Nitric Oxide Production In Humans Research Articles

Beetroot Juice Supplementation Lowers Oxygen Cost of Vigorous Intensity Aerobic Exercise in Trained Endurance Athletes

Nitric oxide (NO) plays a critical role in regulating blood flow to skeletal muscle. NO production in humans is 1) oxygen-dependent via NO-synthases that convert L-arginine to NO and 2) oxygen-independent via the nitrate-nitrite-NO pathway. The latter can be augmented via beetroot juice supplementation (BR). PURPOSE: The purpose of this study was to investigate the effect of BR during vigorous intensity aerobic exercise. METHODS: Using a double-blind, repeated measures crossover design, 11 Division III collegiate distance runners (mean ± SD: age = 20.3 ± 1.1 yr; VO peak = 55.5 ± 8.1 ml·kg-1·min-1) consumed either 120 mL·day-1 of BR or placebo (PL) for 4 days. On day 5 of each 4-day supplementation period, subjects completed an exercise trial on a motorized treadmill consisting of five minutes of running at 65%, 85%, and 100% of volume of oxygen uptake reserve (VO2R) separated by 2 minutes each. BR and PL supplementation protocols were separated by a 7-day washout period. Two-way repeated measures ANOVAs were used to determine the effect of treatment (BR or PL) and exercise intensity (65%, 85%, and 100% VO2R) on VO2, heart rate (HR), respiratory exchange ratio (RER), and rating of perceived exertion (RPE). RESULTS: There were no statistically significant interactions between treatment and exercise intensity for VO2, HR, RER, or RPE. The main effect of treatment was not statistically significant for HR, F(1, 10) = 0.514, p = 0.490; RER, F(1, 9) = 0.590, p = 0.462; or RPE F(1, 10) = 0.562, p = 0.471. However, the main effect of treatment was statistically significant for VO , where BR (2.43±0.18 L·min-1) was lower compared to PL (2.49±0.17 L·min-1), p = 0.029. CONCLUSIONS: These results suggest that a 4-day protocol of 120 mL·day-1 of BR reduces VO during vigorous intensity aerobic exercise in trained endurance athletes.

No Effect of Acute Beetroot Juice Supplementation on Moderate and Vigorous Intensity Aerobic Exercise

Nitric oxide (NO) plays a critical role in regulating blood flow to skeletal muscle. NO production in humans is 1) oxygen-dependent via NO-synthases that convert L-arginine to NO and 2) oxygen-independent via the nitrate-nitrite-NO pathway. The latter pathway is largely dependent on the intake of nitrate-rich foods, such as beetroot and beetroot juice supplements (BR). Consumption of BR has been shown to lower resting blood pressure and the volume of oxygen (VO2) required to perform submaximal aerobic exercise. PURPOSE: The purpose of the present study was to investigate the acute effect of a low dose of BR compared to placebo (PL) during moderate and vigorous intensity aerobic exercise. METHODS: Ten female division-3 collegiate club-level volleyball players (mean ± SD: age = 19.3 ± 1.3 yr, VO2peak = 37.4 ± 3.3 ml·kg-1·min-1) completed three exercise trials consisting of an initial graded test to exhaustion and two performance trials on a motorized treadmill. For the performance trials, participants consumed either 60 mL of BR or PL, three hours prior to five minutes of walking/jogging at 45%, 65%, and 85% of volume of oxygen uptake reserve (VO2R). RESULTS: Separate two-way repeated measures ANOVAs were run to determine the effect of treatment (BR or PL) and exercise intensity (45%, 65%, and 85% VO2R) on VO2, heart rate (HR), and rating of perceived exertion (RPE). Paired samples t-tests were run to compare differences between resting systolic (SBP) and diastolic blood pressure (DBP) between treatments. All data are reported mean ± standard deviation with statistical significance accepted at p < 0.05. There were no statistically significant interactions between treatment and exercise intensity for VO2, HR, or RPE. The main effect of treatment was not statistically significantly different for VO2 (BR: 19.9 ± 6.6 vs. PL: 20.4 ± 6.5 ml·kg-1·min-1; p = .360), HR (BR: 131.3 ± 25.8 vs. PL: 135.4 ± 25.3 beats·min-1; p = .172), or RPE (BR: 9.8 ± 2.2 vs. PL: 9.9 ± 2.4; p = .504). There were no statistically significant differences in resting SBP (BR: 110.6 ± 6.8 vs. PL: 112.7 ± 8.0; p = .166) or DBP (BR: 70.8 ± 5.5 vs. PL: 73.3 ± 6.6; p = .275) between treatments. CONCLUSIONS: These results suggest that a low dose of BR taken three hours prior to moderate and vigorous intensity aerobic exercise has no effect on VO2, HR, RPE, or resting SBP and DBP.

