Urinary Nitric Oxide Research Articles

Short-term antioxidant diet prevents hyperfiltration in young male rat kidney subjected to ischemia/reperfusion injury

Objectives: The process of transplantation is associated with exposure to both long and short cold and warm ischemic times that result in ischemia/reperfusion injury. Oxidative stress contributes to tissue fibrosis, renal dysfunction, and/or rejection. Treatments that scavenge oxygen free radicals and have antioxidant properties can ameliorate the damaging results in renal grafts following ischemia/reperfusion injury. The present study tests the hypothesis that an antioxidant-fortified diet given to rats before and after renal ischemia/reperfusion injury will reduce the kidney damage that results and improve renal function. Endothelial and inducible nitric oxide synthases may change with tissue injury, including ischemia/ reperfusion. Materials and Methods: Male Wistar rats were subjected to ischemia/reperfusion injury at 7 or 19 weeks of age with or without dietary antioxidant supplementation. One week later, glomerular filtration rate, mean arterial pressure and urinary nitric oxide were measured, and renal endothelial and inducible nitric oxide synthases examined. Results: The glomerular filtration rate was elevated more than two-fold above the normal range at 8 weeks in animals on the regular diet exposed to ischemia/reperfu- sion, while in the 8 week antioxidant-fortified diet group the glomerular filtration rate was normal. Also, in 8 week rats, levels of endothelial nitric oxide synthase protein in cortex were higher on the regular than on the antioxidant-fortified diet. Conclusion: Early after ischemia/reperfusion injury renal endothelial nitric oxide synthase levels rise, possibly contributing to vascular dilation and hyperperfusion, and an antioxidant-fortified diet can ameliorate these changes in the younger age group.

Ghrelin counteracts salt-induced hypertension via promoting diuresis and renal nitric oxide production in Dahl rats

Ghrelin is the endogenous ligand for the growth hormone-secretagogue receptor expressed in various tissues including the heart, blood vessels and kidney. This study sought to determine the effects of long-term treatment with ghrelin (10 nmol/kg, twice a day, intraperitoneally) on the hypertension induced by high salt (8.0% NaCl) diet in Dahl salt-sensitive hypertensive (DS) rats. Systolic blood pressure (SBP) was measured by a tail cuff method. During the treatment period for 3 weeks, high salt diet increased blood pressure compared to normal salt (0.3% NaCl) diet, and this hypertension was partly but significantly (P<0.01) attenuated by simultaneous treatment with ghrelin. Ghrelin significantly increased urine volume and tended to increase urine Na⁺ excretion. Furthermore, ghrelin increased urine nitric oxide (NO) excretion and tended to increase renal neuronal nitric oxide synthase (nNOS) mRNA expression. Ghrelin did not alter the plasma angiotensin II level and renin activity, nor urine catecholamine levels. Furthermore, ghrelin prevented the high salt-induced increases in heart thickness and plasma ANP mRNA expression. These results demonstrate that long-term ghrelin treatment counteracts salt-induced hypertension in DS rats primarily through diuretic action associated with increased renal NO production, thereby exerting cardio-protective effects.

1042 Increased Plasma and Urine Nitric Oxide Level in Intrauterine Growth Restricted Late Preterm Infants

Background and AimsNitric oxide (NO) is a vasodilator produced from different groups of nitric oxide synthases and plays an important role in regulation of vascular tone and blood flow in...

Urinary nitric oxide in newborns with sepsis: a useful follow-up marker

Neonatal Sepsis is a major problem in newborn nurseries because of the difficulty of early diagnosis and because of high morbidity and mortality. The objective of this study was to investigate whether urinary nitric oxide (NO) level could be useful for the diagnosis and follow-up of infected newborns. Urinary NO was measured for 30 newborns with sepsis on the first and on the fourth day (group I) and compared with 10 age-matched healthy control (group II). Ninety percent of the septic group showed increase in the urinary NO level during sepsis, while there was decrease in the NO level in the control group. The levels of NO did not differ significantly between cases and control on the first day (p = 0.24), but the difference was significant between the two groups on day 4 (p = 0.02). On comparing the change in NO level from first to fourth day between the two groups, a statistically significant difference was found (p = 0.000). Although urinary NO levels were higher in the infected newborns as compared to the controls on the fourth day, its failure to rise to statistically significant levels on day 1 makes it a nonsuitable marker for early diagnosis of neonatal sepsis, it can however be used for monitoring infection due to its rising level and ease of sample collection.

