ADMA、eNOS及NO水平与急性脑梗死关系的研究
|
摘要
目的:缺血性脑血管病在国内外均具有很高的致残率和病死率,内皮功能的损伤是心脑血管疾病的一种普遍现象,随着对其研究的深入,其治疗方向逐渐分为改善缺血区域供血及保护缺血神经细胞两方面,其中血管内皮细胞产生的一氧化氮(NO)是一项重要的内在脑血流调节剂及保护剂。血管内皮细胞在生理状态下持续释放NO,NO是以L-精氨酸为底物,主要由内皮型一氧化氮合酶(eNOS)催化产生。非对称性二甲基精氨酸(ADMA)是L-精氨酸类似物,可与其竞争结合eNOS活性位点抑制NOS活性,减少NO的生成,从而导致内皮功能的受损。本研究通过对脑梗死患者(包括合并高血压患者)血浆ADMA和血清eNOS、NO水平的检测,探讨ADMA致心脑血管疾病的发病机制及eNOS的神经保护作用,为临床早期干预和药物治疗脑梗死提供理论指导和客观依据。
方法:选取急性脑梗死血压正常患者50例,急性脑梗死合并高血压者60例,健康对照50例,三组间年龄、性别相匹配。脑梗死患者在发病一周内,所有受检对象均至少空腹12小时后静脉取血,分别测定其血浆ADMA和血清eNOS、NO水平。其中ADMA的测定采用高压液相色谱法分析法,eNOS的测定采用ELISA方法,血清NO的测定采用硝酸还原酶法。数值以均数±标准差表示,结果经SPSS11.5统计软件进行统计处理。
结果:1.急性脑梗死正常血压组血浆ADMA水平(0.73±0.16μmol/L),脑梗死合并高血压组血浆ADMA水平为(1.03±0.22umol/L),健康对照组血浆ADMA水平为(0.47±0.16umol/L),三组间差异具有统计学意义(p＜0.05)。并且ADMA与高血压水平(脑梗死合并高血压组)呈正相关(p＜0.05),与年龄、性别、TC、TG、吸烟、饮酒等无相关性。
2.脑梗死合并高血压组患者的血清eNOS水平(47.61±20.21U/ml),明显低于急性脑梗死血压正常组血清eNOS水平(55.70±18.96U/ml)(p＜0.05),并且两者均低于正常对照组血清eNOS水平(66.54±24.13U/ml)(P＜0.05)。
3.脑梗死合并高血压组血清NO水平为(55.28±10.78umol/L),脑梗死正常血压组血清NO水平(60.20±14.03umol/L),两组间无显著差别(p＞0.05),但均低于正常对照组NO水平(70.27±6.78umol/L),差别有统计学意义(p＜0.05)。
4.高血压分级测定脑梗死合并各级高血压患者的检查指标显示:高血压1级患者的血浆ADMA水平为(0.74±0.23umol/L),均显著低于高血压2级和3级患者,而后两组间差别无显著性(p＞0.05);三组间血清eNOS水平比较示:高血压1级组eNOS水平为(51.27±16.76umol/L),高血压2级组为(49.43±19.22umol/L),均较高血压3级组(45.45±14.10umol/L)为高,且差别有显著意义(p＜0.05);三组患者血清NO浓度分别为(53.16±11.48、50.87±16.03和46.02±16.82 umol/L),但组间无显著性差异(p＞0.05)。
5.对病例组OCSP分型后进行主要观察指标的比较发现TACI和PACI组ADMA水平较LACI为高,差别有显著意义;TACI及POCI两组的eNOS水平较LACI为低,TACI组NO水平低于LACI组,差别均有显著意义(p＜0.05)。
6.Pearson相关性分析显示:脑梗死正常血压组ADMA水平与eNOS呈负相关(r=-0.501,p＜0.05);脑梗死合并高血压组ADMA水平与eNOS亦呈负相关(r=-0.717,p＜0.05)。两组ADMA与NO均呈负相关,r分别为-0.484和-0.312。
7.分别将脑梗死的传统危险因素如性别、年龄、高血压、糖尿病、吸烟、饮酒等及ADMA进行单因素分析,将p＞0.05的因素进行剔除,p＜0.05的因素代入多元逐步Logistic回归分析中,发现在控制其他传统缺血性脑血管病危险因素影响后,血浆ADMA水平增高仍有统计学意义(OR=1.142,p=0.002)。
结论:在急性脑梗死患者血浆ADMA水平显著升高,血清eNOS水平明显降低,提示脑梗死患者普遍存在血管内皮功能受损。急性脑梗死伴发高血压患者血浆ADMA水平高于脑梗死正常血压组,血清eNOS水平低于脑梗死正常血压组,而且二者的变化均与高血压的程度有关,提示血浆ADMA及eNOS水平与高血压等心血管并发症明显相关。另外,ADMA的水平可能与脑梗死的梗死面积存在密切相关。ADMA与eNOS呈负相关,而eNOS作为NO合成的关键酶,其活性变化直接调节NO的生成量及其生物学效应,提示ADMA通过eNOS/NO途径影响血管内皮功能。在控制其他影响因素后,多因素分析显示ADMA可能作为脑梗死的独立危险因素,可能是预测急性中风事件发生的的危险因子,对其进行早期干预治疗有望降低缺血性脑血管病的发病率及病死率。
Purpose:Ischemic cerebrovascular disease has high morbidity and mortality both at home and abroad,damage in endothelial function of cardiovascular and cerebrovascul -ar diseases(CCD) be considered as a widespread phenomenon,with the developing of its research,the treatments are divided into improving the lack of regional blood supply gradually and protect the ischemic nerve cells,with in these the nitric oxide (NO) which be produced by vascular endothelial cells is an inportant intrinsic agent in regulate cerebral blood flow and protect nerve cells.Under physiological condition ,NO is released sustainly,L-arginine as its substrate and mainly by endothelial nitric oxide synthase(eNOS) catalytic generated.ADMA is the analogues of L-arginine, and it can compete with eNOS active site to inhibit the activity of NOS,thus will to reduce the generation of NO,resulting in endothelial dysfunction.This study through