Plasma Nitric Oxide Metabolites Research Articles

Asymmetric dimethylarginine and nitric oxide levels in migraine during the interictal period

Nitric oxide (NO), which modulates endothelial function, is thought to be pivotal in the pathophysiology of migraines. The connection between migraine and cardiovascular diseases has also drawn attention to the endothelial dysfunctions and NO pathway abnormalities seen in patients with migraine. Our goal was to assess the levels of NO and the endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), in people with migraine during the interictal period. A total of 49 patients with migraine and 22 control subjects were enrolled in the study. Their plasma NO metabolites (nitrite [ NO 2 - ] and nitrate [ NO 3 - ]) and ADMA levels were measured using the enzyme-linked immunosorbent assay method, and were then compared with their cardiovascular risk factors, anthropometric measurements, and headache frequency and severity. The plasma ADMA, NO 2 - and NO 3 - levels of the patients with migraine during the interictal period did not differ from the control group, and no relationship was found between cardiovascular risk factors and migraine attack severity and frequency. We conclude that, in patients with migraine, there is no dysfunction of baseline NO and ADMA metabolism during the interictal period.

Plasma nitric oxide metabolite (NOM) concentrations are elevated in the obese and type 2 diabetics and are suppressed by insulin

Plasma nitric oxide metabolite (NOM) concentrations are elevated in the obese and type 2 diabetics and are suppressed by insulin

Altered free radical metabolism in acute mountain sickness: implications for dynamic cerebral autoregulation and blood–brain barrier function

We tested the hypothesis that dynamic cerebral autoregulation (CA) and blood-brain barrier (BBB) function would be compromised in acute mountain sickness (AMS) subsequent to a hypoxia-mediated alteration in systemic free radical metabolism. Eighteen male lowlanders were examined in normoxia (21% O(2)) and following 6 h passive exposure to hypoxia (12% O(2)). Blood flow velocity in the middle cerebral artery (MCAv) and mean arterial blood pressure (MAP) were measured for determination of CA following calculation of transfer function analysis and rate of regulation (RoR). Nine subjects developed clinical AMS (AMS+) and were more hypoxaemic relative to subjects without AMS (AMS-). A more marked increase in the venous concentration of the ascorbate radical (A(*-)), lipid hydroperoxides (LOOH) and increased susceptibility of low-density lipoprotein (LDL) to oxidation was observed during hypoxia in AMS+ (P < 0.05 versus AMS-). Despite a general decline in total nitric oxide (NO) in hypoxia (P < 0.05 versus normoxia), the normoxic baseline plasma and red blood cell (RBC) NO metabolite pool was lower in AMS+ with normalization observed during hypoxia (P < 0.05 versus AMS-). CA was selectively impaired in AMS+ as indicated both by an increase in the low-frequency (0.07-0.20 Hz) transfer function gain and decrease in RoR (P < 0.05 versus AMS-). However, there was no evidence for cerebral hyper-perfusion, BBB disruption or neuronal-parenchymal damage as indicated by a lack of change in MCAv, S100beta and neuron-specific enolase. In conclusion, these findings suggest that AMS is associated with altered redox homeostasis and disordered CA independent of barrier disruption.

The correlation between the plasma nitric oxide levels and QT/QTc interval in conscious rabbits

The current study was undertaken to investigate the effects of NOx (plasma concentrations of nitrate plus nitrite which are plasma nitric oxide (NO) metabolites) over QT interval and to determine the level of correlation between them in conscious rabbits. For this purpose, twenty-one New Zealand rabbits (5-7 months old) were used and randomly assigned into the following three groups: control (CG; n = 7, 1 ml isotonic NaCl solution per animal/day), L-arginine (ARG-G; n = 7, L-arginine solution 200 mg/kg/day) and L-NAME (NAME-G; n = 7, L-NAME solution 100 mg/kg/day). Injections were performed intraperitoneally at 9:00 a.m. for 9 days. Blood samples were collected 2 h after the injections on day 1, 5 and 9 and the concentration of plasma NOx was determined using a colorimetric method. ECG was also recorded 2 h after the injection on 1st, 5th and 9th days. The heart rate, QT intervals, corrected QT intervals (QTc) and QT dispersion (QTd), QTc dispersion (QTcd) values were calculated from the ECG recordings. Statistically significant differences were observed between HR, QT and QTc values in all groups for all days (p < 0.001). QTd and QTcd values were found statistically significant different in NAME-G compared to CG and ARG-G (p < 0.001). It was also determined that there was a statistically significant correlation between the NOx and HR and QT and QTc in all days. It is concluded from this study that NO is an important molecule for the electrical activation of heart and has effects on the duration of QT/QTc interval, which should be taken into consideration by the physicians. In addition, application of the L-arginine should be further studied.