Sepsis-induced urinary concentration defect is related to nitric oxide–dependent inactivation of TonEBP/NFAT5, which downregulates renal medullary solute transport proteins and aquaporin-2*

Acute kidney injury associated with reduced urinary concentration is a frequent and severe complication during sepsis. The present study addressed the effect of endotoxemia on the functional and molecular mechanisms that determine urinary concentrating ability. Efficient urinary concentration depends on, amongst other factors, the expression of the Cl channel kidney-specific chloride channel 1 and its subunit Barttin, the urea transporter-A1, and the water channel aquaporin 2, all of which are regulated by the transcription factor TonEBP/NFAT5. Experimental animal and cell culture model. University laboratory. Wistar rats and Madin-Darby canine kidney cells. Rats were injected with lipopolysaccharide (5 mg/kg bodyweight intraperitoneal) or vehicle (phosphate-buffered saline) as control. After 24 hrs, urine, blood, and tissue samples from various kidney zones were analyzed for parameters that determine urinary concentration ability. Madin-Darby canine kidney cells were treated under isotonic or hypertonic conditions with the nitric oxide donor S-nitroso-N-acetylpenicillamine. In rats injected with lipopolysaccharide, urine osmolality was reduced by ~40%, along with medullary induction of inducible nitric oxide synthase and a dramatic increase in urinary nitric oxide degradation products nitrite/nitrate. Concomitantly, expressions of ClC-K1, Barttin, urea transporter-A1, and aquaporin 2 were significantly lower. This was associated with the appearance of S-nitrosylated TonEBP/NFAT5, as monitored by the biotin-switch assay and immunoprecipitation, and reduced TonEBP/NFAT5 DNA binding activity in the renal inner medulla. These results were confirmed in Madin-Darby canine kidney cells transfected with a reporter construct driven by the urea transporter-A promoter, in which the nitric oxide donor S-nitroso-N-acetylpenicillamine reduces urea transporter-A reporter activity under isotonic and hypertonic conditions. The present data demonstrate that lipopolysaccharide increases medullary nitric oxide production by iNOS induction, resulting in impairment of the transcriptional activity of TonEBP/NFAT5 by S-nitrosylation. The consequence thereof is reduced expression of TonEBP/NFAT5 target genes ClC-K1, Barttin, urea transporter-A1, and aquaporin 2 that are required for urinary concentration. Our findings may provide further insight into the molecular mechanisms underlying the urinary concentration defect in sepsis.

Decrease of Postprandial Endothelial Dysfunction by Spice Mix added to High Fat Meat Patty in Men with Type 2 Diabetes Mellitus

BackgroundHigh fat intake has been demonstrated to promote endothelial dysfunction possibly through an increase in lipid peroxidation and decrease in serum nitric oxide.Objectivestudy the effect of spice mixture on malondialdehyde (MDA) production, serum nitric oxide and postprandial endothelial dysfunction measured as peripheral arterial tonometry (PAT).MethodsHamburger meat was mixed with and without spice prior to cooking. Twenty‐two males with type 2 DM on diet or oral medications consumed control burgers with salt only (CB) or salt and spice mix (SPB) in randomized order.ResultEighteen subjects completed the study. Two hours after consumption of the burger, the PAT score decreased by 9.7±21.5% for CB and increased by 18.0±42.4% for SPB. The change of PAT score after CB and SPB was significantly different (p=0.025). The postprandial concentration of glucose, insulin and triglycerides were similar in all subjects after CB or SPB. Urine MDA excretion in μmol/g creatinine was reduced by 31 percent (p&lt;0.001) in the subjects consuming the SPB compared to the CB group. The average urine nitric oxide concentration 6 hours after consumption of burgers was 9.09±5.7 mcM/mg after CB and 12.37±7.00 mcM/mg after SB with a p value of 0.053.ConclusionThis study demonstrates the benefits of a polyphenol‐rich spice mixture in promoting vascular health when added to cooked meats.

