Serum Levels Of Nitric Oxide Metabolites Research Articles

Nitric oxide metabolites in heart failure patients with reduced or preserved ejection fraction and effects of different exercise modes

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): German Centre for Cardiovascular Research (DZHK). Background Alterations of endothelial function and nitric oxide (NO) release are involved in pathophysiology and clinical symptoms of heart failure (HF). Regular exercise training improves vascular and endothelial function and is closely linked to mechanisms of NO pathway by enhancing endothelial NO synthesis. However, it is not well investigated how exercise training affects metabolites of the NO pathway and whether different exercise modes have different effects on NO bioavailability in HF. Purpose The aims of this analysis were to 1) investigate differences in serum levels of the NO metabolites L-arginine, homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) between patients with HF with reduced (HFrEF) or preserved ejection fraction (HFpEF) and 2) to investigate effects of high-intensity interval training (HIIT) and moderate continuous training (MCT) on these parameters. Methods Patients with HF from two clinical exercise intervention trials were included in this analysis. In both trials, patients were randomized (1:1:1) either to HIIT, MCT or guideline control (CG). Clinical data and blood samples were collected at baseline, after three months of supervised exercise training and after 12 months follow-up. NO metabolites were analysed from EDTA-plasma using liquid chromatography-tandem mass spectrometry (LC–MS/MS). Results Data from 366 patients with HF, including 206 HFrEF (median [1. and 3. quartile]: 61 [53;70] years, 18.9% females) and 160 HFpEF patients (71 [66;76] years, 65.6% females), was available for analysis. Patients with HFrEF or HFpEF showed no significant differences in NYHA classification (NYHA III: 30.6% vs. 26.2%, p=0.43) or presence of diabetes mellitus (23.8% vs. 26.2%, p=0.50), while HFpEF had a higher prevalence of hypertension (86.9% vs. 38.5%, p<0.001) but a smaller number of current smoker than HFrEF (4.4% vs. 18.0%, p<0.001). PeakVO2 (18.4 [14.5;22.6] ml/min/kg vs. 17.0 [14.3;20.4] ml/min/kg, p=0.03) and HDL-cholesterol (56 [46;65] mg/dl vs. 42 [36;54] mg/dl, p<0.001) were higher in HFpEF than in HFrEF. At baseline, homoarginine and ADMA levels were higher in HFrEF than in HFpEF, but no differences in L-arginine or SDMA could be observed (Table 1). Changes in metabolite levels from baseline to 3 and 12 months were not significantly different between groups (HIIT, MCT, CG) in either HF phenotype (all p>0.05). In all exercise groups, median adherence to training sessions was at 85% or above with no significant differences between groups (p>0.05). Conclusion At baseline, patients with HFrEF had significantly higher homoarginine and ADMA levels compared to patients with HFpEF. However, in both HF phenotypes neither MCT nor HIIT induced significant changes in serum levels of NO metabolites when compared to patients randomized to CG.

Berry consumption mitigates the hypertensive effects of a high-fat, high-sucrose diet via attenuation of renal and aortic AT1R expression resulting in improved endothelium-derived NO bioavailability

Dysregulation of the renin-angiotensin system (RAS) is a contributor to high-fat diet-related blood pressure (BP) increases. Deleterious effects of dysregulated RAS result in an overproduction of reactive oxygen species and a decrease in endothelial nitric oxide (NO) bioavailability due to increased NADPH oxidase (NOX) expression. Dietary polyphenols have been shown to mitigate the imbalance in the redox state and protect against endothelial dysfunction induced by a high-fat diet. Thus, we aim to determine whether polyphenol-rich blackberry and raspberry, alone and in combination, attenuate the detrimental effects of a high-fat, high-sucrose (HFHS) diet on the vascular endothelium and kidneys of mice. We show that a HFHS diet increased the expression of renal and aortic angiotensin type 1 receptor (AT1R). Further, NOX1 and NOX4 expression were increased in the kidney contributing to fibrotic damage. In human aortic endothelial cells (HAECs), palmitic acid increased the expression of NOX4, potentially driving oxidative damage in the aorta, as evidenced by increased nitrotyrosine expression. Berries reduced the expression of renal and aortic AT1R, leading to a subsequent decrease in renal NOX expression and reduced aortic oxidative stress evidenced by reduced nitrotyrosine expression. Blackberry and raspberry in combination increased the expression of NRF2 and its downstream proteins in HAECs, thereby reducing the oxidative burden to the endothelium. In combination, blackberry and raspberry also increased serum levels of NO metabolites. These findings indicate that blackberry and raspberry unique polyphenols may act synergistically to favorably modulate the abovementioned pathways and attenuate HFHS diet-induced increases in BP.