Estrogen Replacement Suppresses Pressor Response and Oxidative Stress Induced by Cage‐switch Stress in Ovariectomized Rats

We examined the suppressive effects of estradiol on psychological stress-induced cardiovascular responses and oxidative stress in ovariectomized rats, both placebo-treated (OVX+Pla) and estrogen-treated (OVX+E2). The elevations in blood pressure and heart rate induced by cage-switch stress were attenuated in the OVX+E2 as compared with the OVX+Pla group. N(G)-nitro-L-arginine methyl ester, administered via drinking water, reduced the difference in these responses. Furthermore, this stress increased plasma nitrotyrosine and decreased plasma nitric oxide (NO) metabolites only in the OVX+Pla group. We demonstrated that estrogen replacement suppresses cardiovascular responses to psychological stress, at least in part by improving NO bioavailability in ovariectomized rats.

Oxidative Stress and Total Antioxidant Capacity in Diabetic and Nondiabetic Acute Ischemic Stroke Patients

Free radical formation is the pivotal mechanism of neuronal injury of ischemic and reperfused brain tissue. In healthy individuals, antioxidant activity counterbalances free radical production, but in the case of ischemia, the balance between reactive oxygen species and antioxidant activity is shifted toward free radicals, causing oxidative stress. The aim of this study is to assess total antioxidant capacity (TAC) and oxidative stress in diabetic and nondiabetic acute stroke patients with 2 different stroke subtypes: large and small vessel disease stroke. Sixty-five acute ischemic stroke patients (29 diabetic and 36 nondiabetic) and 20 age-matched healthy control subjects were recruited in the study. Plasma TAC and nitric oxide (NO) metabolite levels (nitrite and nitrate) were measured by enzyme-linked immunosorbent assay. The subtypes of stroke were defined according to Trial of Org 10172 in Acute Stroke Treatment criteria. The main findings of this study are that the TAC and NO levels were significantly higher in diabetic acute stroke patients than in nondiabetic patients and control cases (P < .001 and P < .001, respectively). The TAC and NO levels were higher also in nondiabetic stroke patients than in controls, but the difference did not reach any significance. No difference was found between NO and TAC levels in large and small vessel stroke subtypes of diabetic and nondiabetic patients. The authors conclude that oxidative stress and counterbalancing antioxidant capacity are more pronounced in diabetic acute stroke patients than in nondiabetic acute stroke patients.

Liposome-Encapsulated Hemoglobin Transfusion Rescues Rats Undergoing Progressive Hemodilution From Lethal Organ Hypoxia Without Scavenging Nitric Oxide

To investigate the efficacy of liposome-encapsulated hemoglobin (LHb) transfusion in rats undergoing lethal progressive hemodilution. Unlike other acellular hemoglobin-based oxygen carriers, LHb has lipid bilayer membranes that are similar to mammalian red blood cells (RBCs), which prevent hemoglobin from having any direct contact with the blood components and the endothelium. Acellular hemoglobin has a high affinity for nitric oxide (NO), and because they are reported to behave as NO scavengers, acellular hemoglobin-based oxygen carriers could have pressor effects on the peripheral vessels. During a massive hemorrhage, acellular hemoglobin caused vasoconstriction could decrease peripheral perfusion, thereby leading to diminished oxygen delivery. Rats were subjected to blood withdrawal (0.2 mL/min) with a simultaneous resuscitation using an isovolemic fluid transfusion that contained LHb, 5% albumin, or washed rat RBCs for 150 minutes (n = 15 in each group). All rats transfused with LHb or RBCs were rescued from lethal progressive hemodilution, whereas none of the albumin-transfused rats survived. LHb did not affect the plasma NO metabolite levels, suggesting it was not a potent NO scavenger. LHb also improved hemodilution-induced metabolic acidosis, and reduced exaggerated neuroendocrine responses and injuries to the heart, liver, and kidney. It suppressed expression of hypoxia-inducible factor-1alpha in the liver and kidney, suggesting improvement of hypoxia at molecular response levels. However, neither transfused LHb nor RBCs improved the acute lung injury that occurs after progressive hemodilution. LHb transfusion is effective in rescuing rats undergoing progressive hemodilution from lethal organ hypoxia without scavenging NO.

