Nitric Oxide Is Associated with Long-Term Zinc Tolerance in Solanum nigrum

Nitric oxide (NO) has been identified as a signal molecule that interplays with reactive oxygen species in response to heavy metal stresses. Roles of NO in regulating cadmium toxicity and iron deficiency have been proposed; however, the function of NO in zinc (Zn) tolerance in plants remains unclear. Here, we investigated NO accumulation and its role in plant Zn tolerance. Zn-induced NO production promoted an increase in reactive oxygen species accumulation in Solanum nigrum roots by modulating the expression and activity of antioxidative enzymes. Subsequently, programmed cell death (PCD) was observed in primary root tips. Inhibiting NO accumulation by 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (a specific NO scavenger) or N^G-nitro-l-arginine-methyl ester (a NO synthase inhibitor) prevented the increase of superoxide radical and hydrogen peroxide as well as the subsequent cell death in the root tips, supporting the role of NO in Zn-induced PCD in the root tips. Zn-induced NO production affected the length of primary roots, the number of lateral roots, and root hair growth and thereby modulated root system architecture and activity. Investigation of metal contents in Zn-treated roots suggests that NO is required for metal (especially iron) uptake and homeostasis in plants exposed to excess Zn. Taken together, our results indicate that NO production and the subsequent PCD in root tips exposed to excess Zn are favorable for the S. nigrum seedling response to long-term Zn toxicity by modulating root system architecture and subsequent adaptation to Zn stress.Heavy metal contamination is a serious problem for the environment. Some metallic elements, such as zinc (Zn), are essential micronutrients and play a role as enzyme cofactors in many metabolic reactions. However, uptake of high concentrations of Zn is found to be toxic to plant growth and development. High concentrations of Zn (260–16,000 mg kg⁻¹) have been found in the soil near smelting sites (Bi et al., 2006), and Zn contamination has been of increasing concern in these regions due to its threat to agriculture and human health (Bi et al., 2006).Zn homeostasis is a tightly regulated process because Zn can be both essential and deleterious to plants depending on its concentration. The effects of Zn on plants have been widely reported (Broadley et al., 2007; Wang et al., 2009), including tolerance to Zn accumulation and Zn deficiency as well as the protective effects of Zn in plants. Zn is closely involved in protein synthesis and nitrogen metabolism; the growth of Zn-deficient plants is markedly inhibited. Zn is also a constituent of copper/zinc superoxide dismutase (Cu/Zn SOD). Zn deficiency reduces antioxidative enzyme activity and thereby results in reactive oxygen species (ROS) accumulation and oxidative damage (Sharma et al., 2004). Tolerance to Zn accumulation in plants is a complex phenomenon. Aside from Zn deficiency, excess Zn can also inhibit plant growth and development by disequilibrating the uptake and redistribution of mineral nutrition and by disturbing the antioxidant defense system and metabolic processes such as photosynthesis, transpiration, and antioxidative enzyme activity. Recent studies have shown that Zn toxicity affects the activity of antioxidative enzymes, such as SOD, catalase (CAT), and ascorbate peroxidase (APX), in plants (Wójcik et al., 2006; Tewari et al., 2008). The mechanisms of Zn toxicity are not fully understood; however, they may involve competition for catalytic sites or for transporter proteins (González-Guerrero et al., 2005). Zn toxicity also inhibits the uptake of other nutrient elements, such as iron (Fe). Deficiency of these elements can lead to ROS accumulation and oxidative stress (Bonnet et al., 2000). Excess Zn may bind to proteins and lead to the displacement of other ions, such as Fe²⁺, from protein-binding sites. Plants exposed to excess Zn become Fe deficient (Wintz et al., 2003). However, the effects of Zn stress on root system development have not been elucidated.Nitric oxide (NO) is a free radical gas that has emerged as an important signaling molecule in plants (Neill et al., 2002). NO accumulation in roots mediates auxin-induced lateral root formation (Correa-Aragunde et al., 2004), adventitious root growth (Tewari et al., 2008), and root hair development (Lombardo et al., 2006). Graziano and Lamattina (2007) have reported that root hair proliferation induced by Fe deficiency is involved in NO accumulation in tobacco (Nicotiana tabacum). It has also been indicated that NO protects plant cells against oxidative stress by reducing ROS accumulation (Wink and Mitchell, 1998; Xu et al., 2010). NO enhances the tolerance of plants to heavy metal stresses (Yang et al., 2006; Sun et al., 2007; Zhang et al., 2008; Xu et al., 2009). However, very little is known about the level of Zn-mediated NO accumulation in plants and the physiological and molecular mechanisms of the effects of NO on tolerance to Zn toxicity.Programmed cell death (PCD) is an active process of cellular suicide that is essential for development and stress responses in plants. Diverse abiotic stresses, such as salt, drought, nutrient deficiency, and cadmium (Cd) toxicity, can induce PCD in plants. Salt stress has been reported to induce PCD in root apical meristem cells (Huh et al., 2002). Subbaiah and Sachs (2003) have demonstrated that flooding stress induces PCD-like root tip death in maize (Zea mays) and pea (Pisum sativum) plants. Duan et al. (2010) have shown that drought induces PCD in Arabidopsis (Arabidopsis thaliana) root tips. De Michele et al. (2009) have reported that Arabidopsis cell suspension cultures undergo PCD when exposed to Cd stress and that NO is involved in this process. Many studies have indicated that PCD plays a role in the developmental plasticity of plant architecture (Duan et al., 2010). Excess Zn-induced growth inhibition and root death have been found in various plant species (Lingua et al., 2008; Ozdener and Aydin, 2010). However, whether Zn-induced root death occurs through PCD and its underlying mechanisms are poorly understood.In this study, we used a Zn-hyperaccumulator, Solanum nigrum, to study the effects of excess Zn on root system architecture and the roles of NO and ROS in these effects. S. nigrum is known to hyperaccumulate Zn and Cd in natural soil or in soils contaminated with Zn or Cd. In recent years, physiological characteristics of S. nigrum under Zn or Cd stress have been reported (Wei et al., 2004; Sun et al., 2007; Marques et al., 2008; Xu et al., 2009). The aim of this work was to study plant tolerance to excess Zn and the function of NO produced in Zn-treated plants. Our findings support the model in which NO contributes to rapid ROS accumulation and subsequent PCD in root tips in response to heavy metal stresses; our results also indicate that NO is an important regulator of Zn-modulated root system architecture. Potential mechanisms involved in this process are discussed.     