Protective Effects of Nobiletin on Hypertension and Cerebral Thrombosis in Stroke-Prone Spontaneously Hypertensive Rats (SHRSP)

Some citrus flavonoids have been reported to possess antioxidant activities that moderate endothelial dysfunction and show protective effects on cardiovascular disease. We have investigated the protective effects of nobiletin (5,6,7,8,3’,4’-hexamethoxy flavone) derived from the peel of Citrus depressa Hayata (Shiikuwasha), a citrus fruit produced in Okinawa prefecture in Japan on hypertension and thrombogenicity in cerebral vessels of stroke-prone spontaneously hypertensive rats (SHRSP). Nobiletin was added to the diet of male SHRSP (7 weeks old) for 4 weeks. The age-related increase in systolic blood pressure usually observed in SHRSP was significantly suppressed in the treated animals. Thrombogenesis in pial blood vessels, determined using a He-Ne laser technique, and antioxidant activity, assessed by measuring urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG), were significantly reduced after treatment. Urinary nitric oxide (NO) metabolites and acetylcholine-induced endothelial relaxation were increased after dietary intervention. These results strongly suggested that antihypertensive and antithrombotic effects of nobiletin may be related to an increase in bioavailable NO, possibly mediated by the scavenging of reactive oxygen species (ROS).

Vitamin D and Parathyroid Hormone Relationships with Urinary Nitric Oxide Metabolites and Plasma Isoprostanes in African-Americans

Background: Vitamin D deficiency and secondary rises in parathyroid hormone (PTH) are highly prevalent in obese African-Americans. Endothelial dysfunction related to oxidative stress is more common in African-Americans compared to whites. Currently, the association of vitamin D (25-hydroxyvitamin D, 25-OH D) and PTH to nitric oxide metabolites (NOx) – nitrate and nitrite – and oxidative stress in African-Americans is unknown. Objective: A cross-sectional design was utilized to determine the association of 25-OH D and PTH with urinary NOx (UNOx) (n = 101) and plasma isoprostanes (n = 125), an oxidative stress marker, in overweight (body mass index of 25–39.9), normotensive African-Americans aged ≥35 years. Measurements: Multivariable linear regression analysis adjusted for age, sex, body mass index, and season was used to determine the relationship of 25-OH D and PTH to UNOx and isoprostanes. General linear models, adjusted for the same covariates, contrasted UNOx across three mutually exclusive vitamin D/PTH groups: (1) normal 25-OH D (51–249 nmol/l) and normal PTH (≤65 pg/ml); (2) low 25-OH D and normal PTH, and (3) low 25-OH D and high PTH. Results: 25-OH D was directly associated with UNOx before (p = 0.02) and after (p = 0.03) adjustment for PTH levels. A borderline significant association was observed between PTH and isoprostanes (p = 0.08). UNOx was 424, 290, and 270 µmol/8 h, respectively, across vitamin D/PTH groups 1–3 (p = 0.08). Conclusion: 25-OH D was directly associated with NO availability and PTH was positively, though borderline, associated with isoprostanes in overweight, normotensive adult African-Americans.

Astaxanthin inhibits thrombosis in cerebral vessels of stroke-prone spontaneously hypertensive rats

It is known that vitamin E and some carotenoids have antioxidant activities that alleviate endothelial dysfunction and play a protective role against cardiovascular disease. The current study was designed to examine the hypothesis that astaxanthin, a red pigment carotenoid found in salmonid and crustacean aquaculture, protects stroke-prone spontaneously hypertensive rats (SHRSP) from vascular oxidative damage, hypertension, and cerebral thrombosis. Male 6-week-old SHRSP were classified into 4 groups: a control group, 2 astaxanthin groups, and a vitamin E group. The treated animals were given either astaxanthin or vitamin E for 3 weeks. Body weights in each group were not significantly different from control group during the treatment period, but the usual increase in systolic blood pressure in SHRSP observed with age was significantly suppressed by treatment. Thrombogenesis, assessed using a helium-neon (He-Ne) laser technique in pial blood vessels, together with antioxidant activity, assessed by measuring urinary 8-OHdG levels, were significantly moderated. Urinary nitric oxide (NO) metabolites were increased after treatment. These results supported our hypothesis and strongly suggested that the antithrombotic and antihypertensive effects of astaxanthin or vitamin E may be related to an increase in bioavailable NO, possibly mediated by decreased inactivation of NO by reactive oxygen species.