The Effect of Type of Delivery on the Nitric Oxide Metabolites and Endothelial Dysfunction in Pregnant Women.

Background:Since endothelial dysfunction is related to atherosclerosis, this study was planned to determine the effect of type of delivery on Nitric Oxide (NO) metabolites and endothelial function.Materials and Methods:This Cohort study was conducted in 2015 in selected hospitals of Isfahan. 88 nulliparous women with gestational age of 39 weeks and above were enrolled in this study using convenience sampling method and finally, after giving birth, 51 mothers with vaginal delivery, 21 with urgent C-section and 13 with elective C-section were considered for data analysis. The serum levels of NO metabolites were measured in the laboratory with standard kits and data was analyzed using student and paired t-test, one-way ANOVA, and Chi-square test. The significance level was considered less than 0.05 for all tests.Results:The NO metabolites levels in mothers who had vaginal delivery or urgent C-section showed a significant difference before and after delivery (normal vaginal delivery (NVD): t50 = 5.61, p < 0.001, Urgent C-section: t23 = 5.38, p < 0.001). But those with elective C-section showed no significant difference in the nitrate and total nitrite levels before and after delivery (p > 0.05).Conclusions:Since reduction in serum levels of NO metabolites may possibly indicate endothelial dysfunction and predict cardiovascular disease, especially atherosclerosis in the future, it could be concluded that, childbirth, regardless of the type of delivery, could damage the endothelial cells but C-section (urgent or elective) could cause more disruption than vaginal delivery.

Serum Levels of Vaspin and Its Correlation with Nitric Oxide in Type 2 Diabetic Patients with Nephropathy.

Diabetic Nephropathy (DN), a serious and prevalent complication of diabetes, has been rapidly raising worldwide. Vaspin, as an adipokine with anti-diabetic effects, is predominantly released from visceral adipose tissue. Moreover, vaspin has the stimulatory effect on nitric oxide (NO) bioavailability through the activation of NO synthase. The aim of the present study was to investigate the serum levels of vaspin and their correlation with NO metabolite in diabetic patients with normal renal function and renal insufficiency. Volunteers patients with non-nephropathy Type 2 Diabetic Mellitus (T2DM) as control (n=40, age= 56.95±6.11 years) and patients with diabetic nephropathy (DN) (n=40, age=57.85±5.63 years) as case group were enrolled in this study, and serum samples were collected for the measurement of vaspin levels by ELISA technique. Also, serum levels of NO metabolites were calorimetrically assessed. We found that vaspin levels significantly decreased in diabetic patients with nephropathic condition as compared with diabetic patients with normal renal function (p <0.04). In addition, serum levels of NO metabolites were significantly higher in diabetic patients with nephropathy in comparison with non-nephropathic diabetics (p<0.001). When patients with DN were studied, vaspin levels positively correlated with NO metabolites and Homeostasis model assessment of insulin resistance (HOMA-IR) levels. This study showed that low serum vaspin levels may be a risk factor for nephropathy in type II diabetic patients and increased levels of NO may be a defensive mechanism in the DN.

