Urinary Nitric Oxide Research Articles

The Effect of Antidepressant Treatment on Neurocognitive Functions, Redox and Inflammatory Parameters in the Context of COVID-19.

Inflammation is an important component of the etiopathology of depression that uses oxidative and nitrosative stress (O&NS) and elevated inflammatory markers. SARS-CoV-2 infection is also associated with abnormal inflammatory processes, which may impair effective treatment of depression in COVID-19 survivors. In the presented study, thirty-three hospitalized patients with major depressive disorder (MDD) were started on antidepressant treatment, and twenty-one were re-evaluated after 4-6 weeks. The control group consisted of thirty healthy volunteers. All participants underwent neuropsychiatric evaluation, biochemical blood and urine analyses. The results of the research demonstrated positive correlations of the Hamilton Depression Rating Scale (HAM-D) scores with serum catalase (CAT) and urinary S-Nitrosothiols levels, and the Beck Depression Inventory (BDI) scores with serum reduced glutathione (GSH) and superoxide dismutase (SOD) levels. Depressed patients with a history of COVID-19 prior to the treatment had higher urinary nitric oxide (NO) levels and lower serum glutathione peroxidase (GPx) levels. In the control group, COVID-19 survivors had higher levels of urinary N-formylkynurenine (NFK). Our results suggest that the antidepressant treatment has a modulating effect on O&NS, reduces depressive symptoms and improves cognitive functions The present study does not indicate that clinical response to antidepressant treatment is associated with COVID-19 history and baseline SARS-CoV-2 antibody levels. Nevertheless, further research in this area is needed to systematize antidepressant treatment in COVID-19 survivors.

"High Urinary Nitric Oxide Levels May Indicate the Presence of Bladder Outlet Obstruction, But Not Overactive Bladder"

"High Urinary Nitric Oxide Levels May Indicate the Presence of Bladder Outlet Obstruction, But Not Overactive Bladder"

Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function

Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function

S-27-5: DELETION OF AT1A RECEPTORS IN THE PROXIMAL TUBULES AUGMENTS NATRIURETIC RESPONSE TO ATRIAL NATRIURETIC PEPTIDE VIA NPR/CGMP/NO SIGNALING

Objective: The proximal tubules of the kidney play a critical role in maintaining normal body salt and fluid balance and blood pressure homeostasis in part by interactions between two key vasoactive hormone receptors. In the proximal tubules, angiotensin II (Ang II) binds and activate AT1a receptors to stimulate proximal tubule Na+ reabsorption, whereas atrial natriuretic peptide (ANP) binds and activates NPRA receptors to inhibit Ang II-induced proximal tubule Na+ reabsorption. These two vasoactive systems play important counteracting roles in the proximal tubules to control proximal tubule Na+ reabsorption in the kidney and maintain blood pressure homeostasis. However, it is not known whether the hypotensive and natriuretic responses to ANP may be augmented by deletion of AT1 (AT1a) receptors selectively in the proximal tubules of the kidney. Design and Methods: The present study used a novel mouse model with proximal tubule-specific knockout of AT1a receptors in the kidney, PT-Agtr1a -/-, to test the hypothesis that deletion of AT1a receptors selectively in the proximal tubules indeed augments the hypotensive and natriuretic responses to ANP. Four groups (n = 9–12 per group) of adult male wild-type and PT-Agtr1a -/- mice were infused without (served as time controls) or with ANP via osmotic minipump (10 ng/min, i.p.) continuously for 2 weeks. Results: Basal blood pressure was about 16 ± 3 mmHg lower (P < 0.01), fractional proximal tubule Na+ reabsorption was significantly lower (P < 0.05), whereas 24 h urinary Na+ excretion was significantly higher in PT-Agtr1a -/- mice (P < 0.01), compared with age-matched wild-type mice. ANP infusion significantly decreased blood pressure and increased the natriuretic response in PT-Agtr1a -/- mice further by inhibiting proximal tubule Na+ reabsorption, compared with wild-type controls (P < 0.01). The augmented hypotensive and natriuretic responses to ANP infusion in PT-Agtr1a -/- mice was associated with increased plasma and kidney cGMP levels (P < 0.01), kidney cortical NPRA and NPRC mRNA expression (P < 0.05), total endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS proteins (P < 0.01), and urinary nitric oxide (NO) excretion (P < 0.01), respectively. Conclusions: Taken together, the results of the present study provide further new insights into the important physiological roles for intratubular Ang II/AT1a and ANP/NPRA in the proximal tubules to regulate proximal tubule Na+ reabsorption and help maintain blood pressure homeostasis. Supported by 2R01DK067299-10A1, 2R01DK102429-03A1, and 1 R01DK123144-01.

