Nitric Oxide and Portal Hypertension

In liver cirrhosis, an increase in hepatic resistance is the initial phenomenon leading to portal hypertension. This is primarily due to the structural distortion of the intrahepatic microcirculation caused by cirrhosis. However, similar to other vascular conditions, architectural changes in the liver are associated with a deficient nitric oxide (NO) production, which results in an increased vascular tone with a further increase in hepatic resistance and portal pressure. New therapeutic strategies are being developed to selectively provide the liver with NO, overcoming the deleterious effects of systemic vasodilators. On the other hand, a strikingly opposite process occurs in splanchnic arterial circulation, where NO production is increased. This results in splanchnic vasodilatation and subsequent increase in portal inflow, which contributes to portal hypertension. Systemic blockade of NO in portal hypertension attenuates the hyperdynamic circulation, but its effects increasing hepatic resistance may offset the benefit of reducing portal inflow, thus preventing an effective reduction of portal pressure. Moreover, it cannot be ruled out that NO blockade may have a deleterious action on cirrhosis progression, which raises caution about their use in patients with cirrhosis.     

The metabolites of nitric oxide in sickle-cell disease

Summary. Plasma NOx concentrations were raised in 22 acute painful crises in SCD. We have measured blood concentrations of nitric oxide metabolites (NOx) in sickle-cell disease (SCD), and shown that they are increased compared with healthy controls (P = 0.002), and haemoglobin E/β-thalassaemic controls (P=0.05). Concentrations in steady-state SCD were also higher than in healthy controls (P = 0.04) but not significantly different from the concentrations at the beginning of painful crises (P = 0.34). Importantly, in 12 regularly exchanged sicklers, the mean pre-transfusion NOx concentration did not differ significantly from the control population (P=0.52), suggesting that the changes in NO metabolism can be reversed. It is unlikely that the increased concentrations of NOx in SCD result from anaemia or haemolysis as the untransfused haemoglobin E/β-thalassaemics did not show increased levels.     

梅毒患者血清一氧化氮和一氧化氮合酶水平测定

目的　检测梅毒螺旋体感染者血清中一氧化氮 (NO)和一氧化氮合酶 (NOS)的水平。方法　用分光光度法测定血清中NO水平和NOS活性 ,血清中NO3 和NO2 总量代表体内NO水平 ,NOS催化L 精氨酸和氧的反应生成NO的多少代表血清NOS活性。结果　梅毒患者NO浓度为 115± 36 3nmol/L ,NOS活性为 35 8± 7 3U/ml,二者均远远高于正常对照组。结论　梅毒螺旋体的感染引起患者体内NO水平和NOS活性升高 ,NO在梅毒感染中可能发挥重要的作用。     

Current knowledge and significance of coronary artery ectasia: A chronologic review of the literature,recommendations for treatment,possible etiologies,and future considerations

Coronary artery ectasia is the abnormal enlargement of the coronary artery. The prognosis, treatment, and etiology of this disease remain an enigma. There is some evidence to suggest that the incidence of ectasia is increasing, and therefore understanding of this entity needs to improve. This article reviews the current literature on coronary artery ectasia and summarizes the findings. A treatment plan that targets each of the suggested clinical complications is provided. Using multiple indirect observations and current understanding of endothelium-derived relaxation factor, a possible etiology that implicates overstimulation of endogenous nitric oxide is provided. Current literature suggests that ectatic coronary arteries, even without the presence of coronary stenosis, are subject to thrombus formation, vasospasm, and spontaneous dissection. Newer subgroups of ectasia are arising with the use of multiple interventional devices to dilate coronary artery stenosis. By design, these destroy the media of the coronary artery, and it is not clear whether these “iatrogenic” ectatic arteries are subject to the same complications as “idiopathic” coronary artery ectasia. Further investigation is necessary to help define the benefit of the proposed treatment regimen, to clarify the prognosis of these newer groups of “iatrogenic” ectasia, and to confirm or disprove the hypothesis targeting nitric oxide as an etiologic factor.     