Reduced plasma nitric oxide metabolites before and after antipsychotic treatment in patients with schizophrenia compared to controls

BackgroundNitric oxide (NO) is believed to have a role in the pathophysiology of schizophrenia. We examined plasma levels of NO metabolites in patients with schizophrenia and normal controls. We also determined the impact of 6-week risperidone treatment on circulating NO metabolites in patients with schizophrenia. MethodPlasma NO metabolite (NOx) levels were measured in 55 schizophrenia patients before and after 6-week treatment with risperidone and in 55 normal controls. Severity of schizophrenia and response to treatment were assessed with the positive and negative syndrome scale (PANSS) for schizophrenia. NOx levels were estimated by the Griess method. ResultsPre-treatment plasma NOx levels in schizophrenia patients (8.97±6.74 µmol/L) were lower than those of normal controls (14.51±6.30 µmol/L) (p<0.01). Schizophrenia patients had lower post-treatment NOx levels (10.99±8.31 µmol/L) than those of normal controls (p<0.01). There was marginal significant change between plasma NOx levels before and after 6-week treatment (p=0.056). Moreover, in 37 treatment responders (≥30% improvement in PANSS score), post-treatment plasma NOx significantly increased in comparison to pre-treatment NOx (p=0.028). ConclusionsPlasma levels of NOx in patients with schizophrenia were significantly lower than normal controls both before and after the treatment. Our findings suggest that the improvement of psychiatric symptoms can lead to partially normalize a deficiency of NO after treatment in schizophrenia patients. Our findings support the hypothesis that the NO system is dampened in schizophrenia.

Severe liver steatosis correlates with nitrosative and oxidative stress in rats

Little is known about nitric oxide (NO) metabolism and redox changes with hepatocyte adipocytic transformation. The aims of this study were to investigate the changes occurring in plasma and hepatic NO metabolites and redox balance in a rat experimental model of simple fatty liver, and to relate plasma with hepatic and mitochondrial changes at different degrees of steatosis. Circulating and hepatic redox active and nitrogen regulating molecules thioredoxin, glutathione, protein thiols (PSH), mixed disulfides (PSSG), NO metabolites nitrosothiols, nitrite plus nitrate (NOx), and lipid peroxides (TBARs) were measured in rats fed a choline deprived (CD) diet for 30 days. At histology, the CD diet resulted in hepatocellular steatosis (75% of liver weight at day 30) with no signs of necro-inflammation. In plasma, thioredoxin, nitrosothiols and NOx were unchanged, while TBARs levels increased significantly and were positively related with hepatic TBARs (r = 0.87, P < 0.001) and lipid content (r = 0.90, P < 0.001). In the liver, glutathione initially increased (day 3) and then decreased. From day 14, PSH decreased and NO derivatives increased. Thioredoxin 1 had initially increased (days 7-14) and then decreased. In the mitochondria, on day 14, nitrosothiols were inversely related to thioredoxin 2 (r = 0.988, P < 0.05); on day 30, PSH were decreased by 70%, PSSG were doubled and related with nitrosothiols levels (r = 0.925, P < 0.001). Adipocytic transformation of hepatocytes is accompanied by major interrelated modifications of redox parameters and NO metabolism especially at mitochondrial level, suggesting an early adaptive protective response but also an increased predisposition towards pro-oxidant insults.