exam the levels of ADMA in plasma and NO,eNOS levels in serum about patients of who suffered with cerebral infarction combined with or not hypertension.In order to explore the pathogenesis of CCD that through ADMA induced,on the other hand,to explore the neuroprotective effect of eNOS.All of these will be benefit to cerebral infarction in clinical intervent early and drug treatment.Moreover,it will providing theoretical guidance and objective basis to cerebral infarction.
Methods:Select fifty cases who suffered with acute cerebral infarction but normote -nsive,sixty cases of acute cerebral infarction with hypertension,and fifty cases of healthy controls,three groups of age,sex matched.Patients who presented with in one-week after the onset,and collected venous blood after fasting at least twelve hours,then examed the levels of ADMA,NO and eNOS each group.ADMA was examed by HPLC,NO was examed by nitrate reductase method,eNOS was examed by enzyme-linked ELISA method.Value to mean±standard deviation of that result, all statistical analyses were performed with the statistical software SPSS11.5.
Results:1.Acute cerebral infarction with normal blood pressure group plasma ADMA level was(0.73±0.16μmol/L),cerebral infarction with hypertension plasma ADMA level was(1.03±0.22umol/L),the healthy control group,plasma ADMA level was 0.47±0.16umol/L,there have statistically significant difference among there groups(p＜0.05).Moreover,ADMA and the level of hypertension were positive -ly correlated(p＜0.01),there were non-related to age,TC,TG,smoking,drinking and other factors.
2.Cases of infarction patients with hypertension whose eNOS level was(47.61±20.2 1U/ml),significantly lower than the normal blood pressure group which eNOS level was(55.70±18.96U/ml)(p＜0.05),and both lower than the normal control group,its eNOS levels in serum(66.54±24.13U/ml)(P＜0.05).
3.NO level in Infarction combined with hypertension group was(55.28±10.78umol /L),the group cerebral infartion but normal blood pressure whose serum NO level was(60.20±14.03umol/L),there were not significant difference between the two groups(p＞0.05),but were lower than NO level of the control group(70.27±6.78 umol/L),the difference has statistical significance(p＜0.05).
4.Determination of high blood pressure(HBP) classification at all levels with hypert -ension in patients with cerebral infarction inspection indicators:patients of HBP classl whose plasma ADMA level of 0.74±0.23umol/L,were significantly lower than class 2 and 3 patients(whose ADMA levels to(0.96±0.17 umol/L) and(1.05±0.11 umol/L),and between the later two groups was not significant different (p＞0.05);eNOS levels among three HBP groups show:classⅠwas of(51.27±16.76 umol/L),class 2 group was 49.43±19.22umol/L,both they were higher than class 3 group(45.45±14.10 umol/L),and have significant differences(p＜0.05);three groups of patients with serum NO concentrations were(53.16±11.48 umol/L), (50.87±16.03 umol/L) and(46.02±16.82 umol/L),but there were no significant differences(p＞0.05).