Clinical Significance of Serum Nitric Oxide, Urine Nitric Oxide, and Urinary Nitric Oxide-to-Creatinine Ratio in Acute Pancreatitis

Clinical Significance of Serum Nitric Oxide, Urine Nitric Oxide, and Urinary Nitric Oxide-to-Creatinine Ratio in Acute Pancreatitis

Urinary Nitric Oxide Levels Are Associated with Blood Pressure, Fruit and Vegetable Intake and Total Polyphenol Excretion in Adolescents from the SI! Program.

Nitric oxide (NO) is important to cardiovascular health (CVH), and its bioavailability could be regulated by the antioxidant effect of polyphenols, improving endothelial function and consequently blood pressure (BP). However, scant research has been carried out on NO and CVH correlates in adolescent populations. Therefore, our aim was to investigate the association between NO and the CVH status and other health factors in adolescents. NO, total polyphenol excretion (TPE), anthropometric measurements, BP, blood lipid profile, blood glucose, diet, physical activity, and smoking status were recorded, while CVH score was classified as ideal, intermediate, and poor. Negative associations were observed between NO and body mass index, body fat percentage, BP, and triglycerides; and positive associations between NO and skeletal muscle percentage, HDL-cholesterol, fruit and vegetable intake, and TPE was observed. To capture more complex interactions among different factors, multiple linear regression was performed, obtaining a significant association between NO and fruit and vegetable intake (β = 0.175), TPE (β = 0.225), and systolic BP (β = -0.235). We conclude that urinary NO levels are positively associated with the consumption of fruits and vegetables rich in antioxidants such as polyphenols and negatively associated with systolic BP.

LPIN1 is a new target gene for essential hypertension.

We previously showed Lipin1 (LPIN1) to be a candidate gene for essential hypertension by genome-wide association studies. LPIN1 encodes the Lipin 1 protein, which contributes to the maintenance of lipid metabolism and glucose homeostasis. However, little is known about the association between LPIN1 and blood pressure (BP). We evaluated the BP of LPIN1-deficient [fatty liver dystrophy (fld)] mice and explored related mechanisms. Fld mice have very low expression of LPIN1 and exhibit fatty liver, hypertriglyceridemia, insulin resistance and peripheral neuropathy. Fld mice had significantly elevated SBP and heart rate (HR) throughout the day as measured by a radiotelemetric method. Diurnal variation of SBP and HR was also absent in fld mice. Furthermore, urinary excretion of adrenaline and noradrenaline by fld mice was significantly higher compared with that of control mice. The BP response of fld mice to clonidine (a centrally acting α2-adrenergic receptor agonist) was greater than that of control mice. However, levels of Angiotensinogen and Renin 1 mRNA and urinary nitric oxide excretion were comparable between the two groups. The decrease in SBP at 8 weeks after fat grafting surgery was significantly greater in the transplant group compared with the sham operated group. The elevated BP in fld mice may result from activation of the sympathetic nervous system through decreased levels of adipose cytokines. These results indicate that LPIN1 plays a crucial role in blood pressure regulation and that LPIN1 is a new target gene for essential hypertension.

Vasorelaxant-Mediated Antihypertensive Effect of the Leaf Aqueous Extract from Stephania abyssinica (Dillon & A. Rich) Walp (Menispermaceae) in Rat.