Platelet Content of Nitric Oxide Synthase 3 Phosphorylated At Serine1177 Is Associated with the Functional Response of Platelets to Aspirin

Objective

To analyse if platelet responsiveness to aspirin (ASA) may be associated with a different ability of platelets to generate nitric oxide (NO).

Patients/Methods

Platelets were obtained from 50 patients with stable coronary ischemia and were divided into ASA-sensitive (n = 26) and ASA-resistant (n = 24) using a platelet functionality test (PFA-100).

Results

ASA-sensitive platelets tended to release more NO (determined as nitrite + nitrate) than ASA-resistant platelets but it did not reach statistical significance. Protein expression of nitric oxide synthase 3 (NOS3) was higher in ASA-sensitive than in ASA-resistant platelets but there were no differences in the platelet expression of nitric oxide synthase 2 (NOS2) isoform. The highest NOS3 expression in ASA-sensitive platelets was independent of the presence of T-to-C mutation at nucleotide position −786 (T⁻⁷⁸⁶→C) in the NOS3-coding gene. However, platelet content of phosphorylated NOS3 at Serine (Ser)¹¹⁷⁷, an active form of NOS3, was higher in ASA-sensitive than in ASA-resistant platelets. The level of platelet NOS3 Ser¹¹⁷⁷ phosphorylation was positively associated with the closure time in the PFA-100 test. In vitro, collagen failed to stimulate the aggregation of ASA-sensitive platelets, determined by lumiaggregometry, and it was associated with a significant increase (p = 0.018) of NOS3 phosphorylation at Ser¹¹⁷⁷. On the contrary, collagen stimulated the aggregation of ASA-resistant platelets but did not significantly modify the platelet content of phosphorylated NOS3 Ser¹¹⁷⁷. During collagen stimulation the release of NO from ASA-sensitive platelets was significantly enhanced but it was not modified in ASA-resistant platelets.