Arginine and nitric oxide synthase: Regulatory mechanisms and cardiovascular aspects

L-Arginine (L-Arg) is a conditionally essential amino acid in the human diet. The most common dietary sources of L-Arg are meat, poultry and fish. L-Arg is the precursor for the synthesis of nitric oxide (NO); a key signaling molecule via NO synthase (NOS). Endogenous NOS inhibitors such as asymmetric-dimethyl-L-Arg inhibit NO synthesis in vivo by competing with L-Arg at the active site of NOS. In addition, NOS possesses the ability to be "uncoupled" to produce superoxide anion instead of NO. Reduced NO bioavailability may play an essential role in cardiovascular pathologies and metabolic diseases. L-Arg deficiency syndromes in humans involve endothelial inflammation and immune dysfunctions. Exogenous administration of L-Arg restores NO bioavailability, but it has not been possible to demonstrate, that L-Arg supplementation improved endothelial function in cardiovascular disease such as heart failure or hypertension. L-Arg supplementation may be a novel therapy for obesity and metabolic syndrome. The utility of l-Arg supplementation in the treatment of L-Arg deficiency syndromes remains to be established. Clinical trials need to continue to determine the optimal concentrations and combinations of L-Arg, with other protective compounds such as tetrahydrobiopterin (BH4 ), and antioxidants to combat oxidative stress that drives down NO production in humans.

Effect of L-arginine supplementation on NO production in man

L-arginine is the substrate for the enzyme nitric oxide synthase (NOS), which is responsible for the production of nitric oxide (NO), an endogenous messenger molecule involved in many of the processes associated with the development of atherosclerosis. Acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis. Therefore, numerous studies have been conducted to elucidate whether dietary L-arginine supplementation can augment NO production in humans and thereby improve vascular health. In this review, the results of studies of intravenous and oral L-arginine supplementation with a wide spectrum of doses, study duration, and surrogate parameters of endothelial function are summarized. The pharmacokinetics of L-arginine have been investigated; side effects are rare and mostly mild and dose-dependent. Several possible mechanisms of action of L-arginine are discussed. An evaluation of L-arginine as a therapeutic agent from the point of view of a clinical pharmacologist is given.

Aconiti tuber increases plasma nitrite and nitrate levels in humans

Some herbal medicines, including Aconiti tuber ( Aconitum carmichaeli Debeaux, Ranunculaceae), have been recognized as being effective for the treatment of a “peripheral uncomfortable feeling of cold ( hie)”. We hypothesized that these compounds affect peripheral vascular function via the nitric oxide (NO) system, which leads to recovery from “ hie”. To answer this question, we investigated Aconiti tuber-induced changes in plasma levels of nitrite (p-NO 2 −) and nitrate (p-NO 3 −), final nitric oxide-oxidation products measurable in vivo. After written informed consent was obtained, patients suffering from “ hie” were treated with several kinds of kampo (Japanese traditional herbal medicine), selected on the basis of traditional theory. Twenty-four patients took kampo formulas, some included Aconiti tuber ( n = 11; A-group) and others did not ( n = 13; C-group), for 4 weeks. p-NO 2 − and p-NO 3 − levels were measured before the start and after 4 weeks of treatment. In the A-group, the p-NO 2 − plus p-NO 3 − (p-NO x ) level was significantly increased at 4 weeks ( p = 0.04), while that of the C-group was not. There was a statistically significant increase in the p-NO x level of the A-group as compared to the C-group (d.f. = 1,22, F = 9.38, p = 0.006). The results suggest that Aconiti tuber may increase NO production in humans.

Rapid regulation of platelet activation in vivo by nitric oxide.