Stephania abyssinica is a medicinal plant used in Cameroon alternative medicine to treat arterial hypertension (AHT). Previous in vitro studies demonstrated the endothelium nitric oxide-independent vasorelaxant property of the aqueous extract from Stephania abyssinica (AESA). But its effect on AHT is unknown. The present study was undertaken to explore other vasorelaxant mechanisms and to determine the antihypertensive effects of AESA in male Wistar rats. Phytochemical analysis of AESA was carried out using the liquid chromatography-mass spectrometry (LC-MS) method. The vasorelaxant effects of AESA (1-1000 μg/mL) were studied on rat isolated thoracic aorta rings, in the absence or presence of indomethacin (10 μM) or methylene blue (10 μM). The inhibitory effect of AESA on phenylephrine (PE, 10 μM) or KCl- (60 mM) induced contraction as well as the intracellular calcium release was also evaluated. The in vivo antihypertensive activity of AESA (43, 86, or 172 mg/kg/day) or captopril (20 mg/kg/day) administered orally was assessed in L-NAME- (40 mg/kg/day) treated rats. Blood pressure and heart rate (HR) were measured at the end of each week while serum or urinary nitric oxide (NO), creatinine, and glomerular filtration rate (GFR) were determined at the end of the 6 weeks of treatment, as well as histological analysis of the heart and the kidney. The LC-MS profiling of AESA identified 9 compounds including 7 alkaloids. AESA produced a concentration-dependent relaxation on contraction induced either by PE and KCl, which was significantly reduced in endothelium-denuded vessels, as well as in vessels pretreated with indomethacin and methylene blue. Moreover, AESA inhibited the intracellular Ca2+ release-induced contraction. In vivo, AESA reduced the AHT, heart rate (HR), and ventricular hypertrophy and increased serum NO, urine creatinine, and GFR. AESA also ameliorated heart and kidney lesions as compared to the L-NAME group. These findings supported the use of AESA as a potential antihypertensive drug.

Urine Nitric Oxide Is Lower in Parents of Autistic Children.

Parents raising children with autism spectrum disorder (ASD) usually carry on their daily life under tremendous stress, but limited empirical research has been devoted to this population. It is known that parents' health status directly impacts therapeutic outcome of ASD children. As an important regulator in cardiovascular, nervous and immune systems, nitric oxide (NO) levels haven't been reported in parents of ASD children yet. In this study, we measured urine nitrite and nitrate from 43 ASD parents (ASD-P), and 43 healthy adults in the same range of age (Control) who didn't have any ASD descendants. Comparison between the ASD-P and Control groups showed that , , and / were all significantly lower in the ASD-P group. Analysis on the interaction effect of sex and group indicated that urine of mothers in ASD-P was lower than that in females of the Control group, but no significant difference was observed between males in both groups. It is for the first time that urine nitric oxide metabolites (nitrite, nitrate) levels were precisely reported to differentiate parents of autistic children from other adults without ASD descendants. This phenomenon suggests that parents (especially mothers) of autistic children might have experienced more mental and physical stressors, which led to decreased NO levels during metabolism. Further investigations are necessary to uncover the etiology of low urine NO among parents of autistic children.

Physical Training Is a Potential Modifier of Risk for Contrast-Induced Acute Kidney Injury in Diabetes Mellitus.

Background Iodinated contrast (IC) is a leading cause of hospital-based acute kidney injury (AKI). Contrast-induced acute kidney injury (CI-AKI) is a decline in renal function due to iodinated contrast administration and occurs more frequently in individuals with increasingly common risk factors, such as diabetes mellitus (DM). Physical training (PT) can have renoprotective effects on CI-AKI in diabetic nephropathy. The aim of this study was to evaluate the injury in kidneys of diabetic rats submitted to treatment with IC, evaluating the impact of PT on hemodynamics and renal function in addition to oxidative profile in diabetic rats submitted to IC-AKI. Materials and Methods Adult male Wistar rats are randomized into four groups: citrate (n = 7): control group, citrate buffer (streptozotocin-STZ vehicle), intravenous tail (iv), single dose; DM (n = 7): STZ, 60 mg/kg, iv, single dose; DM+IC (n = 7): DM rats treated with IC (sodium meglumine ioxithalamate, 6 mL/kg, intraperitoneal (ip), single dose); DM+IC+PT (n = 7): DM rats treated with IC as mentioned and submitted to physical training. Renal function parameters (inulin clearance, neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine, and urinary albumin), hemodynamics (renal blood flow and renal vascular resistance), and oxidative profile (urinary peroxides, urinary TBARS, urinary nitric oxide, and renal tissue thiols) were evaluated. Results It was possible to observe a decrease in inulin clearance, renal blood flow, and thiols in renal tissue accompanied by an increase in urinary flow, serum creatinine, urinary albumin, renal vascular resistance, urinary peroxides, urinary nitrate, and TBARS in the DM group compared to the citrate group. The DM+IC group showed a reduction in inulin clearance, and the renal dysfunction was also seen by the increased NGAL. Renal hemodynamics and oxidative profile compared were also worsened in the DM group. PT improved renal function by increasing renal blood flow and thiol levels in renal tissue and reduced renal vascular resistance, metabolites of reactive oxygen, nitrogen species, and lipid peroxidation in the DM+IC+PT group compared to DM+IC. Conclusions Our results confirmed that DM induction increases renal vulnerability to the toxicity of IC and an association between DM with IC predisposes to severe AKI with reduced renal function alongside with renal hemodynamic alterations and oxidative mechanism of injury. The PT showed a renoprotective effect in DM animals subjected to damage with IC by modulating renal hemodynamics and oxidative profile, confirming a potential to modify the risk of CI-AKI when diabetes mellitus is present.