Conclusions

Functional platelet responsiveness to ASA was associated with the platelet content of phosphorylated NOS3 at Ser¹¹⁷⁷.     

Inhaled Nitric Oxide Reverses Vascular and Respiratory Effects of ET-1 and PAF in Pigs

In anaesthetized paralysed, mechanically ventilated pigs, the vascular and respiratory effects of 80 ppm nitric oxide (NO) inhaled for 6 min were evaluated. To evoke different levels of smooth muscle contraction ET-1 or PAF, mediators involved in pulmonary disorders, were used. In control conditions, inhaled NO caused selective pulmonary vasodilatation without affecting respiratory resistances. This pulmonary vascular activity influenced the distensibility of the respiratory system and decreased inspiratory work. ET-1 administration significantly increased pulmonary arterial pressure and modestly changed mechanical properties of the respiratory system, while PAF caused potent vasoconstriction and bronchoconstriction associated with a marked change in volume-pressure relationship. In both cases, the changes in vascular and mechanical properties of the respiratory system increased inspiratory work. The vascular and respiratory activities of inhaled NO were correlated with preconstriction levels. The data show that the combination of vascular and respiratory effects improves pulmonary function, suggesting that inhalation of NO is a possible therapeutic approach for obstructive and inflammatory pulmonary diseases.     

Nitric Oxide Synthetic Pathway in Red Blood Cells Is Impaired in Coronary Artery Disease

Background

All the enzymatic factors/cofactors involved in nitric oxide (NO) metabolism have been recently found in red blood cells. Increased oxidative stress impairs NO bioavailability and has been described in plasma of coronary artery disease (CAD) patients. The aim of the study was to highlight a potential dysfunction of the metabolic profile of NO in red blood cells and in plasma from CAD patients compared with healthy controls.

Methods

We determined L-arginine/NO pathway by liquid-chromatography tandem mass spectrometry and high performance liquid chromatography methods. The ratio of oxidized and reduced forms of glutathione, as index of oxidative stress, was measured by liquid-chromatography tandem mass spectrometry method. NO synthase expression and activity were evaluated by immunofluorescence staining and ex-vivo experiments of L-[¹⁵N₂]arginine conversion to L-[¹⁵N]citrulline respectively.

Results

Increased amounts of asymmetric and symmetric dimethylarginines were found both in red blood cells and in plasma of CAD patients in respect to controls. Interestingly NO synthase expression and activity were reduced in CAD red blood cells. In contrast, oxidized/reduced glutathione ratio was increased in CAD and was associated to arginase activity.

Conclusion

Our study analyzed for the first time the whole metabolic pathway of L-arginine/NO, both in red blood cells and in plasma, highlighting an impairment of NO pathway in erythrocytes from CAD patients, associated with decreased NO synthase expression/activity and increased oxidative stress.     

ABO Blood Group Distribution in Serum Hepatitis

A disproportionate excess of blood group O was found in a circumscribed outbreak of serum hepatitis among patients and staff of a haemodialysis unit. The more severe cases were also mostly of group O. This suggests that host factors may be important in the genesis of this disease.     