Effects of Exercise Training on Plasma Nitric Oxide Metabolite Levels: Association with Common eNOS Gene Polymorphisms

Effects of Exercise Training on Plasma Nitric Oxide Metabolite Levels: Association with Common eNOS Gene Polymorphisms

Electron paramagnetic resonance investigation on modulatory effect of benidipine on membrane fluidity of erythrocytes in essential hypertension

It has been shown that benidipine, a long-lasting calcium (Ca) channel blocker, may exert its protective effect against vascular disorders by increasing nitric oxide (NO) production. The purpose of the present study was to investigate whether orally administered benidipine might influence the membrane function in patients with essential hypertension. We measured the membrane fluidity of erythrocytes by using an electron paramagnetic resonance (EPR) and spin-labeling method. In the preliminary study using erythrocytes obtained from healthy volunteers, benidipine decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (ho/h-1) for 16-NS in the EPR spectra in vitro. The finding indicated that benidipine increased the membrane fluidity and improved the microviscosity of erythrocytes. In addition, it was demonstrated that the effect of benidipine on membrane fluidity of erythrocytes was significantly potentiated by the NO-substrate, L-arginine. In the separate series of the study, we observed that orally administered benidipine for 4 weeks significantly increased the membrane fluidity of erythrocytes with a concomitant increase in plasma NO metabolite levels in hypertensive subjects. The results of the present study demonstrated that benidipine might increase the membrane fluidity and improve the microviscosity of erythrocytes both in vitro and in vivo, to some extent, by the NO-dependent mechanism. Furthermore, it is strongly suggested that orally administered benidipine might have a beneficial effect on the rheologic behavior of erythrocytes and the improvement of the microcirculation in hypertensive subjects.

Copper deficient rats exhibit no alterations in plasma or brain NO metabolites, 3‐nitrotyrosine peptide abundance, or NOS mRNA expression

Others have reported that copper deficient (Cu−) rodents have alterations in nitric oxide (NO) biology including: higher nitric oxide synthase (NOS) activity and expression, and higher 3‐nitrotyrosine abundance (a marker of peroxynitrite production predicted to be higher because of higher NO and superoxide). Altered NO could impact brain development and metabolism. Holtzman rat dams were fed a Cu− diet and given either Cu supplemented (Cu+) or deionized water starting on gestation day 7. Cu− dams at weaning and their male pups at P26 had near zero plasma ceruloplasmin activity. Compared to Cu+ P26 male rats Cu− rats had heart/body weight values more than twice as high. However, plasma levels of NO metabolites (nitrite and nitrate) were not altered by Cu deficiency in dams or pups. Mean values in all groups were approximately 60 μM. Cerebellar extracts of P24 Cu− and Cu+ rats contained equivalent NO metabolite levels; furthermore, a 30kD 3‐nitrotyrosine containing peptide was detected in equal amounts in P24 Cu− and Cu+ cerebellar extracts. However, levels of CCS were markedly higher and CCO subunit IV nearly absent in Cu− lanes confirming severe Cu deficiency. Abundance of brain nNOS and eNOS mRNA, detected by real time qPCR, was not different between Cu− and Cu+ rat pups. We conclude perturbation in NO biology is unlikely to impact the altered development and metabolism of Cu− rat brain.Supported in part by NIH HD‐39708.

Adiponectin Prevents Cerebral Ischemic Injury Through Endothelial Nitric Oxide Synthase–Dependent Mechanisms