Nitric Oxide Metabolites Change in Cisplatin-Induced Nephrotoxicity: The Effect of L-Arginine and Losartan

Cisplatin (CP) is an anticancer drug with the most common side effect of nephrotoxicity. CP also alters the level of nitric oxide (NO), and NO itself may promote CP-induced nephrotoxicity. In this short report, we measured the serum levels of NO metabolites in an animal model of CP-induced nephrotoxicity, and tested the effect of two nephroprotectant agents; l-arginine and losartan on serum levels of NO metabolites. The results indicated that CP increased the serum concentration of nitrite but not nitrate. However, l-arginine and losartan significantly decreased the serum level of nitrite. It seems that l-arginine and losartan provide their nephroprotectant effect against CP-induced nephrotoxicity by reducing the serum level of nitrite.

Serum nitric oxide metabolite as a biomarker of visceral fat accumulation: clinical significance of measurement for nitrate/nitrite.

SummaryBackgroundA visceral fat area of more than 100 cm2 as measured by computed tomography (CT) at the umbilical level has been included as a criterion for obesity in all the proposed criteria for metabolic syndrome. However, CT cannot be used frequently because of radiation exposure. We evaluated the usefulness of measurement of the serum levels of nitric oxide (NO), instead of CT and the waist circumference, as a marker of abdominal visceral fat accumulation.Material/MethodsThe study was carried out in 80 subjects. The serum levels of NO metabolites (nitrate/nitrite) were measured using the Griess reagent.ResultsSimple and multiple regression analysis revealed that the serum levels of NO metabolites showed the greatest degree of correlation with the visceral fat area (r=0.743, p<0.0001), and corresponded to a visceral fat area of 100 cm2, as determined using the ROC curve, was 21.0 μmol/ml (sensitivity 88%, specificity 82%); this method was more sensitive than the waist circumference for evaluation of the visceral fat accumulation.ConclusionsMeasurement of the serum levels of NO metabolites may be a simple, safe, convenient and reliable method for the evaluation of visceral fat accumulation in clinical diagnostic screening.

Nitric oxide metabolite levels during the ectopic osteoinduction in rats

Nitric oxide (NO) is a cell-signaling molecule that has diverse biological functions. Recent evidence suggests that its production may regulate the metabolism of the osteoblasts and osteoclasts. The aim of this study was to evaluate levels of nitrite and nitrates (NO metabolites) during ectopic osteoinduction in rats. Eighteen male Sprague–Dawley rats (body weight 200–300 g) were used in this study. All animals were anesthetized and the right and left flank areas were shaved, and under aseptic conditions, a muscular pouch was created in each flank: the left was filled with 20 mg of demineralized bone matrix and the right remained empty (sham). Radiographs were taken at 2, 4, and 6 weeks after surgery to trace the ectopic bone formation and muscle mineralization. Blood samples were taken before (as baseline values) and at 2, 4, and 6 weeks after surgery. The mean values of NO metabolites after 6 weeks were significantly higher (p < 0.05) than baseline data and at 2 weeks post-surgery. Results from this study indicate that the ectopic osteoinduction caused increased activity of the osteoblasts which subsequently caused increased serum levels of NO metabolites (nitrites and nitrates).

3H-1,2-Dithiole-3-thione Targets Nuclear Factor κB to Block Expression of Inducible Nitric-Oxide Synthase, Prevents Hypotension, and Improves Survival in Endotoxemic Rats

Septicemia is a major cause of death associated with noncoronary intensive care. Systemic production of nitric oxide (NO) by inducible nitric-oxide synthase (iNOS) is a major cause of hypotension and poor organ perfusion seen in septic shock. Here, we show that pretreatment of F344 rats with the cancer chemoprotective agent 3H-1,2-dithiole-3-thione (D3T) blocks lipopolysaccharide (LPS)-mediated induction of hepatic iNOS and significantly reduces the associated serum levels of NO metabolites and enzyme markers of toxicity provoked by treatment with LPS. Immunohistochemical analysis shows that this protective effect is largely due to suppression of iNOS expression in hepatocytes. Importantly, pretreatment of animals with D3T blunts LPS-mediated hypotension and dramatically increases their survival. Inasmuch as iNOS expression can be regulated by nuclear factor (NF) kappaB, mechanistic studies show that D3T blocks NFkappaB nuclear translocation and DNA binding and that these effects are accompanied by changes in the levels of phospho-inhibitor of NFkappaB. In conclusion, this study identifies new drug classes and targets that may improve the prevention and treatment of septic shock, as well as chronic diseases associated with the NFkappaB and iNOS pathways.

