Vasopressin does not effect hypertension caused by long-term nitric oxide inhibition

Nitric oxide attenuates both vasopressin-induced vasoconstriction and vasopressin release. We tested whether hypertension and renal dysfunction elicited by chronic inhibition of nitric oxide (NO) synthesis using N(G)-nitro-L-arginine (L-NNA) could be mediated in part by vasopressin V(1A) receptors. Male rats were treated orally for 6 weeks with L-NNA (15 mg/kg per day), a nonpeptide V(1A) receptor antagonist (2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3, 4-dimethoxybenzene-sulfonyl)-3-hydroxy-2, 3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide (SR 49059, 30 mg/kg per day), or a combination of SR 49059 and L-NNA (same doses), or they received no treatment. Both drugs were added to the food. Measurements were performed in conscious rats (urine collection in metabolic cages, tail-cuff arterial pressure) and at the end of the study in anesthetized rats (clearance measurements). L-NNA produced sustained hypertension, decreased glomerular filtration rate, and increased renal vascular resistance, plasma renin activity, and urinary albumin excretion. SR 49059 had no effect per se on these parameters and also did not attenuate the hypertension and renal dysfunction induced by L-NNA. Surprisingly, SR 49059 potentiated L-NNA-induced hypertension at the end of the 6-week treatment. However, the blood pressure response and the renal and mesenteric vasoconstriction elicited by exogenous vasopressin were attenuated in rats treated with SR 49059. L-NNA did not change plasma vasopressin concentration or 24-hour urinary vasopressin excretion. Our findings suggest that activation of vasopressin V(1A) receptors does not contribute to the hypertension and renal dysfunction induced by chronic NO synthesis inhibition. They also document unchanged plasma vasopressin concentration in NO-deficient hypertension.     

Chronic nitric oxide blockade modulates renal Na-K-2Cl cotransporters

OBJECTIVE: The Na-K-2Cl cotransporter (NKCC2 isoform) of the thick ascending limb of Henle's loop (TAL) plays an important role in renal sodium handling, and the vascular isoform (NKCC1) participates in the response to vasoconstrictors. Both isoforms appear to be regulated by nitric oxide. This study aimed to analyze the effect of chronic nitric oxide deficiency on tubular and vascular Na-K-2Cl cotransporters in kidney and their potential role in the development of N-nitro-L-arginine-methyl ester (L-NAME) hypertension. METHODS: Wistar rats were given L-NAME (vehicle, 10, 35 and 80 mg/100 ml drinking water) for 4 weeks. Blood pressure was measured by the tail-cuff method. NKCC2 activity was estimated as the bumetanide-sensitive Rb influx in fresh isolated TAL tubules. NKCC1-contractile function was estimated as the bumetanide-sensitive vasocontractile response to phenylephrine in isolated perfused kidneys. Acute effects of L-NAME and endothelium removal were also evaluated. NKCC2 and NKCC1 protein expression were assessed by western blot analysis. RESULTS: Chronic L-NAME administration increased, in a dose-dependent manner, both blood pressure and NKCC2 activity, and these changes significantly correlated (r2 = 0.89, P < 0.01). NKCC1-contractile activity decreased with the highest dose of L-NAME (80 mg/100 ml drinking water group) but it was not affected by acute nitric oxide blockade or endothelium removal. This 80 mg group showed increased NKCC2 expression in the renal medulla and decreased NKCC1 expression in aorta. CONCLUSIONS: Chronic nitric oxide deficiency stimulates tubular Na-K-2Cl cotransporter, suggesting that NKCC2 hyperactivity contributes to the inability to excrete sodium, and hence to the development of L-NAME hypertension. In contrast, L-NAME hypertension develops independently of vascular NKCC1-contractile activity.     

Circulating nitric oxide products do not solely reflect nitric oxide release in cirrhosis and portal hypertension

