Nitric Oxide End Products Research Articles

Effect of hypoandrogenism on expression of transient receptor potential vanilloid channels in rat penile corpus cavernosum and erectile function.

Hypoandrogenism is a cause of erectile dysfunction (ED). Vascular smooth muscle cell contraction and relaxation are regulated by TRPV1-4 channels. However, the influence of hypoandrogenism on TRPV1-4 and its relationship with erectile function remain unclear. To reveal whether hypoandrogenism affects erectile function by influencing TRPV1-4 expression in the corpus cavernosum of rats. Male Sprague-Dawley rats (N = 36) aged 8 weeks were assigned to 6 groups at random (n = 6): sham operation, castrated, castrated + testosterone replacement, sham operation + transfection, castrated + transfection, and castrated + empty transfection. Four weeks after castration, 20μL of lentiviral vector (1 × 108 TU/mL) carrying the TRPV4 gene was injected into the penile cavernous tissue of the transfection groups. One week after transfection, the maximum intracavernous pressure (ICPmax)/mean arterial pressure (MAP) and the content of TRPV1-4, phosphorylated eNOS (p-eNOS)/eNOS, and nitric oxide (NO) in penile cavernous tissue of each group were measured. Under low androgen conditions, TRPV4 expression in endothelial cells in the rat penile cavernosum was sharply reduced, resulting in a decrease in p-eNOS/eNOS and NO content, which could inhibit erectile function. In rat penile cavernous tissue, TRPV1-4 was expressed in the cell membranes of endothelial cells and smooth muscle cells. The ICPmax/MAP and the content of TRPV4, p-eNOS/eNOS, and NO end product nitrite level in rat penile cavernous tissue was markedly reduced in the castrated group as compared with the sham group (P < .05). The ICPmax/MAP and the content of TRPV4, p-eNOS/eNOS, and NO end product nitrite level in rat penile cavernous tissue were markedly improved in the castrated + transfection group vs the castrated group (P < .01). Upregulation of TRPV4 expression in penile cavernosum tissue might be a viable therapeutic for ED caused by hypoandrogenism. The specific mechanism of TRPV4 in ED needs to be further verified by androgen receptor or TRPV4 gene knockout experiments. Hypoandrogenism may cause ED by reducing the expression of TRPV4 in rat penile cavernous tissue. Upregulation of TRPV4 expression in penile cavernous tissue can increase the ratio of p-eNOS/eNOS and NO levels and ameliorate the erectile function of castrated rats.

Study of blood rheological parameters and NO in coronary artery disease patients with and without collaterals.

In coronary artery disease (CAD), an alternative way of improvement of blood circulation in the ischemic area of the myocardium is coronary collateral circulation. Our study aimed to investigate the rheological parameters of blood and nitric oxide (NO) content in patients with various degrees of collateral development and the likelihood of the influence of blood fluidity on collateral angiogenesis. We studied patients with stable CAD who underwent elective coronary angiography and a control group with the same mean age. We investigated patients with different degrees of developing collaterals and those without them. In studied patients, the blood plasma viscosity, aggregability, and deformability of erythrocytes, as the main indicators of blood rheology. We recorded content of stable metabolic end products of nitric oxide (NOx). Results of the studies showed that in the blood of studied patients with CAD erythrocyte aggregation was increased and NO content decreased compared to the control level; NO content was as lower, as less was the number of developed collaterals was recorded. In this work, the role of the aggregation ability of erythrocytes and the endothelial origin of NO in the direct and feedback regulatory mechanism of angiogenesis in patients with CAD are discussed.

Influence of coffee roasting degree on inflammatory and oxidative stress markers in high-fructose and saturated fat-fed rats

The objective of this study was to evaluate the effect of roasting coffee degree on inflammatory (NF-kβ F-6 and TNF-α) and stress oxidative markers (malondialdehyde (MDA), nitric oxide (NO) end product concentrations, catalase (CAT), and superoxide dismutase (SOD) in high-fructose and saturated fat (HFSFD)-fed rats. Roasting was performed using hot air circulation (200 °C) for 45 and 60 min, obtaining dark and very dark coffee, respectively. Male Wistar rats were randomly assigned to receive a) unroasted coffee, b) dark coffee, c) very dark coffee, or distilled water for the control group (n = 8). Coffee brews (7.4 mL/per day equivalent to 75 mL/day in humans) were given by gavage for sixteen weeks. All treated groups significantly decreased NF-kβ F-6 (∼30 % for unroasted, ∼50 % for dark, and ∼ 75 % for very dark group) and TNF-α in the liver compared with the control group. Additionally, TNF-α showed a significant reduction in all treatment groups (∼26 % for unroasted and dark groups, and ∼ 39 % for very dark group) in adipose tissue (AT) compared with the negative control. Regarding oxidative stress makers, all coffee brews exerted antioxidant effects in serum, AT, liver, kidney, and heart.Our results revealed that the anti-inflammatory and antioxidant effects of coffee vary according to the roasting degree in HFSFD-fed rats.