Platelet activation is a feature of many cardiovascular diseases characterized by endothelial dysfunction. The mechanistic relationship between impaired systemic nitric oxide (NO) bioavailability and platelet activation in vivo remains unclear. We investigated whether acute inhibition of NO production in humans modulates platelet activation in vivo and whether exogenous NO would counteract such an effect. Intravenous injection of the NO synthase inhibitor N(G)-monomethyl-l-arginine in healthy volunteers resulted in NO synthase inhibition as detected by increased blood pressure and by significantly reduced phosphorylation of platelet vasodilator-stimulated phosphoprotein, an indicator of NO signaling. NO synthase inhibition increased platelet activation as determined by enhanced platelet binding of fibrinogen and surface expression of P-selectin, glycoprotein 53, and CD40 ligand, demonstrating tonic inhibition of platelet activation by NO production in vivo. Sublingual administration of the NO donor glyceryl trinitrate normalized platelet VASP phosphorylation and restored markers of platelet activation to baseline levels. Acute inhibition of endogenous NO production in humans causes rapid platelet activation in vivo, which is reversed by exogenous NO, demonstrating that platelet function in vivo is rapidly regulated by NO bioavailability.

Intestinal nitric oxide output during reduced mucosal blood flow in healthy volunteers.

Nitric oxide regulates epithelial permeability and other properties of the intestinal mucosal barrier. It previously has been shown in animals that intestinal mucosal nitric oxide production is impaired during gut hypoperfusion. The study was performed to confirm the presence of intestinal mucosal nitric oxide production in humans and to investigate the effect of gut hypoperfusion due to moderate arterial hypotension on intestinal nitric oxide concentrations. Open study where each subject served as his own control. Clinical research laboratory. Nine healthy volunteers were intubated with a nasogastrointestinal tube for recordings in the distal duodenum. Intestinal nitric oxide output and motility were assessed by tonometry and manometry, respectively. Laser Doppler flowmetry and plasma angiotensin II concentration were used to investigate mucosal perfusion and a vasoregulatory response. Moderate hypotension was induced with lower body negative pressure over 1 hr. Intestinal nitric oxide production varied in parallel with the migrating motor complex. Low values were obtained during phase I and peak values during phase III. Lower body negative pressure was initiated at a well-defined point in the migrating motor complex cycle. It was followed by a 40 +/- 6% reduction of laser Doppler flow signal, a 778 +/- 138% increase in angiotensin II, and a reduction in intestinal mucosal nitric oxide production by 48 +/- 8%. After lower body negative pressure, laser Doppler signal and angiotensin II concentrations returned to baseline levels within 1 hr, whereas intestinal nitric oxide output remained decreased. Intestinal tonometry in humans exhibits a considerable mucosal nitric oxide formation that varies in relation to intestinal motility. Intestinal nitric oxide production is depressed during conditions with lowered mucosal blood perfusion.

Influence of sex and age on serum nitrite/nitrate concentration in healthy subjects

Measurement of serum nitrite/nitrate (NO x) concentrations has been considered useful to estimate nitric oxide production in humans. However little is known about the physiologic range and the factors affecting serum NO x levels. The aim of this study was, thus, to investigate the influence of sex and age on serum NO x levels in healthy subjects. We selected 263 healthy subjects (118 women and 145 men, 20–69 y) from 505 consecutive subjects who received annual medical checkups at our hospital. Serum NO x levels were determined using an analyzer employing the Griess method. The linear regression analysis showed that NO x increased significantly according to age in women ( r=0.22, P<0.05), but did not in men ( P=NS). Women of the younger age group (<40 y) showed significantly lower NO x levels than men of the same age group ( P<0.05), whereas there was no significant difference between men and women of the older age (≥40 y). Then, to investigate whether menopause affects serum NO x levels, middle aged women (46–55 y) were selected. Multiple logistic regression analysis showed that menopause was an independent factor for increased serum NO x levels in middle aged women ( r=0.4, P<0.05). These results suggest that the serum NO x concentration is affected by age in healthy women, possibly depending on menopausal state.