THE PROTECTIVE EFFECT OF L- ARGININE AND ASCORBIC ACID ON DEXAMETHASONE INDUCED-HYPERTENSION IN RATS

Excess use of glucocorticoids either natural or synthetic has been associated with hypertension. Dexamethasone is a synthetic glucocorticoid with multiple uses. Recent studies demonstrated that dexamethasone induced hypertension is of endothelial dysfunction and decreased nitric oxide (NO) production. This work was designed to investigate the protective effect of L-arginine and ascorbic acid on dexamethasone induced hypertension in rats. Thirty adult male Albino rats were used in this study. Rats were equally divided into 5 groups: (G 1) Negative control group, (G 2): Positive hypertensive group, (G 3): L – arginine treated group, (G 4): Ascorbic acid treated group and (G 5): combined L-arginine and ascorbic acid treated group. L – arginine, ascorbic acid were given 2 weeks before induction of hypertension. Rats were followed up by measuring arterial blood pressure, Nitric oxide in urine and tissue homogenate, Total antioxidant capacity in serum and histopathology. Dexamethasone increased systolic (260.16 ± 28.9 mmHg) and diastolic blood pressure (149.8 ± 7.22 mmHg), decaresed NO in tissue (72.1 ± 5.2 μmol/ g (and urine (0.26 ± 0.04 μmol/ 24h(. Combination between L-arginine and ascorbic acid normalized systolic (118.6 ± 5.3 mmHg) and diastolic (79.5 ± 5.04 mmHg ) blood pressure and increased NO in aortic tissue (135.5 ±7.1μmol/ g) and urine (0.6 ± 0.08 μmol/ 24h) denoting that combination between L-arginine and ascorbic acid could effectively prevent dexamethasone induced hypertension

Morinda citrifolia (Noni) fruit juice promotes vascular endothelium function in hypertension via glucagon-like peptide-1 receptor-CaMKKβ-AMPK-eNOS pathway.

Morinda citrifolia (Noni) is extensively used in herbal remedies to prevent and treat various diseases, including hypertension. The purpose of this study was to investigate the vascular effects of noni fruit juice and characterize the upstream signaling pathways. We measured the systolic blood pressure, diastolic blood pressure, 24-hr urinary nitric oxide (NO) metabolite excretion, bodyweight (BW), and urine examination in SHR.Cg-Leprcp/NDmcr (SHR/cp) rats after 6 weeks noni juice (15 ml/kg) treatment. Noni juice significantly decreased blood pressure and 24-hr urinary NO metabolite without change of BW or urine volume. Furthermore, the noni juice extract (NJE) promoted endothelial vasorelaxation in rat aorta rings and NO product through an increase in phosphorylation of endothelial nitric oxide synthase (eNOS) in human umbilical vein endothelial cells (HUVECs). NJE might act on a glucagon like peptide-1 receptor (GLP-1R) via Ca2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMPK signaling with pretreatment of their inhibitors or antagonist in HUVECs. Deacetylasperulosidic acid (DAA) was an active compound in noni juice to improve NO release through same pathway in HUVECs. These results suggested that noni is a novel dietary plant that probably regulates GLP-1R-induced CaMKKβ-AMPK-eNOS pathway to improve endothelium-dependent relaxation, thus reduce the blood pressure probably via one of its responsible ingredient DAA.

Protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes

To examine the cell-protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes, we analyzed the renal phenotype of tamoxifen (TM)-inducible podocyte-specific Atg5-deficient (iPodo-Atg5−/−) mice with experimental endothelial dysfunction. In both control and iPodo-Atg5−/− mice, high fat diet (HFD) feeding induced glomerular endothelial damage characterized by decreased urinary nitric oxide (NO) excretion, collapsed endothelial fenestrae, and reduced endothelial glycocalyx. HFD-fed control mice showed slight albuminuria and nearly normal podocyte morphology. In contrast, HFD-fed iPodo-Atg5−/− mice developed massive albuminuria accompanied by severe podocyte injury that was observed predominantly in podocytes adjacent to damaged endothelial cells by scanning electron microscopy. Although podocyte-specific autophagy deficiency did not affect endothelial NO synthase deficiency-associated albuminuria, it markedly exacerbated albuminuria and severe podocyte morphological damage when the damage was induced by intravenous neuraminidase injection to remove glycocalyx from the endothelial surface. Furthermore, endoplasmic reticulum stress was accelerated in podocytes of iPodo-Atg5−/− mice stimulated with neuraminidase, and treatment with molecular chaperone tauroursodeoxycholic acid improved neuraminidase-induced severe albuminuria and podocyte injury. In conclusion, podocyte autophagy plays a renoprotective role against diabetes-related structural endothelial damage, providing an additional insight into the pathogenesis of massive proteinuria in diabetic nephropathy.

THE SIGNIFICANCE OF ΝО GAS TRANSMITTER AND NUCLEASES IN SHAPING THE SEQUELAE OF TRAUMATIC BRAIN INJURY

Traumatic brain injuries are at present remaining an important worldwide medical problem due to substantial percentages of incapacitation and lethality, especially among people of working age. All therapeutic interventions in TBI and their timeliness and efficacy depend on timely and quality diagnosis of patient’s condition, including laboratory parameters of blood and urine. The aim: To assess for peculiar patterns in changes of NO gas transmitter levels in patients with severe traumatic brain injury during the treatment period and to investigate into its relationship with nuclease enzymes in the context of various treatment outcomes. This research work has used clinical data, history and diagnostic tests obtained in 72 patients with severe traumatic brain injury, age 18 to 76 years (mean age 42.26±15.02 years), who six months later have been divided into the following four groups according to Glasgow outcome scale: “Death”, “Severe disability”, “Moderate disability” and “Recovery”. Biochemical assessments in patients with severe traumatic brain injury have shown supranormal levels of urinary nitric oxide and serum DNAses. Going forward, nitric oxide levels significantly decreased over the time of treatment in subjects with favorable outcomes (“Moderate disability” and “Recovery” groups) and increased with treatment time in subjects with unfavorable outcomes (“Severe disability” and “Death” groups). The diagnostic markers of further unfavorable survival outcomes may be present at the onset of treatment (Day 1) and may include urinary levels of nitric oxide below 1.1 μmol/L and DNAse levels below 26 μU/mL. A positive diagnostic sign of favorable survival and health outcomes may include DNAse І levels over 30.0 μU/mL from Day 7 of treatment. The findings of this work can be used when making a diagnosis/selecting an optimal treatment schedule and predicting the sequelae of traumatic brain injury in a patient, which may cumulatively minimize the impact of the injury.

Tadalafil improves bladder dysfunction and object recognition in rats with pelvic venous congestion.

To examine the effects of tadalafil on bladder function and object recognition ability in rats with alterations in urinary frequency and locomotor activity as a result of pelvic venous congestion. A total of 48 female rats were divided into three groups (sham, pelvic venous congestion and pelvic venous congestion/tadalafil groups). In the pelvic venous congestion and pelvic venous congestion/tadalafil groups, the bilateral common iliac veins and uterine veins were ligated under anesthesia. Rats in the pelvic venous congestion/tadalafil group received a diet containing tadalafil, and the other rats were fed a normal diet. After 4weeks, rats underwent analysis of voiding behavior, locomotor activity, a novel object recognition test, continuous cystometry, measurement of plasma monoamines, and measurement of plasma and urinary nitric oxide metabolites. Expression of nitric oxide synthase messenger ribonucleic acid in the bladder wall was also assessed, along with histological examination of the bladder. Rats with pelvic venous congestion showed a higher urinary frequency, lower locomotor activity, and lower plasma and urinary nitric oxide levels than sham rats. The bladder wall endothelial nitric oxide synthase messenger ribonucleic acid level was low and object recognition was impaired. Pelvic venous congestion/tadalafil rats showed improvement in locomotor activity, bladder function and object recognition compared with pelvic venous congestion rats, as well as elevation of plasma and urinary nitric oxide, plasma monoamines, and bladder neuronal nitric oxide synthase messenger ribonucleic acid expression. Bladder wall vascularity was greater in pelvic venous congestion/tadalafil rats compared with sham rats. In rats with pelvic venous congestion, tadalafil might improve bladder function and the general condition by increasing blood flow to the bladder and brain, and by increasing dopamine levels.