Biological Assessment of the NO-Dependent Endothelial Function.

Nitric oxide (NO) is implicated in numerous physiological processes, including vascular homeostasis. Reduced NO bioavailability is a hallmark of endothelial dysfunction, a prequel to many cardiovascular diseases. Biomarkers of an early NO-dependent endothelial dysfunction obtained from routine venous blood sampling would be of great interest but are currently lacking. The direct measurement of circulating NO remains a challenge due by its high reactivity and short half-life. The current techniques measure stable products from the NO signaling pathway or metabolic end products of NO that do not accurately represent its bioavailability and, therefore, endothelial function per se. In this review, we will concentrate on an original technique of low temperature electron paramagnetic resonance spectroscopy capable to directly measure the 5-α-coordinated heme nitrosyl-hemoglobin in the T (tense) state (5-α-nitrosyl-hemoglobin or HbNO) obtained from fresh venous human erythrocytes. In humans, HbNO reflects the bioavailability of NO formed in the vasculature from vascular endothelial NOS or exogenous NO donors with minor contribution from erythrocyte NOS. The HbNO signal is directly correlated with the vascular endothelial function and inversely correlated with vascular oxidative stress. Pilot studies support the validity of HbNO measurements both for the detection of endothelial dysfunction in asymptomatic subjects and for the monitoring of such dysfunction in patients with known cardiovascular disease. The impact of therapies or the severity of diseases such as COVID-19 infection involving the endothelium could also be monitored and their incumbent risk of complications better predicted through serial measurements of HbNO.

COX/iNOS dependence for angiotensin-II-induced endothelial dysfunction

Vascular dysfunction induced by angiotensin-II can result from direct effects on vascular and inflammatory cells and indirect hemodynamic effects. Using isolated and functional cultured aortas, we aimed to identify the effects of angiotensin-II on cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS) and evaluate their impact on vascular reactivity.Aortic rings from mice were incubated overnight in culture medium containing angiotensin-II (100 nmol/L) or vehicle to induce vascular disfunction. Vascular reactivity of cultured arteries was evaluated in a bath chamber. Immunofluorescence staining for COX-1 and COX-2 was performed. Nitric oxide (NO) formation was approached by the levels of nitrite, a NO end product, and using a fluorescent probe (DAF). Oxidative and nitrosative stress were determined by DHE fluorescence and nitrotyrosine staining, respectively.Arteries cultured with angiotensin-II showed impairment of endothelium-dependent relaxation, which was reversed by the AT1 receptor antagonist. Inhibition of COX and iNOS restored vascular relaxation, suggesting a common pathway in which angiotensin-II triggers COX and iNOS, leading to vasoconstrictor receptors activation. Moreover, using selective antagonists, TP and EP were identified as the receptors involved in this response. Endothelium-dependent contractions of angiotensin-II-cultured aortas were blunted by ibuprofen, and increased COX-2 immunostaining was found in the arteries, indicating endothelium release of vasoconstrictor prostanoids. Angiotensin-II induced increased reactive oxygen species and NO production. An iNOS inhibitor prevented NO enhancement and nitrotyrosine accumulation in arteries stimulated with angiotensin-II.These results confirm that angiotensin-II causes vascular inflammation that culminates in endothelial dysfunction in an iNOS and COX codependent manner.

Plasma Nitrate Levels Are Related to Metabolic Syndrome and Are Not Altered by Treatment with DPP-4 Inhibitor Linagliptin: A Randomised, Placebo-Controlled Trial in Patients with Early Type 2 Diabetes Mellitus.

The depletion of nitrate and nitrite, stable nitric oxide (NO) end-products, promotes adipose tissue dysfunction and insulin resistance (IR). Dipeptidyl peptidase-4 (DPP-4) inhibitors have the potentially beneficial side effect of increasing NO availability. In this study, nitrate and nitrite levels and the effects of DPP-4 inhibitor linagliptin were investigated in relation to metabolic syndrome (MetS) markers. Treatment-naive patients with early type 2 diabetes mellitus (T2DM) (n = 40, median age 63 IQR (55–67) years, 63% male, mean HbA1c 45 ± 4.4 mmol/mol) were randomized (1:1) to linagliptin (5 mg/day) or placebo. MetS-related markers (body mass index (BMI), triglycerides, HOMA-IR, gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and adiponectin), plasma levels of nitrate, nitrite, total free thiols (TFT) and vegetable intake were estimated at baseline and after 4 and 26 weeks of treatment. Plasma nitrate, but not nitrite, correlated positively with vegetable intake (r = 0.38, p = 0.018) and was inversely associated with HOMA-IR (r = −0.44, p = 0.006), BMI (r = −0.35, p = 0.028), GGT (r = −0.37, p = 0.019) and CRP (r = −0.34, p = 0.034). The relationship between nitrate and HOMA-IR remained significant after adjusting for BMI, CRP, vegetable intake and GGT. With stable vegetable intake, nitrate and nitrite, TFT, adipokines and CRP did not change after 26 weeks of linagliptin treatment. While plasma nitrate is inversely associated with MetS, linagliptin treatment does not significantly influence nitrate and nitrite concentrations, oxidative stress, adipose tissue function and systemic inflammation.

