Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention.

AIMS: We investigated the predictive value of plasma concentration of asymmetrical dimethylarginine (ADMA) on clinical outcome in patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: One-hundred and fifty-three consecutive patients with stable angina and undergoing PCI were prospectively enrolled for clinical follow-up. Plasma ADMA levels were determined before procedure by high performance liquid chromatography. The major adverse cardiovascular events included cardiovascular death, myocardial infarction, and repeat revascularization of target vessels. Patients were grouped into tertiles according to their plasma ADMA levels. Over a follow-up period of 16 months (median), cardiovascular events occurred in 6 patients of tertile I (<0.50microM), in 17 patients of tertile II (0.50-0.62microM), and in 28 patients of tertile III (>0.62microM), P<0.001. By multivariate analysis, tertiles of ADMA levels were independently associated with a higher risk of adverse cardiovascular events after PCI (relative risk: tertile II vs I: 3.0 [1.2-7.7], P=0.022; tertile III vs I: 5.3 [2.2-12.9], P<0.001). Moreover, plasma ADMA level in the highest tertile also appeared as a significant risk factor of subsequent death and non-fatal myocardial infarction after PCI (tertile III vs I, P=0.04). CONCLUSION: Pre-procedural plasma ADMA levels may independently predict subsequent adverse cardiovascular events in patients undergoing PCI. Measurement of plasma ADMA levels could provide a rationale for risk stratification of patients by measuring ADMA levels before intervention.     

Asymmetrical dimethylarginine: a novel risk factor for coronary artery disease

BACKGROUND: Asymmetrical dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and has been associated with systemic atherosclerosis; however, the role of ADMA in patients with coronary artery disease (CAD) has not been investigated. HYPOTHESIS: The present study was designed to determine whether the plasma ADMA level predicts the presence of CAD independently, and whether the plasma ADMA level correlates with the extent and severity of coronary atherosclerosis. METHODS: In all, 97 consecutive patients with angina and positive exercise stress test were enrolled prospectively for coronary angiography. According to the result of angiography, the subjects were divided into two groups: Group I (n = 46): patients with normal coronary artery or mild CAD (< 50% stenosis of major coronary arteries); Group 2 (n = 51): patients with significant CAD (> or = 50% stenosis of majorcoronary arteries). Plasma levels of ADMA and L-arginine were determined by high-performance liquid chromatography. In addition, we used coronary atherosclerotic score to assess the extent and severity of CAD. RESULTS: The plasma levels of ADMA in Group 2 patients were significantly higher than those in Group 1 patients (0.66 +/- 0.17 microM vs. 0.44 +/- 0.09 microM, p < 0.001); these were accompanied by significantly lower plasma L-arginine/ADMA ratio in patients with significant CAD (Group 1 vs. 2: 194.0 +/- 55.3 vs. 136.7 +/- 50.3, p < 0.001). In a multivariate stepwise logistic regression analysis, both plasma ADMA level and plasma L-arginine/ADMA ratio were identified as independent predictors for CAD. Moreover, there were significant positive and negative correlations between coronary atherosclerotic score and plasma ADMA level as well as plasma L-arginine/ADMA ratio, respectively (plasma ADMA level: r = 0.518, p < 0.001; L-arginine/ADMA ratio: r = -0.430, p < 0.001). CONCLUSIONS: Both plasma ADMA level and plasma L-arginine/ADMA ratio were useful in predicting the presence of significant CAD and correlated significantly with the extent and severity of coronary atherosclerosis. Our findings suggest that plasma ADMA level may be a novel marker of CAD.     

Nitric oxide production of rat Leydig and Sertoli cells is stimulated by round spermatid factor(s)

In this study, we provide evidence of cell-to-cell interaction between rat germ cells and Leydig or Sertoli cells in relation to nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) expression. As a result of being cultured in a round spermatid-conditioned medium (RSd-CM), NO production in both Leydig and Sertoli cells increased in proportion to the length of the culture period. iNOS mRNA expression in both types of cells also increased in a dose-dependent manner as a result of being cultured with RSd-CM. This increase was detected as early as 3 h and was maintained up to 24 h. In contrast, neither NO production nor iNOS mRNA increased in either type of cell following culture in a pachytene spermatocyte-conditioned medium (PS-CM). Our findings suggest that RSd may control NO production of Leydig and Sertoli cells. This cell-to-cell interaction may be an important mechanism of regulation of testicular function.     