5.After the OCSP classification founded that level of ADMA in both TACI and PACI were higher than LACI;eNOS level in TACI and POCI were lower than LACI group; and the NO level in TACI was lower than LACI.The differences were significant.
6.Pearson-correlation analysis showed:normal blood pressure group cerebral ADMA levels with eNOS were negative correlation(r=-0.501,p＜0.05);cerebral infarction combined with hypertension group ADMA levels with eNOS were also negatively correlated(r=-0.717,p＜0.05).ADMA and NO levels were negatively correlated between two groups,correlation coefficients were -0.484 and -0.312.
7.Respectively,the traditional risk factors for cerebral infarction such as gender,age, hypertension,diabetes,smoking,drinking,etc.and ADMA to do one-factor analysis, statistic standard is p＜0.05,it will be removed if p＞0.05,and factors of p＜0.05 were performed the multiple stepwise Logistic regression analysis found that in the control of other traditional risk factors of ischemic cerebrovascular disease,elevated plasma ADMA levels was still a independent risk factor.
Conclusion:The levels of ADMA in plasma were higher significantly in acute cerebral infarction,but levels of eNOS in serum were lower obviously,indicated that vascular endothelial dysfunction was prevalence in cerebral infarction.There have significant difference in the levels of ADMA and eNOS which in the two groups—CI combined with hypertension and CI but normotension group,the finding suggesting that there have correlation between the hypertension with levels of ADMA and eNOS, and there were correlation with the degree of hypertension.On the other hand,based on OCSP classification,ADMA may be close correlated with cerebral infarction area. ADMA was negatively correlated with eNOS,eNOS as a key enzyme in produce NO, so the quantity and biological effects of NO will be regulated directly by eNOS,thus, we think that the influence of ADMA to vascular endothelial function through the eNOS/NO pathway.
Controlling for other factors,the multi-factor analysis showed that ADMA may serve as an independent risk factor for cerebral infarction,it can be used as predict factor for stroke.As a result,ADMA will be as a treatment target of CI and may expe -cted to reduce its morbidity and mortality.
方法:选取急性脑梗死血压正常患者50例,急性脑梗死合并高血压者60例,健康对照50例,三组间年龄、性别相匹配。脑梗死患者在发病一周内,所有受检对象均至少空腹12小时后静脉取血,分别测定其血浆ADMA和血清eNOS、NO水平。其中ADMA的测定采用高压液相色谱法分析法,eNOS的测定采用ELISA方法,血清NO的测定采用硝酸还原酶法。数值以均数±标准差表示,结果经SPSS11.5统计软件进行统计处理。
结果:1.急性脑梗死正常血压组血浆ADMA水平(0.73±0.16μmol/L),脑梗死合并高血压组血浆ADMA水平为(1.03±0.22umol/L),健康对照组血浆ADMA水平为(0.47±0.16umol/L),三组间差异具有统计学意义(p＜0.05)。并且ADMA与高血压水平(脑梗死合并高血压组)呈正相关(p＜0.05),与年龄、性别、TC、TG、吸烟、饮酒等无相关性。
2.脑梗死合并高血压组患者的血清eNOS水平(47.61±20.21U/ml),明显低于急性脑梗死血压正常组血清eNOS水平(55.70±18.96U/ml)(p＜0.05),并且两者均低于正常对照组血清eNOS水平(66.54±24.13U/ml)(P＜0.05)。
3.脑梗死合并高血压组血清NO水平为(55.28±10.78umol/L),脑梗死正常血压组血清NO水平(60.20±14.03umol/L),两组间无显著差别(p＞0.05),但均低于正常对照组NO水平(70.27±6.78umol/L),差别有统计学意义(p＜0.05)。
4.高血压分级测定脑梗死合并各级高血压患者的检查指标显示:高血压1级患者的血浆ADMA水平为(0.74±0.23umol/L),均显著低于高血压2级和3级患者,而后两组间差别无显著性(p＞0.05);三组间血清eNOS水平比较示:高血压1级组eNOS水平为(51.27±16.76umol/L),高血压2级组为(49.43±19.22umol/L),均较高血压3级组(45.45±14.10umol/L)为高,且差别有显著意义(p＜0.05);三组患者血清NO浓度分别为(53.16±11.48、50.87±16.03和46.02±16.82 umol/L),但组间无显著性差异(p＞0.05)。
5.对病例组OCSP分型后进行主要观察指标的比较发现TACI和PACI组ADMA水平较LACI为高,差别有显著意义;TACI及POCI两组的eNOS水平较LACI为低,TACI组NO水平低于LACI组,差别均有显著意义(p＜0.05)。