Implication of Blood Rheology and Pulmonary Hemodynamics on Exercise-Induced Hypoxemia at Sea Level and Altitude in Athletes.

This study aimed to investigate the changes in blood viscosity, pulmonary hemodynamics, nitric oxide (NO) production, and maximal oxygen uptake (V˙O2max) during a maximal incremental test conducted in normoxia and during exposure to moderate altitude (2,400m) in athletes exhibiting exercise-induced hypoxemia at sea level (EIH). Nine endurance athletes with EIH and eight without EIH (NEIH) performed a maximal incremental test under three conditions: sea level, 1 day after arrival in hypoxia, and 5 days after arrival in hypoxia (H5) at 2,400m. Gas exchange and oxygen peripheral saturation (SpO2) were continuously monitored. Cardiac output, pulmonary arterial pressure, and total pulmonary vascular resistance were assessed by echocardiography. Venous blood was sampled before and 3min after exercise cessation to analyze blood viscosity and NO end-products. At sea level, athletes with EIH exhibited an increase in blood viscosity and NO levels during exercise while NEIH athletes showed no change. Pulmonary hemodynamics and aerobic performance were not different between the two groups. No between-group differences in blood viscosity, pulmonary hemodynamics, and V˙O2max were found at 1 day after arrival in hypoxia. At H5, lower total pulmonary vascular resistance and greater NO concentration were reported in response to exercise in EIH compared with NEIH athletes. EIH athletes had greater cardiac output and lower SpO2 at maximal exercise in H5, but no between-group differences occurred regarding blood viscosity and V˙O2max. The pulmonary vascular response observed at H5 in EIH athletes may be involved in the greater cardiac output of EIH group and counterbalanced the drop in SpO2 in order to achieve similar V˙O2max than NEIH athletes.

Preparation of Rat Skeletal Muscle Homogenates for Nitrate and Nitrite Measurements.

Nitrate ions (NO3-) were once thought to be inert end products of nitric oxide (NO) metabolism. However, previous studies demonstrated that nitrate ions can be converted back to NO in mammals through a two-step reduction mechanism: nitrate being reduced to nitrite (NO2-) mostly by oral commensal bacteria, then nitrite being reduced to NO by several mechanisms including via heme- or molybdenum-containing proteins. This reductive nitrate pathway contributes to enhancing NO-mediated signaling pathways, particularly in the cardiovascular system and during muscular exercise. The levels of nitrate in the body before such utilization are determined by two different sources: endogenous NO oxidation and dietary nitrate intake, principally from plants. To elucidate the complex NO cycle in physiological circumstances, we have examined further the dynamics of its metabolites, nitrate and nitrite ions, which are relatively stable compared to NO. In previous studies skeletal muscle was identified as a major storage organ for nitrate ions in mammals, as well as a direct source of NO during exercise. Therefore, establishing a reliable methodology to measure nitrate and nitrite levels in skeletal muscle is important and should be helpful in extending its application to other tissue samples. This paper explains in detail the preparation of skeletal muscle samples, using three different homogenization methods, for nitrate and nitrite measurements and discusses important issues related to homogenization processes, including the size of the samples. Nitrate and nitrite concentrations have also been compared across four different muscle groups.