Increased serum levels of nitric oxide metabolites among users of levonorgestrel-releasing implants [corrected] a possible role in progestin-induced bleeding.

Nitric oxide (NO) is a potent angiogenic and vasodilator factor that could be involved in progestin-induced bleeding. This study aimed to assess possible changes in the serum levels of NO metabolites in users of levonorgestrel-releasing implants (LNG-implants) [corrected] and to identify any correlation between some of their clinical characteristics and NO metabolite levels. This cross-sectional study included 37 LNG-implants [corrected] users; a single 5 ml venous blood was collected at different periods of [corrected] use. Women were divided into users with acceptable menstrual bleeding (n 5 13) [corrected] and those having abnormal bleeding patterns (n 5 24) [corrected] The controls are 13 age-matched healthy women; they were fertile, had regular menstruation and did not use any contraceptive method in the previous 3 months. NO was determined by the evaluation of its oxidation products (nitrites and nitrates) where the nitrates were reduced to nitrites with cadmium filings; total serum concentrations of nitrites were measured by using the Griess reaction. The mean serum levels of NO metabolites were significantly higher in the LNG-implants [corrected] users than in the controls (mean+/-SE) 34.9+/-11.3 versus 6.1+/-1.5 mumol/l (P<0.001) [corrected] The mean serum levels of NO metabolites were significantly higher in the LNG-implants [corrected] users with abnormal bleeding patterns than in those with normal bleeding patterns (mean+/-SE) 41.3+/-7.4 versus 23.2+/-5.8 mumol/l (P<0.001) [corrected] There was a positive correlation between NO levels and both prolonged spotting and heavy/prolonged bleeding days (P<0.001 and P<0.01, respectively) and negative correlation between NO levels with the duration of use and length of the menstrual cycle (P<0.05). The significantly increased serum levels of NO metabolites among LNG-implants [corrected] users may primarily reflect an increase in its endometrial production, possibly secondary to its increased liberation by systemic vascular endothelium. This may result in enhanced endometrial angiogenesis and vascular dilatation which can induce and perpetuate abnormal excessive/prolonged uterine bleeding.

A defect in HIV-1 transgenic murine macrophages results in deficient nitric oxide production

HIV transgenic mice bearing multiple copies of a noninfectious (Deltagag/pol) proviral DNA were tested for the systemic production of nitric oxide (NO). Serum levels of NO metabolites were reduced about 50% in HIV transgenic mice compared with nontransgenic sibling mice. This difference persisted when NO production was induced with peritoneal injections of bacterial endotoxin (LPS). Peritoneal inflammatory macrophages, but not resident peritoneal macrophages, derived from HIV-1 transgenic mice and activated in vitro with LPS and IFN-gamma (or tumor necrosis factor alpha and IFN-gamma) also produced about 50% less NO than did macrophages harvested from nontransgenic littermates. Isogenic, transgenic mice bearing mutated nef or vpr genes had normal serum levels of NO metabolites and their macrophages produced normal levels of NO when stimulated. An explanation for the reduced NO response of HIV[Vpr+Nef+] macrophages was not apparent from measured levels of iNOS expression, viral gene expression, or arginase activity in activated macrophages. Inhibition of nitric oxide synthase (NOS) isoforms with L-NAME or aminoguanidine blocked time-dependent increases in HIV gene expression in activated macrophages cultured ex vivo. Inhibition with L-NAME occurred despite high levels of NO generated by iNOS, and exogenously supplied NO induced HIV gene expression only weakly, suggesting that cNOS had the greater influence on proviral gene induction. This system is presented as a model of HIV-1 proviral gene expression and dysfunction in macrophages.