Background: Patients with cirrhosis often develop a systemic vasodilatation and a hyperdynamic circulation with activation of vasoconstrictor systems such as the renin–angiotensin–aldosterone system (RAAS), and vasopressin. Increased nitric oxide (NO) synthesis has been implicated in the development of this state of vasodilation and pulmonary dysfunction including increased exhaled NO concentrations. Circulating metabolites (NO_x) may affect the systemic and pulmonary NO‐generation. However, the relations of these abnormalities to the haemodynamic changes remain unclear. Aims: The aims of the present study were to measure changes in exhaled NO in relation to circulating NO_x, RAAS, and haemodynamics. Methods: Twenty patients (eight child class A and 12 class B patients) underwent a liver vein catheterization with determination of splanchnic and systemic haemodynamics. Circulating NO_x and exhaled NO were determined in the supine and sitting positions and related to haemodynamics, RAAS and lung diffusing capacity (D_LCO). Eight matched healthy individuals served as controls. Results: All patients with cirrhosis had portal hypertension. We found no significant difference in exhaled NO between patients and controls and no changes from the supine to the sitting position. Exhaled NO in the patients correlated significantly with plasma volume, heart rate and D_LCO. NO_x concentrations were not significantly increased in the patients. NO_x correlated with portal pressure and haemodynamic indicators of vasodilatation, but not with exhaled NO concentrations. Conclusion: In patients with moderate cirrhosis, exhaled NO is normal. Circulating NO_x do not seem to reflect pulmonary and systemic NO release, but NO_x seems to reflect systemic and splanchnic haemodynamic changes in cirrhosis.     

Chronic nitric oxide inhibition aggravates hypertension in erythropoietin-treated renal failure rats

Alterations in nitric oxide (NO) and endothelin-1 (ET-1) production have recently been reported in erythropoietin (r-HuEPO)-induced hypertension in renal failure rats. The present study was designed to evaluate the effect of NO synthase inhibition with the L-arginine analog NG-nitro-L-arginine methyl ester (L-NAME) on blood pressure (BP) and ET-1 production in control and in uremic rats treated or not treated with r-HuEPO. Renal failure was induced by a two-stage 5/6 nephrectomy. Control and uremic rats were studied separately and subdivided into four groups: vehicle, r-HuEPO, L-NAME + vehicle and L-NAME + r-HuEPO. L-NAME (100 mg/kg/day), r-HuEPO (100 U/kg, subcutaneously, three times per week), the vehicle or both were administered during 4 weeks in control rats and during 2 weeks in uremic rats. Systolic BP was recorded before and after the onset of treatment at weeks 2 and 4 in control rats and at weeks 1 and 2 in uremic rats. Hematocrit, serum creatinine, plasma, blood vessel (thoracic aorta and mesenteric artery bed) and renal cortex immunoreactive (ir) ET-1 concentrations were measured at the end of the protocol. L-NAME enhanced BP in control and uremic rats and the increase was significantly higher in uremic rats under r-HuEPO therapy (222 +/- 7 mmHg vs 198 +/- 6 mmHg, p<0.05). L-NAME induced an increase in thoracic aorta ir-ET-1 concentrations in control and uremic rats. In contrast, ir-ET-1 concentrations were unchanged in the mesenteric arterial bed and the renal cortex of control and uremic animals. R-HuEPO increased thoracic aorta ir-ET-1 contents in L-NAME treated control and uremic rats. These results underline the important role of NO release in opposing the action of vasopressors on blood vessel tone which appears more important in uremic rats treated with r-HuEPO. L-NAME treatment increased large vessel, but not small resistance artery ir-ET-1 concentrations, suggesting differential regulation of ET-1 production in different vascular beds under chronic NO synthase inhibition.     

Lack of inducible nitric oxide synthase does not prevent aging-associated insulin resistance

Inducible nitric oxide synthase (iNOS) is involved in obesity-induced insulin resistance. Since aging is accompanied by increased iNOS expression, the effect of iNOS gene deletion on aging-associated insulin resistance was investigated in 7-month-old (adult) and 22-month-old (old) iNOS knockout and wild-type mice using the hyperinsulinemic–euglycemic clamp. While body weight and fat mass were increased, muscle mass was reduced with aging in wild-type mice. However, body composition was not changed with aging in iNOS knockout mice due to increased locomotor activity. NO metabolites in plasma, and protein levels of iNOS and nitrotyrosine in skeletal muscle increased with aging in wild-type mice. Deletion of iNOS gene attenuated NO metabolites and nitrotyrosine with aging in iNOS knockout mice. Glucose uptake in whole body and skeletal muscle was reduced with aging in both wild-type and iNOS knockout mice and there was no difference between two groups. Plasma level of tumor necrosis factor-α and gene expression of proinflammatory cytokines in peripheral tissues were increased with aging in both groups, and that was more heightened in iNOS knockout mice. These results suggest that lack of iNOS does not prevent aging-associated insulin resistance in mice and heightened production of proinflammatory cytokines may be involved.     