Pneumoperitoneum Aggravates Renal Function in Cases of Decompensated But Not Compensated Experimental Congestive Heart Failure: Role of Nitric Oxide

Congestive heart failure is associated with impaired renal function. Previously we noted that increased intra-abdominal pressure (pneumoperitoneum) in normal rats induced renal dysfunction. In this study we investigated the renal effects of pneumoperitoneum in rats with compensated (urinary Na(+) excretion greater than 1,200 μEq per 24 hours) and decompensated (urinary Na(+) excretion less than 200 μEq per 24 hours) congestive heart failure, and the possible involvement of nitric oxide in these effects. After a baseline period rats with congestive heart failure induced by aorto-caval fistula and sham operated controls underwent consecutive intra-abdominal pressures of 7, 10 or 14 mm Hg for 45 minutes each. Urinary flow, urinary Na(+) excretion, glomerular filtration rate, renal plasma flow and urinary nitric oxide metabolites were determined. There were no changes in urinary flow, urinary Na(+) excretion, glomerular filtration rate or renal plasma flow during 7 mm Hg insufflation in controls. However, significant decreases in these parameters were observed during 10 and 14 mm Hg in correlation with intra-abdominal pressure. Baseline renal function and hemodynamics were lower in rats with congestive heart failure in correlation with disease severity. Rats with decompensated congestive heart failure that underwent 10 and 14 mm Hg showed aggravated decreases in urinary flow, urinary Na(+) excretion, glomerular filtration rate and renal plasma flow. In contrast, no adverse renal effects were observed in rats with compensated congestive heart failure under identical intra-abdominal pressure conditions. Despite unaltered baseline urinary nitric oxide metabolites in the 2 congestive heart failure subgroups, the decompensated group showed decreased urinary nitric oxide metabolites after 14 mm Hg. Finally, rats with compensated congestive heart failure pretreated with the nitric oxide synthase inhibitor L-NAME showed worse renal function in response to pneumoperitoneum. Decompensated congestive heart failure renders rats susceptible to the adverse renal effects of pneumoperitoneum, a phenomenon that may involve alterations in the renal nitric oxide system.

Urinary nitric oxide metabolites and individual blood pressure progression to overt hypertension

Baseline blood pressure (BP) is the strongest known determinant of progression to hypertension, but for an individualized prediction of the incidence of hypertension, the identification of additional biomarkers is crucial. In animal models of hypertension, renal nitric oxide (NO) handling modifies the systemic BP responses prior to the development of hypertension. This study aimed to evaluate whether urinary NO metabolites (NOx) predict the progression of hypertension in normotensive subjects. Among 62 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes, we assessed progression to hypertension over 4.6 years. In a case-control design, 49 normotensive subjects including 10 subjects with high-normal blood pressure were enrolled of whom 25 remained normotensive (controls), whereas 24 'progressed' to hypertension (progressors). Thirteen hypertensive patients served as negative controls. Urinary NOx concentration, renal function and the urinary excretion of electrolytes were assessed at baseline and follow-up. At baseline, progressors showed higher BP values than controls and urinary NOx concentration was significantly lower in progressors as compared to the normotensive controls (p < 0.01). In all initially normotensive subjects baseline urinary NOx concentration was associated with follow-up BP (r = -0.55, p < 0.001) and the relative increase of BP over time (r = -0.47, p < 0.001). In progressors baseline urinary NOx was associated with follow-up BP (r = -0.52, p < 0.009) and the relative increase of BP over time (r = -0.44, p = 0.033). Baseline urinary NOx and BP were independent predictors for the relative BP increase. A urinary NOx threshold of <130.5 mg/L predicted 75% of all progressors. In context with high-normal baseline BP, 87.5% of all progressors were identified. These findings indicate that urinary NO metabolites are associated with BP development in normotensive subjects. Moreover, urinary NOx predicts the progression to hypertension independent of baseline BP suggesting urinary NOx as a biomarker for individual new-onset hypertension.