一氧化氮和内毒素在梗阻性黄疸致病机制方面的作用

梗阻性黄疸（obstructive jaundice）是临床常见的表现。梗阻性黄疸患者术后并发症和死亡率较高，常死于感染和败血症，提示机体术前的免疫功能受到了抑制。梗阻性黄疸可使网状内皮系统功能降低，细菌清除能力减弱。肠道来源的细菌和内毒素逃脱肝脏枯否细胞的监视，进入血液循环。有研究发现梗阻性黄疸常并发肠源性内毒素血症，内毒素激活枯否细胞，产生大量炎性介质，如一氧化氮（NO），肿瘤坏死因子α（TNFα）及氧自由基等。     

Expression of inducible nitric oxide synthase in cultured smooth muscle cells from rat mesenteric lymphatic vessels

OBJECTIVE: The objective was to devise a method for establishing cultures of rat mesenteric lymphatic vessel smooth muscle cells (LSMC) and to investigate if inducible nitric oxide synthase (iNOS) expression could be activated in LSMC treated with bacterial lipopolysaccharide (LPS). METHODS: LSMC were successfully grown from explanted rat lymphatic microvessels and maintained by subculture. Treatment of LSMC for 24 h with LPS (1-100 microg/mL) activated iNOS protein induction, associated with (1) assay of increased nitrite concentrations in the medium representing cellular nitric oxide synthesis, and (2) demonstration of iNOS in cell extracts by Western blotting. RESULTS: The protein synthesis inhibitor cycloheximide (10 microM) blocked both LPS-induced nitrite formation and iNOS protein expression in LSMC. 1400 W (1 microM), a selective iNOS inhibitor, prevented LPS-induced nitrite formation but not iNOS expression. As well as induction of iNOS by LPS, "constitutive" iNOS was present in some cultures, producing nitrite in amounts that were also subsequently reduced after cell treatment with 1400 W. CONCLUSION: Rat mesenteric LSMC produce nitrite and express iNOS in response to bacterial LPS. Cultured LSMC may provide a useful model for studying mechanisms of iNOS induction in relation to possible influences of iNOS upon lymphatic vessel function.     

Nitric oxide inhibits establishment of macroschizont-infected cell lines and is produced by macrophages of calves undergoing bovine tropical theileriosis or East Coast fever

Nitric oxide (NO) was produced when bovine peripheral blood mononuclear cells (PBMC) or purified, adherent PBMC (macrophages) were incubated in vitro with bovine recombinant interferon gamma (Bo rIFN-γ). NO was produced by cells from naive, uninfected calves as well as by cells from cattle either infected with or recovered from infection with Theileria annulata or Theileria parva. PBMC of cattle undergoing tropical theileriosis (T. annulata infection) or East Coast fever (T. parva infection) synthesized NO spontaneously in vitro. NO was also induced when PBMC of immune, but not of naive, cattle were cultured with T. annulata macroschizont-infected cell lines. Macrophages alone were not stimulated to produce NO by such infected cells. In vitro establishment of macroschizont-infected cell lines was suppressed either by incubating sporozoites with S-nitroso-N-acetyl-DL-penicillamine (SNAP), a NO releasing molecule, prior to invasion of PBMC or by pulsing developing cultures of trophozoite-infected cells with SNAP. Proliferation of established macroschizont-infected cell lines was not affected by SNAP. Taken together with the well documented roles of NO in neurotransmission, vasodilatation, cell and tissue damage and immunosuppression, the results presented here indicate that NO may not only protect cattle against T. annulata and T. parva but, if produced in excess, play a prominent role in the pathogenesis of tropical theileriosis and East Coast fever.     