Enhanced sodium retention after acute nitric oxide blockade in mildly sodium loaded patients with essential hypertension

In essential hypertension (ESS) whole body and vascular nitric oxide (NO) synthesis is generally thought to be reduced. We therefore investigated the systemic and renal responses to acute treatment with N(G)-monomethyl-l-arginine (L-NMMA), a competitive NOS-inhibitor, in 12 patients with ESS and 18 healthy controls (CON) in a randomized, placebo-controlled study. Main effect parameters were renal hemodynamics (glomerular filtration rate [GFR] and renal plasma flow [RPF]), systemic blood pressure (BP), and fractional excretions of sodium (FE(Na)) and lithium (FE(Li)). Experiments were performed on two occasions for each subject studying the effects of either L-NMMA (3 mg/kg intravenously) or placebo. The patients with ESS were studied after at least 14 days off antihypertensive medication. Renal hemodynamics were assessed by the clearances of (125)I-hippuran (RPF) and (51)Cr-EDTA (GFR). The L-NMMA induced a significant increase in systemic BP and significant reductions in RPF, FE(Na), and FE(Li) in both groups. The increase in diastolic BP was significantly attenuated in ESS (ESS: 8% +/- 2% v CON: 14% +/- 2%, P < .05). The GFR and RPF were equally reduced by L-NMMA in both groups (RPF(ESS): -19% +/- 4% v RPF(CON): -15% +/- 3%, P = not significant [NS]). However, the reduction in FE(Na) was enhanced in ESS (ESS: -42% +/- 7% v CON: -25% +/- 3%, P < .01). The FE(Li) decreased equally in both groups (ESS: -17% +/- 2% v CON: -17% +/- 6%, P = NS). It is concluded that acute NO blockade in ESS is accompanied by a reduced systemic pressor response, an unchanged renal hemodynamic response, and an enhanced reduction in FE(Na). The results suggest that patients with essential hypertension are highly dependent on NO to maintain sodium excretion.     

Prolonged nitric oxide inhalation during recovery from chronic hypoxia does not decrease nitric oxide-dependent relaxation in pulmonary arteries

STUDY OBJECTIVE: To investigate the effects of long-term nitric oxide (NO) inhalation on the recovery process of right ventricular hypertrophy (RVH) and functional alterations in the NO-cyclic guanosine monophosphate (cGMP) relaxation pathway in rat conduit pulmonary arteries (PAs) in established chronic hypoxic pulmonary hypertension. MATERIALS AND METHODS: A total of 35 rats were exposed to chronic hypobaric hypoxia (380 mm Hg, 10% oxygen), and 39 rats were exposed to air for 10 days. Both groups were then exposed to 3 or 10 days of NO 10 ppm, NO 40 ppm, or air (control groups for each NO concentration), resulting in a total of 16 groups. Acetylcholine- and sodium nitroprusside (SNP)-induced relaxation were evaluated in precontracted PA rings. RVH was assessed by heart weight ratio of right ventricle to left ventricle plus septum. RESULTS: NO inhalation had no effect on either the regression of RVH or the recovery process of impaired relaxation induced by acetylcholine or SNP in a endothelium-intact hypertensive conduit extrapulmonary artery or intrapulmonary artery (IPA). In a normal endothelium-intact conduit IPA, 40 ppm NO inhalation for 10 days partially augmented SNP-induced relaxation, but not that induced by acetylcholine. CONCLUSION: Continuous NO inhalation did not affect the regression process of either established RVH or the impaired endogenous NO-cGMP relaxation cascade in a conduit PA in rats during the recovery period after chronic hypoxia.     

Cyclosporin treatment does not impair the release of nitric oxide in human coronary arteries.