Nitric Oxide Production Is Increased in Patients with Inflammatory Myositis

Nitric oxide (NO) production is increased in several inflammatory disorders. We have previously demonstrated higher levels of NO production among patients with rheumatoid arthritis and systemic lupus erythematosus. In this study we measured serum levels of nitrite and citrulline using calorimetric methods as surrogate markers of NO production among patients with inflammatory myositis (IM). Twenty patients with IM and 19 age- and sex-matched controls were studied. Serum nitrite levels were significantly higher among patients than among controls (986.6 +/- 880 and 204.3 +/- 113.9 nmol/ml, respectively; P = 0.001). Serum citrulline levels, too, were significantly higher among patients than among controls (3755.7 +/- 1905.5 and 189 +/- 177.2 nmol/ml, respectively; P < 0.0001). There was a positive correlation between steroid dosage and serum citrulline levels (r = 0.51, P = 0.036) and a negative correlation between steroid dosage and disease duration (r = -0.54, P = 0.025). It was concluded that NO production is increased in patients with IM and those with more active disease, as indicated by higher steroid dosage, have higher serum citrulline levels.     

Granulocytic Myeloid Derived Suppressor Cells Expansion during Active Pulmonary Tuberculosis Is Associated with High Nitric Oxide Plasma Level

Tuberculosis (TB) is still the principal cause of death caused by a single infectious agent, and the balance between the bacillus and host defense mechanisms reflects the different manifestations of the pathology. The aim of this work was to study the role of myeloid-derived suppressor cells (MDSCs) during active pulmonary tuberculosis at the site of infection. We observed an expansion of MDSCs in the lung and blood of patients with active TB, which are correlated with an enhanced amount of nitric oxide in the plasma. We also found that these cells have the remarkable ability to suppress T-cell response, suggesting an important role in the modulation of the immune response against TB. Interestingly, a trend in the diminution of MDSCs was found after an efficacious anti-TB therapy, suggesting that these cells may be used as a potential biomarker for monitoring anti-TB therapy efficacy.     

Macrophages, Nitric Oxide and microRNAs Are Associated with DNA Damage Response Pathway and Senescence in Inflammatory Bowel Disease

Background

Cellular senescence can be a functional barrier to carcinogenesis. We hypothesized that inflammation modulates carcinogenesis through senescence and DNA damage response (DDR). We examined the association between senescence and DDR with macrophage levels in inflammatory bowel disease (IBD). In vitro experiments tested the ability of macrophages to induce senescence in primary cells. Inflammation modulating microRNAs were identified in senescence colon tissue for further investigation.

Methodology/Principal Findings

Quantitative immunohistochemistry identified protein expression by colon cell type. Increased cellular senescence (HP1γ; P = 0.01) or DDR (γH2A.X; P = 0.031, phospho-Chk2, P = 0.014) was associated with high macrophage infiltration in UC. Co-culture with macrophages (ANA-1) induced senescence in >80% of primary cells (fibroblasts MRC5, WI38), illustrating that macrophages induce senescence. Interestingly, macrophage-induced senescence was partly dependent on nitric oxide synthase, and clinically relevant NO• levels alone induced senescence. NO• induced DDR in vitro, as detected by immunofluorescence. In contrast to UC, we noted in Crohn’s disease (CD) that senescence (HP1γ; P<0.001) and DDR (γH2A.X; P<0.05, phospho-Chk2; P<0.001) were higher, and macrophages were not associated with senescence. We hypothesize that nitric oxide may modulate senescence in CD; epithelial cells of CD had higher levels of NOS2 expression than in UC (P = 0.001). Microarrays and quantitative-PCR identified miR-21 expression associated with macrophage infiltration and NOS2 expression.

Conclusions

Senescence was observed in IBD with senescence-associated β-galactosidase and HP1γ. Macrophages were associated with senescence and DDR in UC, and in vitro experiments with primary human cells showed that macrophages induce senescence, partly through NO•, and that NO• can induce DDR associated with senescence. Future experiments will investigate the role of NO• and miR-21 in senescence. This is the first study to implicate macrophages and nitrosative stress in a direct effect on senescence and DDR, which is relevant to many diseases of inflammation, cancer, and aging.     