Spontaneous labor increases nitric oxide synthesis during the early neonatal period

This paper aimed to assess the influence of spontaneous labor upon endogenous nitric oxide (NO) and endothelin 1 (ET-1) during transition to extrauterine life. The serum levels of NO metabolites (the sum of nitrites and nitrates (NOx)) and the plasma level of ET-1 were determined in 53 healthy full-term infants (spontaneous labor group; n=40, cesarean delivery group; n=13). In both groups, blood samples were obtained from a cord vein at birth and from a peripheral vein at 5 days of age. The differences in serum NOx concentrations between the spontaneous labor group and the elective cesarean group were not significant at birth. By the age of 5 days, serum NOx concentrations had risen significantly in the spontaneous labor group to become significantly higher in the elective cesarean group. It is speculated that spontaneous labor might enhance endogenous NO synthesis at 5 days of age.

Association of Serum Nitric Oxide Levels with Depressive Symptoms: A Study with End-Stage Renal Failure Patients

Background: Nitric oxide (NO) is a soluble gas produced by the activity of an enzyme found in neurons. It has been implicated in a great number of normal physiological functions (such as noradrenaline and dopamine release, memory and learning, regulation of the cerebrovascular system, modulation of wakefulness, modulation of nociception, olfaction, food intake and drinking) as well as pathologies (Alzheimer’s, Huntington’s disease, cerebral ischemia, stroke). Two reports have addressed the involvement of NO in depression. Methods: The objective of the study was to examine the association between NO and specific depressive symptoms. For this purpose, in a sample of 28 end-stage renal failure patients (who have increased NO levels), we tested the hypothesis that the subgroup of patients with these specific depressive symptoms was differentiated from the patients without these symptoms with regard to serum levels of NO metabolites. The depressive symptoms were assessed using the Zung self-rating scale. Results: Our study revealed an association of NO with the following depressive symptoms: sexual dysfunction, weight loss, psychomotor retardation, indecisiveness and irritability. Conclusion: The association between NO system and symptoms of depression does not necessarily imply a pathogenetic association between NO and depressive disorder. Further research is needed to verify these findings and study their possible pathogenetic implications.

Physiologic significance of nitric oxide and endothelin-1 in circulatory adaptation.

The purpose of the present paper was to evaluate the physiologic significance of nitric oxide (NO) and endothelin (ET)-1 in circulatory adaptation in the neonate. The serum levels of NO metabolites (NOx; the sum of nitrites and nitrates) and the plasma level of ET-1 were determined in 14 healthy full-term infants at 0-6 h, 24 h and 5 days after birth. We measured the heart rate, the mean systemic blood pressure and the mean pulmonary arterial pressure, estimated by pulsed Doppler echocardiography, at each time point. The serum concentration of NOx was lowest at birth and increased with age. The plasma concentration of ET-1 was highest at birth and decreased with age. The ratio of NOx to ET-1 was inversely related to the estimated mean pulmonary arterial pressure in the early neonatal period. The ratio of NOx to ET-1 was not correlated with the systemic blood pressure. Increased NO synthesis and decreased production of ET-1 during the early neonatal period may contribute to the decrease in pulmonary arterial pressure.

Levels of nitric oxide metabolites do not increase during penile erection

Cavernosal smooth muscle relaxation, one of the primary events in penile erection, is initiated by the synthesis and release of nitric oxide (NO) from the neurons of the cavernosa. The present study was undertaken to determine whether or not serum levels of NO metabolites rise during an erection. Since NO is rapidly converted into nitrites and nitrates, and nitrites, we measured these serum levels in the peripheral and cavernosal blood of 15 potent adult male volunteers who were exposed to erotic stimuli in order to elicit a penile erection. Our data demonstrate that both nitrite and nitrate levels in the peripheral and cavernosal blood do not appreciably change during and immediately following an erection. This indicates that the determination of whether or not abnormalities in the synthesis and release of NO play any role in erectile dysfunction will require alternative testing methods.