Leukocyte and Platelet Depletion Improves Blood Flow and Function in a Renal Transplant Model

Donation after cardiac death (DCD) donors are an important source of organs for transplantation. Due to warm and cold ischemic injury, DCD kidneys undergo a significant reperfusion insult when transplanted. This is manifested clinically as a high incidence of delayed graft function (DGF) and primary non-function (PNF). The importance of leukocytes in the generation of reperfusion injury is pivotal. Using an ex vivo porcine model of kidney transplantation, the effects of reperfusion with leukocyte and platelet depleted blood (LDB) and whole blood (WB) on renal blood flow and function were compared. Hemodynamic measurements were recorded, and biochemical, hematological, and histologic samples taken at set time-points. Reperfusion with LDB improved renal blood flow significantly compared with WB reperfusion. In addition, there was a significant improvement in creatinine clearance and renal oxygen consumption, but not fractional excretion of sodium, acid-base homeostasis, urinary nitric oxide (NO), or 8-isoprostane levels. This study represents a good model for the initial reperfusion period in renal transplantation. Improvement in only some functional markers and neither urinary NO nor 8-isoprostane levels indicates that improved blood flow alone is not sufficient to reverse the severe ischemic insult endured by DCD kidneys.

Phosphorylated Endothelial NOS Ser1177 via the PI3K/Akt Pathway Is Depressed in the Brain of Stroke-Prone Spontaneously Hypertensive Rat

Stroke-prone spontaneously hypertensive rats (SHRSP) demonstrate impaired endothelium-dependent relaxation and often develop brain injuries. We investigated whether the regulatory mechanism for endothelial NOS (eNOS) phosphorylation and activation is altered in the cerebral cortex of SHRSP at a younger age. Western blot analysis revealed a low ratio of phosphor-eNOS (Ser1177) to total eNOS in SHRSP at 10 weeks of age. In addition, urinary nitric oxide metabolites (ie, nitrate and nitrite) were decreased compared with normal control WKY rats. Likewise, Akt phosphorylation (especially Ser473) was significantly reduced, with no changes in total Akt. Furthermore, the amount of the phosphatidylinositol 3-kinase (PI3K) was upstream of Akt was diminished, although attenuation of the PI3K/Akt pathway was not an effect of mTOR, another downstream target of Akt. Our findings indicate that abnormalities of the PI3K/Akt pathway in the cerebral cortex are involved in the impaired eNOS phosphorylation and activation in SHRSP.

Urinary nitric oxide excretion in infants with eczema

Eczema is characterized by inflammation of the skin and is commonly associated with food allergy. It has been suggested that nitric oxide (NO) is an important player in eczema, food allergy and intestinal inflammation. The aim of this study was to assess the levels of urinary NO breakdown products in infants with eczema and the effect of eczema treatment on NO levels. Ninety-four infants with eczema, 58 boys and 36 girls, with a mean age of 7.5 ± 5.2 months (mean ± s.d.) at inclusion were examined twice with an interval of 6 wk. The sum of nitrite and nitrate was measured colorimetrically in urinary samples from both visits and compared with clinical data concerning eczema severity, nutrition, gastrointestinal symptoms, asthma and skin prick positivity. The levels of NO products increased significantly from the first to the second visit: 289; 374 μm (median; IQR) vs. 457; 678 μm (median; IQR) (p < 0.001) in parallel with a significant improvement of the eczema. After eczema treatment consisting of skin care and elimination diet during the 6-wk interval between evaluations, the NO levels approached the values previously found in healthy children. The results support previous studies indicating that the homeostasis of nitrogen radicals is disturbed in childhood eczema.

Exercise Training, NADPH Oxidase p22phox Gene Polymorphisms, and Hypertension

Oxidative stress that is mediated through NADPH oxidase activity plays a role in the pathology of hypertension, and aerobic exercise training reduces NADPH oxidase activity. The involvement of genetic variation in the p22phox (CYBA) subunit genes in individual oxidative stress responses to aerobic exercise training has yet to be examined in Pre and Stage 1 hypertensives. Ninety-four sedentary Pre and Stage 1 hypertensive adults underwent 6 months of aerobic exercise training at a level of 70% VO2max to determine whether the CYBA polymorphisms, C242T and A640G, were associated with changes in urinary 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), urinary nitric oxide metabolites (NOx), and plasma total antioxidant capacity (TAC). Demographic and subject characteristics were similar among genotype groups for both polymorphisms. At baseline, a significant (P = 0.03) difference among the C2424T genotype groups in 8-iso-PGF2alpha levels was detected, with the TT homozygotes having the lowest levels and the CC homozygotes having the highest levels. However, no differences were found at baseline between the A640G genotype groups. After 6 months of aerobic exercise training, there was a significant increase in VO2max (P < 0.0001) in the entire study population. In addition, there were significant increases in both urinary 8-iso-PGF2alpha (P = 0.002) and plasma TAC (P=0.03) levels and a significant decrease in endogenous urinary NOx (P < 0.0001). Overall, aerobic exercise training elicited no significant differences among genotype groups in either CYBA variant for any of the oxidative stress variables. We found that compared with CYBA polymorphisms C242T and A640G, it was aerobic exercise training that had the greatest influence on the selected biomarkers; furthermore, our results suggest that the C242T CYBA variant influences baseline levels of urinary 8-iso-PGF2alpha but not the aerobic exercise-induced responses.