Psoriasis, An inflammatory condition associated with oxidative stress

Background: Psoriasis is a chronic inflammatory skin disease characterized by pathological skin lesions due to various exogenous and endogenous factors. Oxidative stress can be one of the causes for the occurrence of psoriasis as well as significant contributor to its progression. Skin exposure to a number of irritants or proinflammatory agents including UVA and UVB generates ROS through the oxidative burst in infiltrating leukocytes at the site of inflammation which damages the skin cells. Measurement of the oxidative stress marker like lipid peroxidation product Malondialdehyde (MDA) and Nitric Oxide end products (NO2+NO3) along with the inflammatory marker hs-CRP in Psoriasis patients can uncover their role in disease causation, progression and development of various co-morbidities and timely prevention can significantly improve the quality of life of the psoriasis patients.&#x0D; Aims and Objectives: To measure the oxidative stress marker like lipid peroxidation product Malondialdehyde (MDA) and Nitric Oxide end products (NO2+NO3) along with the inflammatory marker hs-CRP in Psoriasis patients to uncover their role in disease causation, progression and development of various co-morbidities and timely prevention to significantly improve the quality of life of the psoriasis patients.&#x0D; Materials and Methods: Fifty patients of psoriasis mainly plaque type of either sex, in the age group of 35 ± 15.5 (range: 7-79) years were taken following inclusion and exclusion criteria. To evaluate the oxidative stress lipid peroxidation product malondialdehyde (MDA) and Nitric Oxide end products (NO2 + NO3) were measured. hs-CRP was measured as an inflammatory marker and their correlation with the disease severity and duration was evaluated.&#x0D; Results: A significant increase in malondialdehyde (MDA), Nitric Oxide end products (NOx) and hs-CRP levels (P&lt;0.001) was noted in Psoriatic patients as compared to controls. There was a positive correlation between MDA, NOx and hs-CRP levels with the severity and duration of the disease. The correlation between hs-CRP and MDA and NOx also showed positive trend.&#x0D; Conclusion: Oxidative stress is one of the factors which can lead to the causation of Psoriasis and also significantly contribute to the disease progression and development of various co-morbidities. By measuring the oxidative stress marker and inflammatory marker in psoriasis patients early in the disease process we can employ preventive strategies for better management and improve the survival and quality of life.

Is there a gender difference in endothelial response on exercise training in heart failure patients with preserved ejection fraction?

Abstract Purpose To examine the reaction of endothelium, assess through changes of circulating blood markers of endothelial function: the stable end products of nitric oxide (NOx), S – nitrosothiols (RSNO – reservoir for bioavailable nitric oxide), dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) that promotes exercise training in female and male patients (pts) with heart failure with preserved ejection fraction (HFpEF). Methods A total of 78 pts with HFpEF were enrolled in the study: 43 male (M group) and 35 female (F group). In all pts, before and after a short-term supervised 3 weeks exercise training at residential center values of NOx, RSNO, ADMA and SDMA were determined and exercise test was performed. Results After 3 weeks of exercise training NOx increased significantly in both groups: in M group (from 34.4±7.5 to 42.3±9.5 μmol/l, P&amp;lt;0.001), and in F group (from 31.3±6.8 to 41.5±7.2 μmol/l, P&amp;lt;0.001), as well as RSNO: In M group RSNO increased from 3.6±1.7 to 4.6±1.9 μmol/l (P&amp;lt;0.05) and in F group from 3.1±1.5 to 4.2±2.2 μmol/l (P&amp;lt;0,05). Increase in NOX and RSNO after exercise training was higher in F than in M group: NOx 32,6% vs 22,9%; RSNO 35,1% vs 27%. Value of ADMA as well of SDMA decreased in both groups after 3 weeks: ADMA in M group from 0.315±0.09 to 0.278±0.12 μmol/l (by 11.7%; ns), and in F group from 0.342±0.08 to 0.297±0.13 μmol/l (by 13.1%; ns); SDMA in M group from 0.269±0.08 to 0.234±0.09 μmol/l (by 13%; ns), and in F group from 0.285±0.09 to 0.245±0.10 μmol/l (by 14%; ns). After 3 weeks, level and duration of exercise test were significantly higher in M (both P&amp;lt;0,001), as well as, in F group (both P&amp;lt;0.001), compared to baseline values. Conclusions There was no gender difference in the way of endothelial response on exercise training in pts with HFpEF. Exercise training induced favorable modification of endothelial function, expressed through significant increased of NOx, RSNO and decreased of ADMA, SDMA in male as well as in female pts. Those positive changes in endothelial function were associated with significant improvement in exercise capacity. Some higher percentage of NOx and RSNO increase in women suggests that they have more pronounced benefit of exercise training than men. Funding Acknowledgement Type of funding source: None

Differential nitric oxide induced by Mycobacterium bovis and BCG leading to dendritic cells apoptosis in a caspase dependent manner

Dendritic cells (DCs) are critical for both innate and adaptive immunity. Meanwhile, nitric oxide (NO) is a member of reactive nitrogen species (RNS) generally considered to play a key role in the bactericidal process in innate immunity against Mycobacterium tuberculosis complex infection. The present study therefore investigated the mechanism of NO production in murine DCs induced by Mycobacterium bovis (M.bovis) and its attenuated strain Bacillus Calmette-Guérin (BCG) infection. The expression of genes Slc7A1, Slc7A2, iNOS, and ArgI essential to NO synthesis was up-regulated in M.bovis/BCG infected DCs. IFN-γ addition further increased, while the iNOS inhibitor L-NMMA significantly inhibited their expression. Accordingly, the end products of arginine metabolism, NO and urea, were found to be significantly increased. In addition, BCG induced significantly higher levels of apoptosis in DCs compared to M.bovis shown by higher levels of DNA fragmentation using flow cytometry and release of mitochondrial Cytochrome C, and up-regulation of the genes caspase-3, caspase-8, caspase-9 and dffa critical to apoptosis by qRT-PCR detection and western blot analysis. Furthermore, IFN-γ increased, but L-NMMA decreased apoptosis of M.bovis/BCG infected DCs. In addition, mycobacterial intracellular survival was significantly reduced by IFN-γ treatment in BCG infected DCs, while slightly increased by L-NMMA treatment. Taken altogether, our data show that NO synthesis was differentially increased and associated with apoptosis in M.bovis/BCG infected DCs. These findings may significantly contribute to elucidate the pathogenesis of M.bovis.