Lack of urea transporters, UT-A1 and UT-A3, increases nitric oxide accumulation to dampen medullary sodium reabsorption through ENaC.

Although the role of urea in urine concentration is known, the effect of urea handling by the urea transporters (UTs), UT-A1 and UT-A3, on sodium balance remains elusive. Serum and urinary sodium concentration is similar between wild-type mice (WT) and UT-A3 null (UT-A3 KO) mice; however, mice lacking both UT-A1 and UT-A3 (UT-A1/A3 KO) have significantly lower serum sodium and higher urinary sodium. Protein expression of renal sodium transporters is unchanged among all three genotypes. WT, UT-A3 KO, and UT-A1/A3 KO acutely respond to hydrochlorothiazide and furosemide; however, UT-A1/A3 KO fail to show a diuretic or natriuretic response following amiloride administration, indicating that baseline epithelial Na+ channel (ENaC) activity is impaired. UT-A1/A3 KO have more ENaC at the apical membrane than WT mice, and single-channel analysis of ENaC in split-open inner medullary collecting duct (IMCD) isolated in saline shows that ENaC channel density and open probability is higher in UT-A1/A3 KO than WT. UT-A1/A3 KO excrete more urinary nitric oxide (NO), a paracrine inhibitor of ENaC, and inner medullary nitric oxide synthase 1 mRNA expression is ~40-fold higher than WT. Because endogenous NO is unstable, ENaC activity was reassessed in split-open IMCD with the NO donor PAPA NONOate [1-propanamine-3-(2-hydroxy-2-nitroso-1-propylhydrazine)], and ENaC activity was almost abolished in UT-A1/A3 KO. In summary, loss of both UT-A1 and UT-A3 (but not UT-A3 alone) causes elevated medullary NO production and salt wasting. NO inhibition of ENaC, despite elevated apical accumulation of ENaC in UT-A1/A3 KO IMCD, appears to be the main contributor to natriuresis in UT-A1/A3 KO mice.

There Is No Impact of Diabetes on the Endothelial Function of Chronic Kidney Disease Patients.

Background Patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (DM) have increased risk of endothelial dysfunction, cardiovascular disease, and mortality. Several studies have separately analyzed endothelial function in these populations. However, data of patients with both CKD and DM are scarce. The aim of this study was to evaluate whether the presence of DM has any additional effect on the endothelial dysfunction of CKD patients. Methods We measured endothelial progenitor cells (EPCs), stromal-derived factor 1 alpha (SDF-1α), serum and urinary nitric oxide (NO), flow-mediated dilation (FMD), and pulse wave velocity (PWV) in 37 CKD patients with DM (CKD-DM group) and in 37 without DM (CKD group). Results CKD-DM group had a higher prevalence of obesity (P < 0.01), previous myocardial infarction (P = 0.02), myocardial revascularization (P = 0.04), and a trend for more peripheral artery disease (P = 0.07). Additionally, CKD-DM group had higher EPC (P = 0.001) and PWV (P < 0.001) values. On the other hand, no difference in SDF-1α and serum or urinary NO and FMD was observed between the groups. Conclusions Endothelial dysfunction is frequent in CKD patients, and an additive effect of diabetes cannot be implicated, suggesting the predominant role of uremia in this condition.