Curcumin improves vascular function and alleviates oxidative stress in non-lethal lipopolysaccharide-induced endotoxaemia in mice

Oxidative stress is implicated in various pathological conditions, including septic shock, and other diseases associated with local or systemic inflammation. Curcumin, a major component from turmeric ( Curcuma longa), possesses diverse anti-inflammatory, anti-tumour and antioxidant properties. The aim of this study was to investigate the effect of curcumin on modulation of vascular dysfunction and oxidative stress induced by lipopolysaccharide (LPS) in mice. Male ICR mice were treated with curcumin (50 or 100 mg/kg), administered intragastrically, either before or after intraperitoneal injection of LPS (10 mg/kg). Fifteen hours after LPS administration, arterial blood pressure was measured and vascular response to vasoactive agents were assessed. Aortic tissues and blood samples were taken for assays of antioxidant and oxidative stress markers. LPS caused marked hypotension, tachycardia and vascular hyporeactivity. The mean arterial pressures in responses to phenylephrine, acetylcholine, and sodium nitroprusside of LPS-treated mice were significantly decreased when compared with the untreated controls. Curcumin modulated heart rate and restored arterial blood pressure in a dose-dependent manner in both protectively- and therapeutically-treated regimens. Furthermore, the vascular responsiveness of LPS-treated mice was improved by curcumin. Interestingly, the improvements of haemodynamics and vascular response during endotoxaemia were related to alleviation of oxidative stress by reducing aortic-derived superoxide production, suppression of lipid peroxidation and protein oxidation, and decrease in urinary nitric oxide metabolites with preservation of the ratio of glutathione/glutathione disulfide. This study provides the first evidence for the potential role of curcumin in prevention and treatment of vascular dysfunction in mice with endotoxaemia elicited by LPS.

Inhibition of natriuretic factors increases blood pressure in rats

Renal dopamine and nitric oxide contribute to natriuresis during high-salt intake which maintains sodium and blood pressure homeostasis. We wanted to determine whether concurrent inhibition of these natriuretic factors increases blood pressure during high-sodium intake. Male Sprague-Dawley rats were divided into the following groups: 1) vehicle (V)-tap water, 2) NaCl-1% NaCl drinking water, 3) 30 mM l-buthionine sulfoximine (BSO), an oxidant, 4) BSO plus NaCl, and 5) BSO plus NaCl with 1 mM tempol (antioxidant). Compared with V, NaCl intake for 10 days doubled sodium intake and increased urinary dopamine level but reduced urinary nitric oxide content. NaCl intake also reduced basal renal proximal tubular Na-K-ATPase activity with no effect on blood pressure. However, NaCl intake in BSO-treated rats failed to reduce basal Na-K-ATPase activity despite higher urinary dopamine levels. Also, dopamine failed to inhibit proximal tubular Na-K-ATPase activity and these rats exhibited reduced urinary nitric oxide levels and high blood pressure. Tempol supplementation in NaCl plus BSO-treated rats reduced blood pressure. BSO treatment alone did not affect the urinary nitric oxide and dopamine levels or blood pressure. However, dopamine failed to inhibit proximal tubular Na-K-ATPase activity in BSO-treated rats. BSO treatment also increased basal protein kinase C activity, D1 receptor serine phosphorylation, and oxidative markers like malondialdehyde and 8-isoprostane. We suggest that NaCl-mediated reduction in nitric oxide does not increase blood pressure due to activation of D1 receptor signaling. Conversely, oxidative stress-provoked inhibition of D1 receptor signaling fails to elevate blood pressure due to presence of normal nitric oxide. However, simultaneously decreasing nitric oxide levels with NaCl and inhibiting D1 receptor signaling with BSO elevated blood pressure.