四氢生物喋呤对内皮细胞产生一氧化氮和超氧阴离子的影响

目的 探讨四氢生物喋呤(BH_4)对人脐静脉内皮细胞产生一氧化氮(NO)和超氧阴离子(O_2~(?))的影响。方法 在培养液中分别加入不同浓度的D—葡萄糖、胰岛素和BH_4，24h后取细胞培养液分别测定一氧化氮合酶(NOS)、超氧化物歧化酶(SOD)活性、NO和O_2~(?)浓度。结果 BH_4(10、100、500μmol／L)使内皮细胞NOS活性增高，500μmol／L BH_4使内皮细胞NO产生增加，10或100μmol／L BH_4对内皮细胞产生NO有增加的趋势，但与对照组比较无显著性差异(P＞0.05)；25mmol／L葡萄糖 BH_4(10、100、500μmol／L)对内皮细胞产生NO与对照组比较无显著性差异(P＞0.05)；高浓度胰岛素(10、100、1000mU／L) BH_4(10、100、500μmol／L)使内皮细胞NOS活性增强，NO产生增加。BH_4(10、100、500μmol／L)对内皮细胞SOD活性无明显影响，但可以改善25mmol／L葡萄糖对内皮细胞SOD活性的影响；胰岛素 BH_4对内皮细胞SOD活性无明显影响(P＞0.05)。BH_4(10、100、500μmol／L)使内皮细胞产生O_2~(?)减少，并可以改善25mmol／L葡萄糖对内皮细胞产生O_2~(?)影响；胰岛素 BH_4组O_2~(?)浓度明显低于对照组和不同浓度胰岛素组(P＜0.01)。结论 BH_4可以增加培养的人脐静脉内皮细胞NOS活性，使NO产生增加而使O_2~(?)水平下降。     

Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs

BACKGROUND & AIMS: Hydrogen sulfide (H(2)S), an endogenous gaseous mediator that causes vasodilation, is generated in mammalian tissues by cystathionine beta-synthase (CBS) and cystathionine-gamma-lyase (CSE). Here, we have investigated the role of H(2)S in a rodent model of nonsteroidal anti-inflammatory drug (NSAID) gastropathy. METHODS: Rats were given acetyl salycilic acid (ASA) or an NSAID alone or in combination with NaHS, an H(2)S donor, and killed 3 hours later. Gastric blood flow was measured by laser-Doppler flowmetry, whereas intravital microscopy was used to quantify adhesion of leukocytes to mesenteric postcapillary endothelium. RESULTS: At a dose of 100 micromol/kg, NaHS attenuated by 60%-70% the gastric mucosal injury, and tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1, and lymphocyte function-associated antigen (LFA)-1 mRNA up-regulation induced by NSAIDs (P < .05) NaHS administration prevented the associated reduction of gastric mucosal blood flow (P < .05) and reduced ASA-induced leukocyte adherence in mesenteric venules. NaHS did not affect suppression of prostaglandin E(2) (PGE(2)) synthesis by NSAIDs. Glibenclamide, a K(ATP) channel inhibitor, and DL-propargylglycine, a CSE inhibitor, exacerbated, whereas pinacidil, a K(ATP) opener, attenuated gastric injury caused by ASA. Exposure to NSAIDs reduced H(2)S formation and CSE expression (mRNA and protein) and activity by 60%-70%. By promoter deletion and mutation analysis, an Sp1 consensus site was identified in the CSE promoter. Exposure to NSAIDs inhibits Sp1 binding to its promoter and abrogates CSE expression in HEK-293 cells transfected with a vector containing the core CSE promoter. Exposure to NSAIDs inhibits Sp1 and ERK phosphorylation. CONCLUSIONS: These data establish a physiologic role for H(2)S in regulating the gastric microcirculation and identify CSE as a novel target for ASA/NSAIDs.     