Adiponectin is a fat-derived plasma protein that has beneficial actions on cardiovascular disorders. A low level of plasma adiponectin is associated with increased mortality after ischemic stroke; however, the causal role of adiponectin in ischemic stroke is unknown. To explore the role of adiponectin in the development of acute cerebral injury, we subjected adiponectin-deficient (APN-KO) and wild-type (WT) mice to 1 hour of middle cerebral artery occlusion followed by 23 hours of reperfusion. APN-KO mice exhibited enlarged brain infarction and increased neurological deficits after ischemia-reperfusion compared with WT mice. Conversely, adenovirus-mediated supplementation of adiponectin significantly reduced cerebral infarct size in WT and APN-KO mice. APN-KO mice showed decreased cerebral blood flow during ischemia by laser speckle flowmetry methods. Adiponectin colocalized within the cerebral vascular endothelium under transient ischemic conditions by immunohistochemical analysis. Phosphorylation of endothelial nitric oxide synthase in ischemic brain tissues and the production of nitric oxide metabolites in plasma were attenuated in APN-KO mice compared with WT mice. Adenovirus-mediated administration of adiponectin stimulated endothelial nitric oxide synthase phosphorylation and nitric oxide metabolites during cerebral ischemia in both WT and APN-KO mice. Neuronal nitric oxide synthase expression during ischemia did not differ between WT and APN-KO mice. Adenovirus-mediated delivery of adiponectin did not affect brain infarction in mice deficient in endothelial nitric oxide synthase. These data provide causal evidence that adiponectin exerts a cerebroprotective action through an endothelial nitric oxide synthase-dependent mechanism. Adiponectin could represent a molecular target for the prevention of ischemic stroke.

Effect of sulphated polysaccharides on erythrocyte changes due to oxidative and nitrosative stress in experimental hyperoxaluria.

Kidney stones are known to haunt humanity for centuries and increase in oxalate is a predominant risk factor for stone formation. The present study was initiated with a notion to study the oxidative and nitrosative stress on erythrocytes under oxalate stress and the putative role of sulphated polysaccharides. Hyperoxaluria was induced in two groups by the administration of 0.75% ethylene glycol in drinking water for 28 days and one of them was treated with sulphated polysaccharides from Fucus vesiculosus from the 8th day to the end of the experimental period of 28 days at a dose of 5 mg/kg body weight subcutaneously. Control and drug control (sulphated polysaccharides alone) were also included in the study. Glycolic and glyoxylic acid levels of urine were analyzed as an index of hyperoxaluria. The plasma enzymic markers of cellular integrity, redox status of red blood cells, osmotic fragility, and (14)C-oxalate binding were investigated. Urine and plasma nitric oxide metabolites, expression of inducible nitric oxide synthase protein, and mRNA were assessed in kidney to evaluate the nitrosative stress. Increased levels of glycolic and glyoxylic acid in urine indicated the prevalence of hyperoxaluria in ethylene glycol-administered groups. Plasma aspartate and alanine transaminase were not altered, but alkaline phosphatase and lactate dehydrogenase of hyperoxaluric group were increased indicating tissue damage. Activities of antioxidant enzymes were decreased, whereas erythrocyte membrane lipid peroxidation was increased in hyperoxaluric rats. Moreover, an altered fragility with an increase in oxalate binding activity was observed in hyperoxaluric group. Increase in nitric oxide metabolites levels in urine and plasma along with an increase in expression of inducible nitric oxide synthase protein and mRNA in kidney were observed in hyperoxaluric rats. Administration of sulphated polysaccharides to hyperoxaluric rats averted the abnormal increase in urinary glycolic and glyoxylic acid levels and enzyme activities, decreased lipid peroxidation, and increased the activities of antioxidant enzymes. Furthermore, increased nitrosative stress accompanying hyperoxaluria was also normalized on sulphated polysaccharides treatment. To conclude, sulphated polysaccharide administration was able to maintain the integrity of erythrocyte membrane and decrease the damage to erythrocytes in hyperoxaluria.

Mental stress induces sustained elevation of blood pressure and lipid peroxidation in postmenopausal women

Mental stress is thought to underlie cardiovascular events, but there is information on oxidative stress induced by mental stress in association with cardiovascular responses in women. Using a sensitive assay for plasma 4-hydroxy-2-nonenal (HNE), as a marker for oxidative stress, we addressed the relation between pressor responses and oxidative stress induced by mental or physical stress in premenopausal and postmenopausal women. Healthy subjects (7 postmenopausal and 8 premenopausal women, in early and late follicular phases) were subjected to mental and physical stress evoked by a Color Word Test (CWT) and isometric handgrip, respectively. The CWT induced a rapid elevation of diastolic blood pressure (DBP), at a higher level in the postmenopausal than in the premenopausal women ( p < 0.01), and this higher DBP was sustained during the CWT and recovery ( p < 0.01). The CWT induced a significant elevation in plasma noradrenaline in premenopausal women in the early follicular phase and in postmenopausal women ( p < 0.05). Plasma nitric oxide metabolites were higher in postmenopausal than in the premenopausal women in the late follicular phase ( p < 0.05), but did not change during exposure to the two types of stress in either group. Plasma HNE was increased during recovery from the CWT, but not the handgrip, in postmenopausal women (2.4 times, p < 0.05). There was a significant difference in the time course of the CWT-induced HNE response between the postmenopausal and premenopausal women ( p < 0.05). These findings suggest that mental, but not physical, stress causes sustained diastolic blood pressure elevation in postmenopausal women, accompanied by heightened oxidative stress.