Combined aerobic and low-intensity resistance exercise training increases basal nitric oxide production and decreases arterial stiffness in healthy older adults.

Meta-analyses have concluded that combined aerobic and high-intensity or moderate-intensity resistance exercise training has no effects on arterial stiffness. However, a recent study demonstrated that combined aerobic training and resistance training using rubber bands increases basal nitric oxide (NO) production and decreases arterial stiffness with marked reduction of body weight in obese adolescent girls. To investigate whether combined aerobic and low-intensity resistance training increases basal NO production and decreases arterial stiffness without body weight reduction in older adults, 27 healthy older individuals participated in a 6-week program as a part of the training group (mean body mass index, 21 kg/m2; walking and resistance training using one’s body weight) or the control group (22 kg/m2, asked not to modify their lifestyle). The exercise intervention increased aerobic capacity, muscle strength, and plasma concentrations of nitrite/nitrate (end products of NO) and decreased pulse wave velocity (an index of arterial stiffness) without changes in body weight. In the control group, there were no differences in these measures before and after the study period. These results suggest that combined aerobic and low-intensity resistance exercise training increases basal NO production and decreases arterial stiffness in healthy older adults.

Cardiotoxicity and lung toxicity in male rats induced by long-term exposure to iron oxide and silver nanoparticles.

Engineered nanoparticles (NPs) have been increasingly used in numerous fields over the last decade. In particular, iron oxide NPs (Fe2O3NPs) and silver NPs (AgNPs) have contributed to the current increase in NP usage. However, the possible side effects of increased NP exposure remain not fully elucidated. The present study aimed to assess the toxic effects of Fe2O3NPs and AgNPs, both individually and in combination, on the heart and lungs of male rats. To evaluate the in vivo NP toxic effects, the experimental animals were orally administered with Fe2O3NPs (5 mg/kg) and/or AgNPs (50 mg/kg). Animals were treated every day for 79 days. The results demonstrated that at the molecular level, Fe2O3NPs and AgNPs caused marked DNA base oxidation as indicated by the elevated DNA content of 8-hydroxy-2−deoxyguanosine in the heart and lungs. Fe2O3NPs and/or AgNPs decreased paraoxonase 1, antioxidant enzymes, total antioxidant capacity, and reduced glutathione in heart and lung. A dose-dependent increase in production of creatine kinase, thiobarbituric acid-reactive substances, nitric oxide end products, tumor necrosis factor-α, interleukin-6 and lipid profiles was detected. Histological changes were also evident in heart and lung tissues. The two NPs demonstrated similar toxic effects for the majority of factors when co-supplemented. In conclusion, the present study identified that Fe2O3NPs and AgNPs, alone and in combination, induced cardiotoxicity and lung toxicity. Furthermore, findings demonstrated that there was a greater toxic effect due to administration of both NPs compared to individual administration. It was hypothesized that the toxic effects may be mediated through the induction of oxidative DNA damage, lipid peroxidation, shifting redox status, disrupted gene expression, and deregulation in cytokine production.

P638High intensity interval exercise training improves endothelial function in patients with heart failure with preserved ejection fraction