运脾润肠法对慢传输型功能性便秘结肠动力的影响

[目的]观察中医运脾润肠法治疗慢传输型便秘(STC)的临床疗效及对血清一氧化氮(NO)、血浆P物质(SP)水平、结肠动力的影响.[方法]选择确诊为STC患者90例按2∶1比例随机分为2组,治疗组(应用秘通治疗)60例,对照组(莫沙必利治疗)30例,并设正常对照(正常)组30例.采用放射免疫法(RIA)测定2组治疗前、后空腹血清NO和血浆SP水平,并与正常组测得值对比.并比较2组治疗前、后的结肠通过时间(GITT).[结果]治疗组临床症状总有效率为93.3%,对照组为73.3%(P＜0.05).治疗前,2组血浆SP水平比正常组显著降低,血清NO水平比正常组显著增高;治疗后2组NO及SP水平均有显著改善,与治疗前比较差异有统计学意义(P＜0.05).但治疗组治疗后NO及SP与正常组比较P＞0.05,而对照组治疗后NO及SP与正常组比较P＜0.05.结果表明秘通、莫沙必利均可明显降低血清NO及升高血浆SP水平,而治疗组的效果优于对照组.治疗前2组GITT示48 h后停留在右半结肠或横结肠的标志物超过80%,用药后标志物显著减少并接近正常,但治疗组减少情况优于对照组.[结论]中医运脾润肠法治疗STC患者疗效显著,能缩短GITT、调节血清NO和血浆SP水平,推动肠道蠕动,促进肠道排空,达到改善患者临床症状的目的.     

Effects of chronic noradrenaline on the nitric oxide pathway in human endothelial cells

Altered endothelium-dependent vasodilation has been observed in congestive heart failure (CHF), a disease characterized by a sustained adrenergic activation. The purpose of our study was to test the hypothesis that chronically elevated catecholamines influence the nitric oxide (NO) pathway in the human endothelium. Human umbilical vein endothelial cells (HUVEC) were exposed for 7 days to a concentration of noradrenaline (NA, 1 ng/mL) similar to that found in the blood of patients with CHF. Kinetics of endothelial constitutive NO synthase (ecNOS) and inducible NO synthase (iNOS) activity, measured by [³H]L-arginine to [³H]L-citrulline conversion, and protein expression of ecNOS and iNOS, assessed by Western blot analysis, were unaffected by chronic NA treatment. Furthermore, no changes in subcellular fraction-associated ecNOS were found; this indirectly shows that chronic NA did not cause phosphorylation of the enzyme. Moreover, [³H]L-arginine transport through the plasma membrane was conserved in chronically NA-treated cells. The data demonstrate that prolonged in vitro exposure to pathologic CHF-like NA does not affect the L-arginine NO pathway in human endothelial cells. Received: 11 July 1997, Returned for revision: 13 August 1997, Revision received: 6 October 1997, Returned for 2. revision: 17 November 1997, 2. Revision received: 5 January 1998, Accepted: 26 January 1998     

低高密度脂蛋白胆固醇血症患者血浆一氧化氮合酶和一氧化氮水平相关性研究

目的:对低高密度脂蛋白胆固醇(HDL-C)血症患者和正常人群的血浆一氧化氮合酶(nitric oxide synthase,NOS)和一氧化氮(nitric oxide,NO)进行分析比较,探讨低HDL-C血症致动脉粥样硬化的可能机制。方法:根据血脂水平选取87例(男51例,女36例)低HDL-C血症患者作为低HDL-C血症组和66例(男35例,女31例)正常人群作为健康对照组,分别测定血浆NOS(用化学比色法测定)和NO(用硝酸酶还原法测定)。结果:低HDL-C血症组血浆NOS和血浆NO水平均显著低于健康对照组(P均<0．05);在低HDL-C血症组男性血浆NOS水平和血浆NO水平均显著低于相应健康对照组男性(P均<0．05);在低HDL-C血症组女性血浆NOS水平和血浆NO水平亦均显著低于相应健康对照组女性(P均<0．05)。结论:低HDL-C患者血浆NOS和NO水平较健康人(包括男性和女性)显著降低。