Effects of chronic nitric oxide synthase inhibition on responses to acute exercise in swine

Nitric oxide (NO) is potentially involved in several responses to acute exercise. We tested the hypotheses that inhibition of NO formation reduces maximal O(2) delivery to muscle, but does not affect O(2) utilization by muscle, therefore lowering maximal O(2) consumption. To test these hypotheses, swine (approximately 30 kg) drank either tap water (Con, n = 25) or water with N(G)-nitro-l-arginine methyl ester (8.0 +/- 0.4 mg x kg(-1) x day(-1) for >or=4 wk; LN, n = 24). Treatment efficacy was reflected by higher mean arterial pressure and lower plasma NO metabolite concentration in LN than Con (both P < 0.05). Swine completed two graded treadmill running tests to maximum. In the first test, O(2) consumption was determined at rest through maximal exercise intensity. O(2) consumption did not differ between groups at rest or at most exercise intensities, including maximum (Con, 40.8 +/- 1.8 ml x min(-1) x kg(-1); LN, 40.4 +/- 2.9; not significant). In the second test, tissue-specific blood flows were determined using the radiolabeled-microsphere technique. At rest, blood flows were lower (P < 0.05) in LN compared with Con for a number of tissues, including kidney, adrenal, lung, and several skeletal muscles. During both submaximal and maximal exercise, however, blood flows were similar between Con and LN for all 16 muscles examined; only blood flows to kidney (Con, 99 +/- 16 ml x min(-1) x 100 g; LN, 55 +/- 15; P < 0.05) and pancreas (Con, 25 +/- 7; LN, 6 +/- 2; P < 0.05) were lower in LN at maximum. Endothelium-dependent, but not -independent, relaxation of renal arterial segments was reduced (P < 0.05) in vitro. These data indicate that exercise-induced increases in muscle blood flows are maintained with chronic inhibition of NO formation and that maximal O(2) consumption is therefore preserved. Redundant vasodilatory pathways and/or upregulation of these pathways may underlie these findings.

Lack of effect of aerobic physical exercise on endothelium-derived nitric oxide concentrations in healthy young subjects.

Previous experimental research showed an attenuated vasoconstrictor response after acute exercise. This study aims to determine the effect of aerobic physical exercise on the endothelium-derived circulating nitric oxide (NO) concentrations among healthy young persons. A total of 10 subjects (5 men and 5 women) aged 21-28 were examined for the difference in concentrations of serum and plasma NO metabolites (NOx) before and after a single bout of aerobics, in which they performed cycling exercises at a constant workload corresponding to 90% of the subject-specific anaerobic threshold. A paired t-test resulted in no statistically significant differences between pre- and post-exercise concentrations of serum or plasma NOx. It is suggested that the acute effect of aerobic exercise on the vasoconstrictor/vasodilator response is not mediated by an increase in the endothelial NO release.