Abstract Background Cardiac rehabilitation has traditionally invoved low-to moderate intensity continuous exercise training (MICT). There is growing evidence that high intensity interval exercise training (HIIT) shows similar or greater efficacy compared with MICT. However, the relationship between the training modality and its effects on endothelial function still remains to be elucidated. Purpose To evaluate the impact of high intensity interval exercise training versus low-to moderate intensity continuous exercise training on circulating blood markers of endothelial function: the stable end product of nitric oxide (NOx), S–nitrosothiols (RSNO–reservoir for bioavailable nitric oxide), dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) in patients (pts) with heart failure with preserved ejection fraction (HFpEF). Methods A total of 43 pts with HFpEF (mean age 57.5±6.8y) admitted at residential rehabilitation center were enrolled in the study. Patients were randomized to HIIT, (HIIT group, n=20) and MICT, (MICTgroup, n=23). At baseline and 3 weeks later, in all pts values of NOx, RSNO, ADMA and SDMA were determined and exercise test was performed. Results After 3 weeks NOx increased significantly in both groups: in HIITgroup (from 34.7±7.5 to 48.5±8.3 μmol/l, P&lt;0.0001), in MICTgroup (from 35.0±9.5 to 42.5±10.0 μmol/l, P&lt;0.05), and value of NOx after 3 weeks was higher in HIIT than in MICT group (P&lt;0.05). Value of ADMA as well of SDMA decreased in both groups after 3 weeks, and this decrease was significant in HIIT group: ADMA in HIIT group (from 0.305±0.055 to 0.250±0.077 μmol/l, P&lt;0.005) and in MICT group (from 0.325±0.069 to 0.280±0.140 μmol/l, ns); SDMA in HIIT group (from 0.285±0.050 to 0.240±0.060 μmol/l, P&lt;0,005) and in MICT group (from 0.270±0.080 to 0.247±0.063 μmol/l, ns). Value of RSNO significantly increased in both groups, with higher increase in HIIT group: in HIIT group (from 3.0±1.5 to 5.1±1.7 μmol/l, P&lt;0.001), in MICTgroup (from 3.2±1.7 to 4.5±2.3 μmol/l, P&lt;0.05). Compared to the baseline, at the end of the study, exercise capacity (METs) was significantly higher in both groups (P&lt;0.0001). Higher increase in METs in HIIT group during exercise training (by 39.8%), compared to increase in MICT group (by 27.2%), resulted in significantly higher exercise tolerance in HIIT than in MICT group at the end of the study (P&lt;0.02). In both groups, adverse events during or after exercise training, were not occurred. Conclusions In pts with HFpEF high intensity interval exercise training as well as low-to moderate intensity continuous exercise training induced favorable modification of endothelial function, expressed through increase of NOx and RSNO, and decrease of ADMA and SDMA. More significant increase of NOx and RSNO, and significant decrease of ADMA and SDMA gives an advantage to HIIT over MICT exercise training in patients with HFpEF.

Nitric Oxide and Decreases in Resistance Exercise Blood Pressure With Aerobic Exercise Training in Older Individuals.

An exaggerated blood pressure response to resistance exercise is a marker of masked hypertension and a risk factor for future essential hypertension. Habitual aerobic exercise decreases systolic blood pressure (SBP) during resistance exercise in older individuals, but the underlying mechanisms have not been explored. This study tested the hypothesis that nitric oxide (NO) mediates a reduction of resistance exercise SBP with aerobic training in older individuals. Normotensive older adults participated in a 6-week program as a part of the aerobic training group (n = 23, exercised for an average of 4.4 d/wk and 59 min/d) or the control group (n = 26, asked not to modify their lifestyle during the experimental period). The aerobic exercise intervention increased plasma concentrations of nitrite/nitrate (NOx, end products of NO) and decreased SBP during a one-hand arm curl exercise at 20% and 40% of one-repetition maximum and brachial-ankle pulse wave velocity (an index of arterial stiffness). In the control group, there were no differences in these measures before and after the experimental period. Changes in plasma NOx concentrations during the study period were correlated with changes in resistance exercise SBP. Stepwise regression revealed that changes in plasma NOx concentrations during the experimental period are a significant factor of changes in resistance exercise SBP, independent of age, sex, and changes in serum lipid profile, maximal oxygen uptake, resting SBP, and other variables. These results suggest that NO is associated with decreases in resistance exercise SBP with aerobic training in older individuals and help us better understand why habitual aerobic exercise prevents cardiovascular disease.

Cinnamaldehyde protects from methylglyoxal-induced vascular damage: Effect on nitric oxide and advanced glycation end products.

The protective effect and mechanism(s) of action of cinnamaldehyde on the highly reactive secondary sugar derivative, methylglyoxal, induced vascular damage were investigated using isolated rat thoracic aorta. Aorta was incubated with methylglyoxal and cinnamaldehyde where vascular reactivity was assessed through phenylephrine- and acetylcholine-induced contraction and relaxation, respectively. Cinnamaldehyde's antioxidant activity, ability to induce aortic nitric oxide release, and effect on advanced glycation end products formation (AGEs) was also studied. Results showed that cinnamaldehyde significantly alleviated the exaggerated contraction and improved the attenuated dilation of the aorta secondary to incubation with methylglyoxal. Furthermore, cinnamaldehyde stimulated aortic nitric oxide production from isolated aorta giving levels similar to acetylcholine and significantly reduced both methylglyoxal-induced AGEs and protein oxidation products formation. In conclusion, cinnamaldehyde protects from methyglyoxal-induced vascular damage mainly by improving the vasodilation in addition to endothelial nitric oxide production and reducing the detrimental AGE-inflicted vascular damage. PRACTICAL APPLICATIONS: The use of naturally occurring products to alleviate various disease-related complications is highly attractive due to their easy availability, relatively affordable prices compared to pharmaceutical products, and their favorable safety profile. In the case of cinnamaldehyde, its excessive and highly reputable consumption in the food industry facilitates promoting a daily intake of the natural compound with the purpose of counteracting the destructive effect that elevated blood glucose has on vascular function. According to findings obtained from this study, frequent cinnamaldehyde intake will improve vascular reactivity by acting on vasodilatory mechanisms and inhibiting glycation reactions, hence improving the hyperglycemia associated hypertensive state. The study also paves the way for future research to determine the clinical efficacy of cinnamaldehyde having established its competence in protecting vascular function in a lab setting.