OBJECTIVE--It has been hypothesised that compromised endothelial function can contribute to the toxic manifestations associated with cyclosporin therapy. In vitro animal studies have implicated inhibition of release of the endothelium derived relaxing factor, nitric oxide; however, this has not been investigated in human tissue. The present study investigated the effect of cyclosporin A on nitric oxide release in human coronary arteries. DESIGN--Study of in vitro organ bath preparations and in vivo angiographic measurements in the coronary circulation. PATIENTS--For the in vitro experiments coronary arteries were harvested from the excised hearts of 10 patients requiring transplantation for reasons other than ischaemic heart disease. Three of these patients were being re-transplanted for obliterative bronchiolitis and had been receiving cyclosporin for a mean of 22 months. The in vivo study was performed on a group of 12 cardiac transplant recipients who were clinically well 1-5 years postoperatively and were not undergoing allograft rejection at the time of assessment. RESULTS--Isolated vessel segments in vitro relaxed in a dose dependent manner in response to substance P (10(-11)-10(-7) mol/l). The maximum response was 76.6 (7.4)% of the response to 1 microgram/ml glyceryl trinitrate. Incubation with 1000 and 2000 ng/ml cyclosporin reduced the response to 63.0 (11.5)% and 62.2 (11.1)% respectively; this was not statistically significant. In segments taken from the explanted hearts of three patients requiring re-transplantation, the mean maximum response was 78.0 (11.0)% and there was no correlation between maximum response in segments from each patient and the duration of cyclosporin therapy. The effect of intracoronary substance P in 12 cardiac transplant recipients was also examined (mean cyclosporin blood concentration 228.9 (42.8) ng/ml). The mean maximum dilatations measured as the percentage diameter change induced by substance P and isosorbide dinitrate were 22.1 (3.2)% and 26.0 (2.5)% respectively. There was no correlation between the degree of endothelium mediated vasodilatation in response to substance P and cyclosporin concentration. CONCLUSIONS--The nitric oxide response was preserved in the coronary arteries of patients exposed to cyclosporin. The mechanisms that initiate cyclosporin associated toxicity remain to be elucidated.     

Inhibition of neuronal nitric oxide synthase activity does not alter vasopressin secretion in septic rats

Background/Purpose

During the early phase of sepsis, hypotension is accompanied by increase of plasma vasopressin hormone (AVP) levels, which decline during the late phase. This hypotension is due in part to increase of nitric oxide (NO) synthesis by nitric oxide synthase (NOS) enzyme. Neuronal isoform of this enzyme (nNOS) is present in vasopressinergics neurons of hypothalamus, but its role in vasopressin secretion during sepsis is unknown.

Methods

We evaluated the role of nNOS in NO production and vasopressin secretion during sepsis. Wistar rats received 7-nitroindazole (50 mg/kg, i.p.), an inhibitor of nNOS activity, or vehicle and were submitted to septic stimulus by cecal ligation and puncture (CLP). At the time points 0, 4, 6, 18 and 24 h after sepsis induction the animals were decapitated and neurohypophysis and hypothalamus were removed for analysis of vasopressin content and NOS activity, respectively. Hematocrit, serum sodium, osmolality, proteins and plasmatic AVP were quantified.

Results

Mortality was not affected by 7-nitroindazole (7-NI). Sodium and plasma proteins levels decreased after CLP and the treatment anticipated the protein loss, and delayed serum sodium decrease. Septic animals treated with 7-NI showed decrease of osmolality 4 h after CLP. Nitric oxide synthase activity in hypothalamus increased at 4 and 24 h after CLP and was reduced with 7-NI. Neurohypophysis content of AVP diminished after CLP and 7-NI did not alter this parameter. Plasma AVP levels increased at 6 h and decreased 18 and 24 h after CLP. Treatment with 7-NI did not alter plasma vasopressin levels.

Conclusion

We concluded that nNOS does not have a substantial role in vasopressin secretion during experimental sepsis.

     

Cyclosporin treatment does not impair the release of nitric oxide in human coronary arteries.

OBJECTIVE--It has been hypothesised that compromised endothelial function can contribute to the toxic manifestations associated with cyclosporin therapy. In vitro animal studies have implicated inhibition of release of the endothelium derived relaxing factor, nitric oxide; however, this has not been investigated in human tissue. The present study investigated the effect of cyclosporin A on nitric oxide release in human coronary arteries. DESIGN--Study of in vitro organ bath preparations and in vivo angiographic measurements in the coronary circulation. PATIENTS--For the in vitro experiments coronary arteries were harvested from the excised hearts of 10 patients requiring transplantation for reasons other than ischaemic heart disease. Three of these patients were being re-transplanted for obliterative bronchiolitis and had been receiving cyclosporin for a mean of 22 months. The in vivo study was performed on a group of 12 cardiac transplant recipients who were clinically well 1-5 years postoperatively and were not undergoing allograft rejection at the time of assessment. RESULTS--Isolated vessel segments in vitro relaxed in a dose dependent manner in response to substance P (10(-11)-10(-7) mol/l). The maximum response was 76.6 (7.4)% of the response to 1 microgram/ml glyceryl trinitrate. Incubation with 1000 and 2000 ng/ml cyclosporin reduced the response to 63.0 (11.5)% and 62.2 (11.1)% respectively; this was not statistically significant. In segments taken from the explanted hearts of three patients requiring re-transplantation, the mean maximum response was 78.0 (11.0)% and there was no correlation between maximum response in segments from each patient and the duration of cyclosporin therapy. The effect of intracoronary substance P in 12 cardiac transplant recipients was also examined (mean cyclosporin blood concentration 228.9 (42.8) ng/ml). The mean maximum dilatations measured as the percentage diameter change induced by substance P and isosorbide dinitrate were 22.1 (3.2)% and 26.0 (2.5)% respectively. There was no correlation between the degree of endothelium mediated vasodilatation in response to substance P and cyclosporin concentration. CONCLUSIONS--The nitric oxide response was preserved in the coronary arteries of patients exposed to cyclosporin. The mechanisms that initiate cyclosporin associated toxicity remain to be elucidated.     