Nitric Oxide Sensing in Plants Is Mediated by Proteolytic Control of Group VII ERF Transcription Factors

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Expression of Biliverdin Reductase A in Peripheral Blood Leukocytes Is Associated with Treatment Response in HCV-Infected Patients

Background and Aims

Hepatitis C virus (HCV) infection is associated with systemic oxidative stress. Since the heme catabolic pathway plays an important role in antioxidant protection, we attempted to assess the gene expression of key enzymes of heme catabolism, heme oxygenase 1 (HMOX1), heme oxygenase 2 (HMOX2), and biliverdin reductase A (BLVRA) in the liver and peripheral blood leukocytes (PBL) of patients chronically infected with HCV.

Methods

Gene expressions (HMOX1, HMOX2, BLVRA) and HCV RNA were analyzed in PBL of HCV treatment naïve patients (n = 58) and controls (n = 55), with a subset of HCV patients having data on hepatic gene expression (n = 35). Based upon the therapeutic outcome, HCV patients were classified as either responders (n = 38) or treatment-failure patients (n = 20). Blood samples in HCV patients were collected at day 0, and week 12, 24, 36, and 48 after the initiation of standard antiviral therapy.

Results

Compared to the controls, substantially increased BLVRA expression was detected in PBL (p<0.001) of therapeutically naïve HCV patients. mRNA levels of BLVRA in PBL closely correlated with those in liver tissue (r2 = 0.347,p = 0.03). A marked difference in BLVRA expression in PBL between the sustained responders and patients with treatment failure was detected at week 0 and during the follow-up (p<0.001). Multivariate analysis revealed that BLVRA basal expression in PBL was an independent predictor for sustained virological response (OR 15; 95% CI 1.05–214.2; P = 0.046). HMOX1/2 expression did not have any effect on the treatment outcome.

Conclusion

Our results suggest that patients with chronic HCV infection significantly upregulate BLVRA expression in PBL. The lack of BLVRA overexpression is associated with non-responsiveness to standard antiviral therapy; whereas, HMOX1/2 does not seem to have any predictive potential.     

NCPAP在治疗新生儿急性呼吸衰竭中的应用价值

目的：探讨鼻塞持续正压通气(NCPAP)治疗新生儿急性呼吸衰竭的临床应用价值。方法：选取我院2008 年2 月至2014 年5月接收确诊的新生儿急性呼吸衰竭98 例,根据治疗方法不同均分为对照组和治疗组,每组49 例,对照组采用持续头罩吸氧治疗,治疗组采用鼻塞持续正压无创通气治疗,对比分析两组患儿的治疗效果。结果：治疗24 h 后,治疗组患儿的呼吸、心率、PaO2和PaCO2临床指标改善程度要高于对照组(P<0.05),且治疗组的治愈率高于对照组(89.4 %>67.4 %,X2=3.671,P<0.05),同时并发症的发生率低于对照组(P<0.05)。结论：NCPAP 能够有效地治疗新生儿急性呼吸衰竭,同时减少并发症的发生,值得临床进一步推广与应用。     

Neuroprotective Effect of Inhaled Nitric Oxide on Excitotoxic-Induced Brain Damage in Neonatal Rat

Background

Inhaled nitric oxide (iNO) is one of the most promising therapies used in neonates. However, little information is known about its impact on the developing brain submitted to excitotoxic challenge.

Methodology/Principal Findings

We investigated here the effect of iNO in a neonatal model of excitotoxic brain lesions. Rat pups and their dams were placed in a chamber containing 20 ppm NO during the first week of life. At postnatal day (P)5, rat pups were submitted to intracranial injection of glutamate agonists. At P10, rat pups exposed to iNO exhibited a significant decrease of lesion size in both the white matter and cortical plate compared to controls. Microglia activation and astrogliosis were found significantly decreased in NO-exposed animals. This neuroprotective effect was associated with a significant decrease of several glutamate receptor subunits expression at P5. iNO was associated with an early (P1) downregulation of pCREB/pAkt expression and induced an increase in pAkt protein concentration in response to excitotoxic challenge (P7).

Conclusion

This study is the first describe and investigate the neuroprotective effect of iNO in neonatal excitotoxic-induced brain damage. This effect may be mediated through CREB pathway and subsequent modulation of glutamate receptor subunits expression.     