Recent developments in the treatment of osteoarthritis

1. Summary Osteoarthritis (OA) is a worldwide heterogeneous group of conditions that lead to joint symptoms and signs which are associated with defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margins. The prevalence of the disease after the age of 65 years is about 60% in men and 70% in women. The aetiology of OA is multifactorial, with the end result being mechanical joint failure and varying degrees of loss of joint function. The pathophysiological events associated with OA are beginning to be understood. Inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor-α (TNF-α) are involved, and these initiate a vicious cycle of catabolic and degradative events in cartilage mediated by metalloproteinases, which degrade cartilage extracellular matrix. The role of inflammation in the pathophysiology and progression of early OA is supported further by the observation that C-reactive protein (CRP) levels are raised in women with early knee OA, and higher levels predicted those whose disease would progress. Nitric oxide (NO) is another potent pro-inflammatory chemical released during inflammation. Cartilage from patients with rheumatoid arthritis (RA) and OA spontaneously produces NO in vitro, and in experimental OA, NO induces chondrocyte apoptosis, thus contributing to cartilage degradation. Hence, dysregulated NO production in humans plays a part in the pathophysiology of the disease. These recent observations suggest that therapy can now be targeted at specific pathophysiological pathways involved in the pathogenesis of OA. The

Nonenzymatic Nitric Oxide Production in Humans

The tiny diatomic gas nitric oxide is synthezised in biological systems by complex enzymes known as nitric oxide synthases. Recently, a novel pathway for NO production in humans was discovered that involves chemical reduction of inorganic nitrite, a reaction that takes place predominantly during acidic and reducing conditions. Nonenzymatic NO production has been demonstrated, e.g., in the stomach, on the surface of the skin, in the ischemic heart, and in infected nitrite-containing urine. NO produced by this mechanism is likely to play a role in similar biological events as when produced froml-arginine by NO synthases.

Nitric oxide production during Vibrio cholerae infection.

Vibrio cholerae induces massive intestinal fluid secretion that continues for the life of the stimulated epithelial cells. Enhanced regional blood flow and peristalsis are required to adapt to this obligatory intestinal secretory challenge. Nitric oxide (NO) is a multifunctional molecule that modulates blood flow and peristalsis and possesses both cytotoxic and antibacterial activity. We demonstrate that, compared with those in asymptomatic control subjects, levels of stable NO metabolites (NO2-/NO3-) are significantly increased in sera from acutely ill Peruvian patients with natural cholera infection as well as from symptomatic volunteers from the United States infected experimentally with V. cholerae. In a rabbit ileal loop model in vivo, cholera toxin (CT) elicited fluid secretion and dose-dependent increases in levels of NO2-/NO3- in the fluid (P < 0.01). In contrast, lipopolysaccharide (LPS) elicited no such effects when applied to the intact mucosa. NO synthase (NOS) catalytic activity also increased in toxin-exposed tissues (P < 0.05), predominantly in epithelial cells. The CT-induced NOS activity was Ca2+ dependent and was not suppressed by dexamethasone. In conclusion, symptomatic V. cholerae infection induces NO production in humans. In the related animal model, CT, but not LPS, stimulated significant production of NO in association with increases in local Ca(2+)-dependent NOS activity in the tissues.

Experimentally induced acute hyperinsulinemia stimulates endogenous nitric oxide production in humans: Detection using urinary [formula omitted] excretion

Insulin-mediated glucose metabolism in skeletal muscle is associated with a proportional increase in muscle perfusion. The vasodilatory effect of insulin is thought to be mediated in part by endothelium-derived nitric oxide (NO). The present study was performed to determine whether acute hyperinsulinemia has any stimulatory effect on endogenous NO production in humans. Bolus intravenous injection of insulin (0.1 IU/kg body weight) caused a significant increase in urinary excretion of NO 2 − NO 3 − together with a significant decrease in blood pressure, whereas saline infusion alone had no effect on these parameters. The increased NO response to insulin was almost comparable to that obtained with infusion of 30 g l-arginine. The acute effect of hyperinsulinemia on endogenous NO formation supports the concept that NO may mediate the vasodilatory action of insulin in humans.

Intragastric nitric oxide production in humans: measurements in expelled air.

High values (800-6000 parts per billion) of nitric oxide (NO) in expelled air from the stomach were shown in humans by chemiluminescence technique. These NO values were more than 100 times higher than those found in orally exhaled air. Intragastric NO production is probably non-enzymatic, requiring an acidic environment, as NO in expelled air was reduced by 95% after pretreatment with the proton pump inhibitor omeprazole. Furthermore, large amounts of NO were formed in vitro from lettuce and saliva when placed in hydrogen chloride (pH < 2). In conclusion, large amounts of NO are formed intragastrically in humans and this source of NO may be of importance for the integrity of the gastric mucosa in health and disease. Measurements of NO in expelled air might be of value as a non-invasive method for estimation of gastric acidity.