A small amount of inhaled nitric oxide does not increase lung diffusing capacity.

The aim of the present study was to determine: 1) whether 40-50 ppm nitric oxide (NO) increases diffusing capacity of the lung for NO (D(L,NO)) and carbon monoxide (D(L,CO)), membrane diffusing capacity for CO (D(m,CO)) and pulmonary capillary blood volume (V(c)); 2) the actual number of tests required to provide a reasonable estimate of D(L,NO), D(L,CO), D(m,CO) and V(c); and 3) repeatability of these parameters using the single-breath D(L,NO)-D(L,CO) method. In total, 31 subjects performed five single-breath hold manoeuvres at rest, inhaling 43+/-3 ppm NO together with a standard diffusion mixture. D(L,NO) (D(m,CO)) remained unchanged from the first to fifth trial. However, compared with the first trial, D(L,CO) and V(c) had decreased by the fourth (-4+/-5%; 95% confidence interval (CI) = -5- -2%) and third trial (-5+/-7%; 95% CI = -7- -2%), respectively. Repeatability over five trials was 17, 3 and 7 mL.min(-1).mmHg(-1) for D(L,NO), D(L,CO) and D(m,CO), respectively, and 13 mL for V(c) when D(m,CO) = D(L,NO)/2.42. In conclusion, nitric oxide inhaled during sequential single-breath manoeuvres has no effect on diffusing capacity of the lung for nitric oxide and, thus, membrane diffusing capacity for carbon monoxide. Since more than two and three trials will lower pulmonary capillary blood volume and diffusing capacity of the lung for carbon monoxide, respectively, the average value of only two properly performed trials is suggested.     

Chronic hypertension leads to hyperinsulinemia in sprague-dawley rats treated with nitric oxide synthase inhibitor

Insulin resistance and hypertension, as well as dyslipidemia, frequently cooccur. Evidence that nitric oxide (NO) plays a crucial role in the long-term regulation of systolic blood pressure led us to examine whether enhanced vasoconstriction and hypertension induced by NO synthase inhibitor could lead to insulin and lipid disorders.N^G-Nitro-l-arginine methyl-ester (L-NAME), an inhibitor of NO synthase, was given for 4 weeks in drinking water (100 mg/kg/day) to 12 Sprague-Dawley rats. Another nine rats received both L-NAME and verapamil (100 mg/kg/day), whereas 12 animals fed rat chow only served as controls. Systolic blood pressure was measured weekly by the indirect tail cuff method. Blood samples were taken at the beginning of the experiment, and after 2 and 4 weeks from all rats. The samples were assayed for insulin, glucose, and triglyceride concentrations. L-NAME treatment resulted in a marked and sustained increase in systolic blood pressure from 130 ± 7 to 171 ± 3 mm Hg by the second week, which was succeeded by a significant elevation in insulin level at the end of 4 weeks, from 2.3 ± 1.8 to 5.4 ± 2.0 ng/mL. Triglycerides and glucose were unaffected throughout the experiment. The combination of L-NAME and the NO-independent vasodilator, verapamil, attenuated the hypertension induced by L-NAME and prevented the following rise in insulin level. Data suggest that chronic elimination of NO after chronic inhibition of NO synthase may lead to a state of hyperinsulinemia, possibly as an outcome of insulin resistance.     