6.Pearson相关性分析显示:脑梗死正常血压组ADMA水平与eNOS呈负相关(r=-0.501,p＜0.05);脑梗死合并高血压组ADMA水平与eNOS亦呈负相关(r=-0.717,p＜0.05)。两组ADMA与NO均呈负相关,r分别为-0.484和-0.312。
7.分别将脑梗死的传统危险因素如性别、年龄、高血压、糖尿病、吸烟、饮酒等及ADMA进行单因素分析,将p＞0.05的因素进行剔除,p＜0.05的因素代入多元逐步Logistic回归分析中,发现在控制其他传统缺血性脑血管病危险因素影响后,血浆ADMA水平增高仍有统计学意义(OR=1.142,p=0.002)。
结论:在急性脑梗死患者血浆ADMA水平显著升高,血清eNOS水平明显降低,提示脑梗死患者普遍存在血管内皮功能受损。急性脑梗死伴发高血压患者血浆ADMA水平高于脑梗死正常血压组,血清eNOS水平低于脑梗死正常血压组,而且二者的变化均与高血压的程度有关,提示血浆ADMA及eNOS水平与高血压等心血管并发症明显相关。另外,ADMA的水平可能与脑梗死的梗死面积存在密切相关。ADMA与eNOS呈负相关,而eNOS作为NO合成的关键酶,其活性变化直接调节NO的生成量及其生物学效应,提示ADMA通过eNOS/NO途径影响血管内皮功能。在控制其他影响因素后,多因素分析显示ADMA可能作为脑梗死的独立危险因素,可能是预测急性中风事件发生的的危险因子,对其进行早期干预治疗有望降低缺血性脑血管病的发病率及病死率。
Purpose:Ischemic cerebrovascular disease has high morbidity and mortality both at home and abroad,damage in endothelial function of cardiovascular and cerebrovascul -ar diseases(CCD) be considered as a widespread phenomenon,with the developing of its research,the treatments are divided into improving the lack of regional blood supply gradually and protect the ischemic nerve cells,with in these the nitric oxide (NO) which be produced by vascular endothelial cells is an inportant intrinsic agent in regulate cerebral blood flow and protect nerve cells.Under physiological condition ,NO is released sustainly,L-arginine as its substrate and mainly by endothelial nitric oxide synthase(eNOS) catalytic generated.ADMA is the analogues of L-arginine, and it can compete with eNOS active site to inhibit the activity of NOS,thus will to reduce the generation of NO,resulting in endothelial dysfunction.This study through exam the levels of ADMA in plasma and NO,eNOS levels in serum about patients of who suffered with cerebral infarction combined with or not hypertension.In order to explore the pathogenesis of CCD that through ADMA induced,on the other hand,to explore the neuroprotective effect of eNOS.All of these will be benefit to cerebral infarction in clinical intervent early and drug treatment.Moreover,it will providing theoretical guidance and objective basis to cerebral infarction.
Methods:Select fifty cases who suffered with acute cerebral infarction but normote -nsive,sixty cases of acute cerebral infarction with hypertension,and fifty cases of healthy controls,three groups of age,sex matched.Patients who presented with in one-week after the onset,and collected venous blood after fasting at least twelve hours,then examed the levels of ADMA,NO and eNOS each group.ADMA was examed by HPLC,NO was examed by nitrate reductase method,eNOS was examed by enzyme-linked ELISA method.Value to mean±standard deviation of that result, all statistical analyses were performed with the statistical software SPSS11.5.
Results:1.Acute cerebral infarction with normal blood pressure group plasma ADMA level was(0.73±0.16μmol/L),cerebral infarction with hypertension plasma ADMA level was(1.03±0.22umol/L),the healthy control group,plasma ADMA level was 0.47±0.16umol/L,there have statistically significant difference among there groups(p＜0.05).Moreover,ADMA and the level of hypertension were positive -ly correlated(p＜0.01),there were non-related to age,TC,TG,smoking,drinking and other factors.
2.Cases of infarction patients with hypertension whose eNOS level was(47.61±20.2 1U/ml),significantly lower than the normal blood pressure group which eNOS level was(55.70±18.96U/ml)(p＜0.05),and both lower than the normal control group,its eNOS levels in serum(66.54±24.13U/ml)(P＜0.05).