Chronic Insulin Infusion Down-Regulates Circulating and Urinary Nitric Oxide (NO) Levels Despite Molecular Changes in the Kidney Predicting Greater Endothelial NO Synthase Activity in Mice

Insulin therapy is often needed to overcome insulin receptor resistance in type 2 diabetes; however, the impact of providing additional insulin to already hyperinsulinemic subjects is not clear. We infused male TALLYHO/Jng (TH) mice (insulin resistant) with insulin (50 U/kg·bw/d) or vehicle (control) by osmotic minipump for 14 days. One group of insulin-infused mice was switched to 4% NaCl diet (high-sodium diet, HSD) in the second week. Blood chemistry revealed a significantly higher anion gap and blood sodium concentrations with insulin infusion, i.e., relative metabolic acidosis. Systolic BP and heart rate were slightly (~5 mm Hg) higher in insulin-infused versus control mice. HSD resulted in a modest and transient rise in mean arterial blood pressure (BP), relative to control or insulin-infused, normal-NaCl-fed mice. In kidney, insulin infusion: (1) increased total and phosphorylated (serine-1177) endothelial nitric oxide synthase (eNOS) band densities; (2) reduced band density of the uncoupled form of eNOS; and (3) increased renal homogenate nitric oxide synthase (NOS) activity. Despite this, plasma and urine levels of nitrates plus nitrites (NOx) fell with insulin infusion, by day 14 (40–50%) suggesting worsening of resistance. Overall, insulin infusion ramps up the cellular means in kidney to increase vasodilatory and natriuretic NO, but in the long term may be associated with worsening of insulin receptor resistance.

The Effects of Morinda citrifolia (Noni) Fruit Juice on the Prevention of Stroke by Promoting Production of Nitric Oxide through the Brain of the Spontaneously Hypertensive Stroke Prone (SHRSP) Rats

Morinda citrifolia (Noni) is a traditional folk medicinal plant and has a long history of use as a food and medicine. In order to reveal the effects of Noni fruit juice (NFJ) on stroke prevention, we performed experiments using spontaneously hypertensive stroke prone (SHRSP) rats. NFJ did not change rat body weight, food intake, and water intake. However, both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly decreased after NFJ treatment in SHRSP rats. Furthermore, NFJ significantly increased the survival rate, urinary nitric oxide (NO) concentration was significantly higher in the NFJ group, and endothelial NO synthase (eNOS) phosphorylation levels increased in the brain after NFJ treatment. Two pathways regulate eNOS phosphorylation: the insulin-dependent pathway and the insulin-independent pathway. For the insulin-dependent pathway, phosphorylation of insulin receptor substrate 1 (IRS1) and protein kinase B (Akt) did not change in the NFJ group. For the insulin-independent pathway, expression of adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, liver kinase B 1 (LKB1), and silent information regulator 1 (Sirt1) significantly increased in the brain of SHRSP rats after NFJ treatment. These data suggested that NFJ prevented stroke by improved blood circulation, increased NO production, and elevated eNOS phosphorylation by stimulating the insulin-independent pathway (Sirt1-LKB1-AMPK-eNOS).

Influence of dietary nitrate food forms on nitrate metabolism and blood pressure in healthy normotensive adults

Inorganic nitrate (NO3−) supplementation has been shown to improve cardiovascular health indices in healthy adults. The purpose of this study was to investigate how the vehicle of NO3− administration can influence NO3− metabolism and the subsequent blood pressure response. Ten healthy males consumed an acute equimolar dose of NO3− (∼5.76 mmol) in the form of a concentrated beetroot juice drink (BR; 55 mL), a non-concentrated beetroot juice drink (BL; 456 mL) and a solid beetroot flapjack (BF; 60 g). A drink containing soluble beetroot crystals (BC; ∼1.40 mmol NO3−) and a control drink (CON; 70 mL deionised water) were also ingested. BP and plasma, salivary and urinary [NO3−] and [NO2−] were determined before and up to 24 h after ingestion. All NO3−-rich vehicles elevated plasma, salivary and urinary nitric oxide metabolites compared with baseline and CON (P<0.05). The peak increases in plasma [NO2−] were greater in BF (371 ± 136 nM) and BR (369 ± 167 nM) compared to BL (283 ± 93 nM; all P<0.05) and BC (232 ± 51 nM). BR, but not BF, BL and BC, reduced systolic (∼5 mmHg) and mean arterial pressure (∼3–4 mmHg; P<0.05), whereas BF reduced diastolic BP (∼4 mmHg; P < 0.05). Although plasma [NO2−] was elevated in all conditions, the consumption of a small, concentrated NO3−-rich fluid (BR) was the most effective means of reducing BP. These findings have implications for the use of dietary NO3−supplements when the main objective is to maintain or improve indices of cardiovascular health.