Administration of a nitric oxide synthase inhibitor does not suppress low-dose streptozotocin-induced diabetes in mice

Summary Nitric oxide (NO) has been reported as being a key mediator of the autoimmune destruction of B-cells in type I diabetes, and studies have described a suppression of low-dose streptozotocin-induced (LDS) diabetes in mice after the use of NO synthase inhibitors. However, these studies disagree with regard to the outcome of hyperglycemia and insulitis after treatment with thesel-arginine analogs. The present study tries to clarify this topic by administeringN-nitro-l-arginine-methylester (NAME) (15 mg/d/mouse/15 d) after an LDS treatment in 108 male C57BL6/J mice. Glycemia measured at the end of the NAME treatment did show a slight, but significant, reduction when compared to LDS control animals (p<0.001), but values returned to diabetic levels 2 wk after withdrawal of NAME. Morphological observations demonstrated that the degree of infiltration and islet B-cell damage was absolutely not inhibited by NAME. In conclusion, treatment withl-arginine analogs is not capable of protecting mice from LDS-induced diabetes.     

Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension.

Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginine orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angiotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164 +/- 6 mm Hg at 4-6 weeks, compared with 108 +/- 3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125 +/- 6 mm Hg, still elevated compared with rats receiving losartan alone (98 +/- 3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfusion, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment. Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomeruli. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice

Genetic deletion of inducible nitric oxide synthase (NOS) in mice has been shown to improve high-fat diet (HFD)-induced insulin resistance. However, a pathophysiological role of endogenous nitric oxide (NO) in obesity-related insulin resistance remains controversial. To address this issue, we examined the metabolic phenotypes in HFD-induced obese mice with chronic blockade of NO synthesis by a NOS inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME). Six-week-old male C57BL/6j mice were provided free access to either a standard diet (SD) or a HFD and tap water with or without L-NAME (100 mg/kg.d) for 12 wk. L-NAME treatment significantly attenuated body weight gain of mice fed either SD or HFD without affecting calorie intake. L-NAME treatment in HFD-fed mice improved glucose tolerance and insulin sensitivity. HFD feeding induced inducible NOS mRNA expression, but not the other two NOS isoforms, in white adipose tissue (WAT) and skeletal muscle. L-NAME treatment up-regulated uncoupling protein-1 in brown adipose tissue of HFD-fed mice but down-regulated monocyte chemoattractant protein-1 and CD68 mRNAs levels in WAT. HFD feeding up-regulated leptin mRNA levels but conversely down-regulated adiponectin mRNA levels in WAT, but these effects were unaffected by L-NAME treatment. Moreover, L-NAME treatment also increased peroxisome proliferator-uncoupling protein-3 mRNA levels in skeletal muscles of HFD-fed mice. Increased urinary excretion of norepinephrine after HFD feeding was augmented in L-NAME-treated mice. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and serine phosphorylation of Akt/Akt2 in soleus muscle was markedly impaired in HFD-fed mice but reversed by L-NAME treatment. In conclusion, chronic NOS blockade by L-NAME in mice ameliorates HFD-induced adiposity and glucose intolerance, accompanied by reduced adipose inflammation and improved insulin signaling in skeletal muscle, suggesting that endogenous NO plays a modulatory role in the development of obesity-related insulin resistance.     

Real-life environmental tobacco exposure does not affect exhaled nitric oxide levels in asthmatic children.

Serial measurement of exhaled nitric oxide (eNO) has been shown to be a good noninvasive marker of asthma control. Active smoking decreases eNO levels. The effect of real-life environmental exposure to tobacco smoke (ETS) on eNO levels is not known. Our objective was to study the impact of environmental tobacco exposure on eNO levels in asthmatic and non-asthmatic children. Single breath off-line collection of eNO was performed in asthmatic and non-asthmatic children with and without ETS. Urine was collected for cotinine/nicotine analysis. Fifty-seven children were enrolled, of which 25 were asthmatic and 32 had smoke exposure. One active smoker was excluded from the data analysis. The mean eNO was 11.1 ppb (n = 31; SD = 18.5) in those passively exposed vs. 11.1 ppb (n = 25; SD = 19.9) among the unexposed (not statistically significant). The mean eNO was 6.1 (n = 32; SD = 4.4) among the non-asthmatics and 17.8 (n = 24; SD = 27.4) among the asthmatics (p = 0.02; CI: 1.9-21.6). Real-life environmental tobacco exposure does not appear to decrease eNO levels in asthmatic children. Off-line collection of exhaled nitric oxide with a Mylar collection device helps differentiate asthmatics from non-asthmatics.