Nitric Oxide Metabolites Are Associated with Survival in Older Patients

To assess the efficacy of various vascular endocrinological substances, such as plasma nitric oxide metabolites (NOx), as surrogate markers of survival in older patients. Prospective cohort, observational. Nagoya University Hospital and related hospitals, Japan. One hundred fifty patients aged 70 and older, recruited consecutively from the outpatient clinics of Nagoya University Hospital and related hospitals. Serum biochemical analyses such as albumin and total cholesterol, various prognostic markers, such as tumor necrosis factor (TNF)-alpha, NOx, activities of daily living (ADLs), and instrumental ADLs (IADLs) were evaluated on enrollment. ADLs, IADLs, and comorbidities, especially depression and impaired cognition, were evaluated on enrollment. The main outcome was survival rate over 2.75 years. Forty-nine patients died during the follow-up period. Mann-Whitney U-test showed that hemoglobin, total protein, serum albumin, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high sensitive c-reactive protein, NOx, B-type natriuretic peptide, interleukin-6, and TNF-alpha levels; ADLs; cognitive impairment; and depressive status were significantly different for subjects who survived and those who died. Of the dependent variables in the Cox proportional hazards regression analyses, only ADLs, NOx, and albumin were significantly different. In the Kaplan-Meier analyses of mortality, the prognosis of patients in the third and fourth quartiles of NOx was significantly worse than that of patients in the first or second quartile. The prognosis of patients with impaired ADLs was worse than that of other patients for the overall period. Lower levels of NOx may be associated with survival in older patients. It may be an effective marker, like ADLs, which is a well-known marker.

Effects of moderate and severe intermittent hypoxia on vascular endothelial function and haemodynamic control in sedentary men

Acclimatization to intermittent hypoxia (IH) improves exercise performance by enhancing oxygen delivery and utilization, but the effect of IH on hemodynamic control remains unclear. This study investigates how two intensities of IH influence hemodynamic control to develop an IH regimen that improves aerobic fitness and minimizes risk of peripheral vascular disorder. Thirty healthy sedentary men were randomly divided into severe (SIH) and moderate (MIH) IH and control (C) groups. The subjects were exposed to 12% (SIH), 15% (MIH), or 21% (C) O2 for 1 h/day, 5 days/week for 4 weeks in a normobaric hypoxia chamber. The results demonstrate that (1) improved pulmonary ventilation and oxygen uptake by SIH and MIH; (2) SIH elevated blood pressure during exercise and increased plasma malondialdehyde and nitric oxide (NO) metabolite levels, accompanied by reduced hyperaemic arterial response, venous compliance, endothelium-dependent vasodilatation, and decreased plasma total antioxidant and vitamin E levels; (3) while such effects were not seen following MIH; and (4) there were no significant differences in endothelium-independent vasodilatation during all experimental periods among the three groups. We conclude that both SIH and MIH regimens improve pulmonary ventilation. However, SIH but not MIH decreases anti-oxidative capacity and increases lipid peroxidation in circulation, leading to suppression of vascular endothelial function, causing impairment of vascular haemodynamics.

Nitric oxide differentially regulates renal ATP-binding cassette transporters during endotoxemia

Nitric oxide (NO) is an important regulator of renal transport processes. In the present study, we investigated the role of NO, produced by inducible NO synthase (iNOS), in the regulation of renal ATP-binding cassette (ABC) transporters in vivo during endotoxemia. Wistar–Hannover rats were injected with lipopolysaccharide (LPS+) alone or in combination with the iNOS inhibitor, aminoguanidine. Controls received detoxified LPS (LPS−). After LPS+, proximal tubular damage and a reduction in renal function were observed. Furthermore, iNOS mRNA and protein, and the amount of NO metabolites in plasma and urine, increased compared to the LPS− group. Coadministration with aminoguanidine resulted in an attenuation of iNOS induction and reduction of renal damage. Gene expression of 20 ABC transporters was determined. After LPS+, a clear up-regulation in Abca1, Abcb1/P-glycoprotein (P-gp), Abcb11/bile salt export pump (Bsep), and Abcc2/multidrug resistance protein (Mrp2) was found, whereas Abcc8 was down-regulated. Up-regulation of Abcc2/Mrp2 was accompanied by enhanced calcein excretion. Aminoguanidine attenuated the effects on transporter expression. Our data indicate that NO, produced locally by renal iNOS, regulates the expression of ABC transporters in vivo. Furthermore, we showed, for the first time, expression and subcellular localization of Abcb11/Bsep in rat kidney.Electronic supplementary materialThe online version of this article (doi: 10.1007/s00424-007-0210-x) contains supplementary material, which is available to authorized users.