Exploring the role of body mass index in relationship of serum nitric oxide and advanced glycation end products in apparently healthy subjects.

This study aimed to identify any association of serum nitric oxide (NO) and advanced glycation end products (AGEs) with body mass index (BMI) in apparently healthy subjects. In this cross-sectional study, participants were 90 apparently healthy subjects, categorized into three BMI groups as follows: BMI≤19.5 (n = 21), 19.6≤BMI≤24.9 (n = 35), and BMI≥25 (n = 34). Serum levels of NO were measured by griess reaction method. Determination of serum pentosidine and carboxymethyllysine (CML) was done using ELISA. Median (95% confidence interval [CI]: lower- upper) of serum NO in subjects with BMI≥25 were 68.94 (CI: 55.01–70.56) μmol/L, which was higher compared with 19.6≤BMI≤24.9 and BMI≤19.5 groups (22.65 (CI: 19.29–28.17) μmol/L and 8.00 (CI: 9.12–29.58) μmol/L, respectively). Serum NO positively correlated with BMI in total subjects (r = 0.585, p<0.001), which this correlation was significant in both male and female groups (r = 0.735, p<0.001 and r = 0.476, p = 0.001, respectively). Serum pentosidine and CML were significantly lower in subjects with higher BMI. Further, BMI showed negative correlations with pentosidine and CML (r = -0.363, p<0.001 and r = -0.484, p<0.001, respectively). There were not any significant differences in serum NO, pentosidine, and CML levels between sex groups. After adjusting the effects of confounders (BMI, sex, age, and waist to hip ratio), serum NO significantly correlated with serum pentosidine and CML (r = -0.319, p = 0.003 and r = -0.433, p<0.001, respectively). It is concluded that higher BMI is accompanied by increased serum NO and suppressed pentosidine and CML.

Transcriptional Regulation of Nos2 via STAT5B Binding to Nos2 Gene Promoter Mediates Nitric Oxide Production: Relevance in β-Cell Maintenance.

Type 1 Diabetes (T1D) involves autoimmune attack due to reduced regulatory T cells as an effect of mutant Stat5b(C1462A) in non-obese diabetic (NOD) mice, a T1D model resulting in pancreatic β-cell destruction. Although reactive oxygen species are considered to orchestrate the immune attack, the role of nitric oxide (·NO) still remains debatable. Since JAK-STAT pathway is known to induce Nos2, we investigated the role of STAT5B in nitric oxide generation and oxidative stress. In this study, we have used chromatin immunoprecipitation with STAT5B antibody to explore whether STAT5B binds Nos2 promoter. Using Stat5b gene silencing and overexpression models in MIN6 mouse pancreatic β-cell line we have assayed nitric oxide and its end products, superoxide levels, H₂O₂ levels, and expression of genes related to redox pathway by immunocytochemistry, biochemical assays, quantitative real time PCR and western blotting. Our results prove that STAT5B binds to the candidate gamma-interferon-activated (GAS) element in Nos2 promoter thereby inducing Nos2 mRNA transcription resulting in NOS2 protein expression in MIN6, a mouse pancreatic β-cell line. Our findings are substantiated by reduced ·NO as well as nitric oxide end products (nitrate and nitrite), and increased superoxide production in Stat5b silenced MIN6 cells. Our results indicate that C1462A mutant STAT5B shows lack of ·NO generation ability. To detoxify excess superoxide as a consequence of lowered Nos2, an overexpressed SOD2 in Stat5b silenced cells results in increased H₂O₂ production. H₂O₂ metabolizing enzymes do not show upregulation upon Stat5b silencing, and thus oxidative stress is brought about by amassed H₂O₂. Stat5b silencing finally reduces AKT expression, a prosurvival signal. Our study enables us to conclude that β-cell stress is aggravated by the incapability of STAT5B to induce Nos2 resulting in H₂O₂ accumulation and the ensuing oxidative stress enhances β-cell damage.

