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). ...
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. ...
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]. ...
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.