Circulating Endothelial Progenitor Cells Decrease in Infants with Bronchopulmonary Dysplasia and Increase after Inhaled Nitric Oxide

Background

Impairment of endothelial progenitor cells (EPCs) has been shown to contribute to the development of bronchopulmonary dysplasia (BPD). In the current study, the relationship between EPC changes of after birth and the development of BPD was investigated, and the effects of inhaled nitric oxide (iNO) on EPCs were evaluated.

Methods

Sixty infants with a gestational age of less than 32 weeks and a birth weight of less than 1500 g were studied. NO was administered to infants who were receiving mechanical ventilation or CPAP for at least 2 days between the ages of 7 and 21 days. EPC level was determined by flow cytometry at birth, 7, 21 and 28 days of age and 36 weeks’ postmenstrual age (PMA), before and after the iNO treatment. Plasma concentrations of vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 and granulocyte-macrophage colony-stimulating factor were determined via immunochemical assay.

Results

Twenty-five neonates developed BPD, 35 neonates survived and did not develop BPD. EPC level was decreased on day 7 and 21 in infants who later developed BPD compared with infants that did not develop BPD. From birth to 21 days of age, BPD infants had a persistently lower VEGF concentration compared with non-BPD infants. No difference was found between the two groups at day 28 or 36 weeks PMA. In infants that later developed BPD, iNO raised the KDR⁺CD133⁺ and CD34⁺KDR⁺CD133⁺ EPC numbers along with increasing the level of plasma VEGF.

Conclusion

EPC level was reduced at 7 days of age in infants with BPD, and iNO increased the EPC number along with increasing the level of VEGF. Further studies are needed to elucidate the mechanism leading to the decrease of EPCs in infants with BPD and to investigate the role of iNO treatment in the prevention of BPD.     

壳寡糖诱导植物防御反应中一氧化氮信号的研究

壳寡糖可以增强植物对病虫害的防御能力,为了深入研究壳寡糖的作用机理,首次运用荧光酶标仪及一氧化氮(Nitric oxide,NO)荧光探针Diaminofluorescein diacetate (DAF-2DA)对壳寡糖诱导的NO信号进行研究。研究发现,不同浓度的壳寡糖均可诱导烟草悬浮细胞产生NO;NO的清除剂Carboxy-PTIO potassium salt(cPTIO)和一氧化氮合酶(Nitric oxide synthase,NOS)抑制剂N^ω-nitro-L-arginine methyl Ester(L-NAME)可以明显抑制NO的产生;硝酸还原酶(Nitrate reductase, NR)的抑制剂叠氮化钠和钨酸钠对NO的产生无影响;Ca²⁺流相关抑制剂氯化镧和钌红均可抑制NO的产生。NO和Ca²⁺流的相关抑制剂可明显抑制壳寡糖诱导的抗性相关基因的表达。结果显示:壳寡糖主要通过NOS酶催化合成NO,且NO参与调节壳寡糖诱导的抗性相关基因的表达,在此过程中,Ca²⁺可以调节NO的合成。     

Differential Immune Response Associated to Malaria Outcome Is Detectable in Peripheral Blood following Plasmodium yoelii Infection in Mice

Malaria infection in humans elicits a wide range of immune responses that can be detected in peripheral blood, but we lack detailed long-term follow-up data on the primary and subsequent infections that lead to naturally acquired immunity. Studies on antimalarial immune responses in mice have been based on models yielding homogenous infection profiles. Here, we present a mouse model in which a heterogeneous course of Plasmodium yoelii lethal malaria infection is produced in a non-congenic ICR strain to allow comparison among different immunological and clinical outcomes. Three different disease courses were observed ranging from a fatal outcome, either early or late, to a self-resolved infection that conferred long-term immunity against re-infection. Qualitative and quantitative changes produced in leukocyte subpopulations and cytokine profiles detected in peripheral blood during the first week of infection revealed that monocytes, dendritic cells and immature B cells were the main cell subsets present in highly-parasitized mice dying in the first week after infection. Besides, CD4⁺CD25^high T cells expanded at an earlier time point in early deceased mice than in surviving mice and expressed higher levels of intracellular Foxp3 protein. In contrast, survivors showed a limited increase of cytokines release and stable circulating innate cells. From the second week of infection, mice that would die or survive showed similar immune profiles, although CD4⁺CD25^high T cells number increased earlier in mice with the worst prognosis. In surviving mice the expansion of activated circulating T cell and switched-class B cells with a long-term protective humoral response from the second infection week is remarkable. Our results demonstrate that the follow-up studies of immunological blood parameters during a malaria infection can offer information about the course of the pathological process and the immune response.     