Cognitive impairments and microvascular endothelial dysfunction in unilateral occlusion of the carotid artery

The study was aimed at determining cognitive impairments, vascular endothelial dysfunction and morphofunctional alterations of neurons in brain structures (neocortex and hippocampus) in unilateral occlusion of the common carotid artery in albino rats. The experiments were carried out on Wistar albino rats. The animals were divided into two groups: group 1 - the control group composed of sham-operated rats and group 2 - the study group consisting of rats with cerebral ischaemia. The model of cerebral ischaemia was reproduced by occlusion of the left common carotid artery. Cognitive functions in rats were assessed by means of the object recognition test and conditioned passive avoidance response (CPAR). The degree of vascular endothelial dysfunction was evaluated by the number of circulating endotheliocytes and concentration of end products of nitric oxide - nitrites in blood plasma. Pathomorphological studies of the brain and morphometric analysis of the number of damaged neurons after ischaemic exposure were carried out by means of light microscopy. It was determined that unilateral occlusion of the common carotid artery in rats resulted in memory impairment revealed by the object recognition test and CPAR (p≤0.05). Cerebral ischaemia induced an elevated level of circulating endotheliocytes and a decrease in end products of nitric oxide - nitrates as compared with the controls (p≤0.05). Morphological study demonstrated signs of vasoconstrictive reactions, microvascular endothelial oedema, as well as an increase in the proportion of damaged neurons localized in the fronto-bregmatic region of the cortex of the cerebral hemispheres and hippocampus on the ipsilateral side (p≤0.05). Unilateral occlusion of the common carotid artery in albino rats resulted in cognitive impairments, damage of neurons in the most vulnerable areas of the cortex of the cerebral hemispheres and hippocampus predominantly on the ipsilateral side. Cognitive impairments and ischaemic lesions of the brain structures are induced by endothelial dysfunction, enhanced desquamation of endotheliocytes and prevalence of vasoconstrictive reactions resulting from decreased production of the major vasorelaxing factor - nitric oxide.

Human brain blood flow and metabolism during isocapnic hyperoxia: the role of reactive oxygen species.

It is unknown whether excessive reactive oxygen species (ROS) production drives the isocapnic hyperoxia (IH)-induced decline in human cerebral blood flow (CBF) via reduced nitric oxide (NO) bioavailability and leads to disruption of the blood-brain barrier (BBB) or neural-parenchymal damage. Cerebral metabolic rate for oxygen (CMR ) and transcerebral exchanges of NO end-products, oxidants, antioxidants and neural-parenchymal damage markers were simultaneously quantified under IH with intravenous saline and ascorbic acid infusion. CBF and were reduced during IH, responses that were followed by increased oxidative stress and reduced NO bioavailability when saline was infused. No indication of neural-parenchymal damage or disruption of the BBB was observed during IH. Antioxidant defences were increased during ascorbic acid infusion, while CBF, , oxidant and NO bioavailability markers remained unchanged. ROS play a role in the regulation of CBF and metabolism during IH without evidence of BBB disruption or neural-parenchymal damage. To test the hypothesis that isocapnic hyperoxia (IH) affects cerebral blood flow (CBF) and metabolism through exaggerated reactive oxygen species (ROS) production, reduced nitric oxide (NO) bioavailability, disturbances in the blood-brain barrier (BBB) and neural-parenchymal homeostasis, 10 men (24± 1years) were exposed to a 10min IH trial (100% O2 ) while receiving intravenous saline and ascorbic acid (AA, 3 g) infusion. Internal carotid artery blood flow (ICABF), vertebral artery blood flow (VABF) and total CBF (tCBF, Doppler ultrasound) were determined. Arterial and right internal jugular venous blood was sampled to quantify the cerebral metabolic rate of oxygen (CMR ), transcerebral exchanges (TCE) of NO end-products (plasma nitrite), antioxidants (AA and AA plus dehydroascorbic acid (AA+DA)) and oxidant biomarkers (thiobarbituric acid-reactive substances (TBARS) and 8-isoprostane), and an index of BBB disruption and neuronal-parenchymal damage (neuron-specific enolase; NSE). IH reduced ICABF, tCBF and , while VABF remained unchanged. Arterial 8-isoprostane and nitrite TCE increased, indicating that CBF decline was related to ROS production and reduced NO bioavailability. AA, AA+DA and NSE TCE did not change during IH. AA infusion did not change the resting haemodynamic and metabolic parameters but raised antioxidant defences, as indicated by increased AA/AA+DA concentrations. Negative AA+DA TCE, unchanged nitrite, reductions in arterial and venous 8-isoprostane, and TBARS TCE indicated that AA infusion effectively inhibited ROS production and preserved NO bioavailability. Similarly, AA infusion prevented IH-induced decline in regional and total CBF and re-established . These findings indicate that ROS play a role in CBF regulation and metabolism during IH without evidence of BBB disruption or neural-parenchymal damage.