Androgen-Androgen Receptor System Protects against Angiotensin II-Induced Vascular Remodeling

Age-related andropause promotes cardiovascular disease in males. Although we had previously reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and remodeling, the system's involvement in vascular remodeling remains unclear. To clarify this role, 25-wk-old male AR knockout (ARKO) mice and littermate male wild-type (WT) mice were divided into two groups with and without angiotensin II (Ang II) administration (2.0 mg/kg . d) for 14 d, respectively. No morphological differences in the coronary artery and thoracic aorta were observed between the groups without Ang II. Ang II stimulation markedly increased medial thickness and perivascular fibrosis in ARKO mice, with enhanced TGF-beta1, collagen type I, and collagen type III gene expression in the aorta. Ang II stimulation also prominently increased superoxide production, lipid peroxidation, and gene expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components in ARKO mice compared with WT mice. In addition, phosphorylation of c-Jun N-terminal kinase (JNK) and phosphorylated (Smad2/3) was remarkably enhanced in Ang II-treated ARKO mice compared with Ang II-treated WT mice. Notably, daily urinary nitric oxide (NO) metabolites excretion as a marker of NO bioavailability, aortic endothelial NO synthase expression and phosphorylation, and Akt phosphorylation were significantly reduced in ARKO mice compared with WT mice, regardless of Ang II stimulation. In conclusion, the androgen-AR system is required for the preservation of NO bioavailability through Akt-endothelial NO synthase system activation and exerts protective effects against Ang II-induced vascular remodeling by regulating oxidative stress, c-Jun N-terminal kinase (JNK) signaling, and the TGF-beta-phosphorylated Smad pathway.

Serum and urine nitric oxide levels in children with Henoch–Schonlein purpura during activity and remission: a study from North India

The objective of this study is to compare serum and urine reactive nitrogen intermediates (RNI) and citrulline levels in children with Henoch-Schonlein purpura (HSP) during activity and remission. The study group consisted of 14 children with HSP. We measured serum and urine RNI and citrulline levels by spectrophotometry in the active phase of the disease and then during remission. Serum RNI levels were 303.95 +/- 221.44 nmol/ml in children with active HSP and 72.57 +/- 26.56 nmol/ml during remission, the differences being statistically significant (P = 0.002). Mean urine RNI levels in children with active HSP were significantly higher than that seen during remission (3.25 +/- 1.80 vs. 1.68 +/- 0.65 nmol/ml; P = 0.003). Similarly, serum citrulline levels during disease activity were 790.65 +/- 707.87 nmol/ml as compared to 281.49 +/- 307.29 nmol/ml at the time of remission, the differences being statistically significant (P = 0.002). Mean urine citrulline levels in children with active disease was 1,969.94 +/- 1655.42 nmol/ml as compared to 1,099.34 +/- 955.82 nmol/ml in children with remission, (P = 0.007). Serum and urine RNI and citrulline levels were significantly higher during the acute phase of HSP as compared to the levels obtained during the phase of disease remission. These findings suggest that nitric oxide may perhaps have a role in the pathogenesis of HSP. Further, these laboratory parameters could be of value in monitoring disease activity. To the best of our knowledge, this study is the most comprehensive work published on the subject so far. Our findings, however, need to be confirmed on a larger study sample before firm conclusions can be drawn.

Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism.

Angiostatin, a proteolytic fragment of plasminogen, is a potent anti-angiogenic factor recently shown also to have an inhibitory effect on leukocyte recruitment and macrophage migration. Because both angiogenesis and inflammation play key roles in the progression of chronic kidney disease, we evaluated the effect of angiostatin treatment in the rat remnant kidney model. Rats were pretreated for 4 wk with recombinant adeno-associated viruses expressing either angiostatin or green fluorescence protein. Chronic renal disease was then induced by a subtotal nephrectomy, and rats were killed 8 wk later for analysis. Angiostatin treatment was associated with significantly less proteinuria but no alterations in serum creatinine, creatinine clearance, and blood urea nitrogen levels. Treatment with angiostatin reduced renal peritubular capillary number and decreased urinary nitric oxide levels. Despite reducing capillary density, angiostatin diminished interstitial fibrosis in association with reduced macrophage and T-cell infiltration and renal monocyte chemoattractant protein-1 mRNA levels. In conclusion, angiostatin overexpression was associated with attenuated renal disease progression in a model of chronic kidney injury, likely because of its anti-inflammatory actions. However, its anti-angiogenic actions suggest countering effects that could partially offset its benefit in chronic kidney diseases.