Acutely Elevated Cortisol in Response to Stressor Is Associated with Attentional Bias Toward Depression-Related Stimuli but Is Not Associated with Attentional Function

Cortisol induces attentional bias toward a negative stimulus and impaired attentional function. Depressed individuals have high levels of cortisol, and exhibit an attentional bias toward a depression-related stimulus and impaired processing speed and executive attention, which are components of attentional function. Therefore, the study tested the hypotheses that an acute increase in cortisol in response to a stressor is associated with attentional bias toward a depression-related stimulus and impaired processing speed and executive attention. Thirty-six participants were administered the dot-probe task for the measurement of attentional bias toward a depression-related stimulus and the Trail Making Test A and B for the measurement of processing speed and executive attention before and after a mental arithmetic task. It was revealed that attentional bias toward a depression-related stimulus following the stressor was observed only among the responders (i.e., participants with cortisol elevation in response to a stressor). On the other hand, no differences in the performance of processing speed and executive attention were noted between the responders and non-responders. The results indicate that acutely elevated cortisol is related to attentional bias, but is not related to processing speed and executive attention. The results have an implication for the etiology of depression.     

Inhaled Nitric Oxide Counterbalances ET-1 Dependent Pulmonary Hypertension and Bronchoconstriction in the Pig

In anaesthetized, paralysed, ventilated pigs the ability of inhaled nitric oxide (80 ppm in 0(2)) to reduce the haemodynamic and respiratory effects of endothelin-1 administration (200 pmol/kg, i.v.) was evaluated. The mechanical properties of the respiratory system were evaluated by the rapid airway occlusion technique. The overall respiratory resistance, the interrupter resistance and the additional resistance that reflects the viscoelastic properties of tissues and the inequality of the time constant within the system were also evaluated. The results show that inhaled nitric oxide can act as a selective pulmonary vasodilator and as a bronchodilator to counteract the vasoconstrictor and bronchoconstrictor activity of endothelin-1. In the pig, nitric oxide inhaled at 80 ppm for 6 mitt reduced the changes in respiratory-, interrupter- and additional resistance due to endothelin-1 administration without significantly changing the static and dynamic elastance of the respiratory system.     

Nitric Oxide and Blood Pressure in Mice Lacking Extracellular-Superoxide Dismutase

Nitric oxide is a major vasorelaxant and regulator of the blood pressure. The blood vessels contain several active sources of the superoxide radical, which reacts avidly with nitric oxide to form noxious peroxynitrite. There are large amounts of extracellular-superoxide dismutase (EC-SOD) in the vascular wall. To evaluate the importance of EC-SOD for the physiology of nitric oxide, here we studied the blood pressure in mice lacking the enzyme. In chronically instrumented non-anaesthetized mice there was no difference in mean arterial blood pressure between wild-type controls and EC-SOD mutants. Extensive inhibition of nitric oxide synthases with N -monomethyl- l -arginine however resulted in a larger increase in blood pressure, and infusion of the nitric oxide donor nitrosoglutathione caused less reduction in blood pressure in the EC-SOD null mice. We interpret the alterations to be caused by a moderately increased consumption of nitric oxide by the superoxide radical in the EC-SOD null mice. One role of EC-SOD may be to preserve nitric oxide, a function that should be particularly important in vascular pathologies, in which large increases in superoxide formation have been documented.