运脾法对幼龄厌食大鼠胃窦和结肠中一氧化氮的调节作用

目的 :研究一氧化氮在幼龄厌食大鼠胃窦、十二指肠和结肠中的含量变化及其运脾中药对其的干预。方法 :运用免疫组化技术测定幼龄厌食大鼠和中药干预后大鼠胃窦、十二指肠和结肠中一氧化氮的含量。结果 :幼龄厌食大鼠胃窦和结肠中一氧化氮含量明显高于中药干预后的大鼠 ,有显著性差异 (P <0 .0 1)。结论 :运脾中药能调节幼龄厌食大鼠胃窦和结肠中紊乱的一氧化氮水平。     

Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture

The antiproliferative and proapoptotic properties of melatonin in human colon cancer cells in culture were recently reported. To address the mechanisms involved in these actions, HT-29 human colon cancer cells were cultured in RPMI 1640 medium supplemented with fetal bovine serum at 37 degrees C. Cell proliferation was assessed by the incorporation of [(3)H]-thymidine into DNA. Cyclic nucleotide levels, nitrite concentration, glutathione peroxidase and reductase activities, and glutathione levels were assessed after the incubation of these cells with the following drugs: melatonin membrane receptor agonists 2-iodo-melatonin, 2-iodo-N-butanoyl-5-methoxytryptamine, 5-methoxycarbonylamino-N-acetyltryptamine (GR-135,531), and the antagonists luzindole, 4-phenyl-2-propionamidotetralin, and prazosin; the melatonin nuclear receptor agonist CGP 52608, and four synthetic kynurenines analogs to melatonin 2-acetamide-4-(3-methoxyphenyl)-4-oxobutyric acid, 2-acetamide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid, 2-butyramide-4-(3-methoxyphenyl)-4-oxobutyric acid and 2-butyramide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid. The results show that the membrane receptors are not necessary for the antiproliferative effect of melatonin and the participation of the nuclear receptor in this effect is suggested. Moreover, the antioxidative and anti-inflammatory actions of melatonin, counteracting the oxidative status and reducing the production of nitric oxide by cultured HT-29 cells seem to be directly involved in the oncostatic properties of melatonin. Some of the synthetic kynurenines exert higher antiproliferative effects than melatonin. The results reinforce the clinical interest of melatonin due to the different mechanisms involved in its oncostatic role, and suggest a new synthetic pathway to obtain melatonin agonists with clinical applications to oncology.     

Exhaled nitric oxide measure using multiple flows in clinically relevant subgroups of COPD

Although there is widespread interest in fractional exhaled nitric oxide (FeNO) as a non-invasive, time and cost effective biomarker for assessing airway inflammation in chronic obstructive pulmonary disease (COPD), its usefulness is still controversial. We examined the FeNO levels in clinically meaningful subgroups of COPD in a group of 91 COPD patients with FEV(1) 17-77% of predicted. Multiple flow rates FeNO at 10, 30, 50, 100 and 200 mL/s were measured and a two-compartment model was used to estimate the diffusion Capacity (D), alveolar NO concentration (Calv) and airway wall NO concentration (Caw). All patients had spirometry, assessment of symptoms with questionnaires and low-dose CT scan as well as assessment of weight and body composition. We examined the following subgroups of COPD: Patients with 1) Severe emphysema, 2) Chronic bronchitis, 3) Frequent exacerbations, 4) Loss of lean body mass and 5) Low fat-free mass index. We used advanced non-linear mixed model adjusted for age and gender. The modelled differences in D, Calv or Caw among COPD subgroups were small and not statistically significant. The analysis showed significant effects of current smoking on Caw and of gender on D and Calv. The results were the same if the advanced non-linear mixed model was substituted by more standard analysis techniques. This study questions the relevance of using FeNO as a biomarker to evaluate local inflammation in COPD and points to a need for developing novel non-invasive biomarkers for research laboratory work and daily clinical practice.