3.NO level in Infarction combined with hypertension group was(55.28±10.78umol /L),the group cerebral infartion but normal blood pressure whose serum NO level was(60.20±14.03umol/L),there were not significant difference between the two groups(p＞0.05),but were lower than NO level of the control group(70.27±6.78 umol/L),the difference has statistical significance(p＜0.05).
4.Determination of high blood pressure(HBP) classification at all levels with hypert -ension in patients with cerebral infarction inspection indicators:patients of HBP classl whose plasma ADMA level of 0.74±0.23umol/L,were significantly lower than class 2 and 3 patients(whose ADMA levels to(0.96±0.17 umol/L) and(1.05±0.11 umol/L),and between the later two groups was not significant different (p＞0.05);eNOS levels among three HBP groups show:classⅠwas of(51.27±16.76 umol/L),class 2 group was 49.43±19.22umol/L,both they were higher than class 3 group(45.45±14.10 umol/L),and have significant differences(p＜0.05);three groups of patients with serum NO concentrations were(53.16±11.48 umol/L), (50.87±16.03 umol/L) and(46.02±16.82 umol/L),but there were no significant differences(p＞0.05).
5.After the OCSP classification founded that level of ADMA in both TACI and PACI were higher than LACI;eNOS level in TACI and POCI were lower than LACI group; and the NO level in TACI was lower than LACI.The differences were significant.
6.Pearson-correlation analysis showed:normal blood pressure group cerebral ADMA levels with eNOS were negative correlation(r=-0.501,p＜0.05);cerebral infarction combined with hypertension group ADMA levels with eNOS were also negatively correlated(r=-0.717,p＜0.05).ADMA and NO levels were negatively correlated between two groups,correlation coefficients were -0.484 and -0.312.
7.Respectively,the traditional risk factors for cerebral infarction such as gender,age, hypertension,diabetes,smoking,drinking,etc.and ADMA to do one-factor analysis, statistic standard is p＜0.05,it will be removed if p＞0.05,and factors of p＜0.05 were performed the multiple stepwise Logistic regression analysis found that in the control of other traditional risk factors of ischemic cerebrovascular disease,elevated plasma ADMA levels was still a independent risk factor.
Conclusion:The levels of ADMA in plasma were higher significantly in acute cerebral infarction,but levels of eNOS in serum were lower obviously,indicated that vascular endothelial dysfunction was prevalence in cerebral infarction.There have significant difference in the levels of ADMA and eNOS which in the two groups—CI combined with hypertension and CI but normotension group,the finding suggesting that there have correlation between the hypertension with levels of ADMA and eNOS, and there were correlation with the degree of hypertension.On the other hand,based on OCSP classification,ADMA may be close correlated with cerebral infarction area. ADMA was negatively correlated with eNOS,eNOS as a key enzyme in produce NO, so the quantity and biological effects of NO will be regulated directly by eNOS,thus, we think that the influence of ADMA to vascular endothelial function through the eNOS/NO pathway.
Controlling for other factors,the multi-factor analysis showed that ADMA may serve as an independent risk factor for cerebral infarction,it can be used as predict factor for stroke.As a result,ADMA will be as a treatment target of CI and may expe -cted to reduce its morbidity and mortality.
引文
[1]江文,黄远桂.一氧化氮合酶与局灶性脑缺血[J].中风与神经疾病杂志,1998,15(6):375-377.
[2]Boger R H,Bode-Boger SM.Asymmetric dimenthylarginine,derangemengts of the endothelial nitric oxide synthase pathway,and cardiovascular disease[J].Semin Thromb Hemost,2000,26(5):539-545.
[3]叶任高,陆在英.内科学[M].第六版.北京:人民卫生出版社,2004:247.
[4]王维治,罗祖明.神经病学[M].第5版.北京:人民卫生出版社,2005:134.
[5]Yoo JH,Lee SC.Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke[J].Atherosclerosis,2001,158:425-430.
[6]Wanby P,Teerlink T,Brudin L,et al.Asymmetric dimethylarginine(ADMA) as a risk marker for stroke and TIA in a Swedish population[J].Atherosclerosis,2006,185:271-277.
[7]Luscher TF,Barton M.Biology of the endothelium[J].ClinCardiol,1997,20(11):3-10.
[8]Boger RH.The emerging role of asymmetric dimethylarginine as a novel car diovascular risk factor[J].Circ Res,2003,59:824-833.
[9]Teerlink T.ADMA metabolism and clearance[J].Vascular Medicine 2005,10:S73-81.
[10]Tojo A,Welch WJ,Bremer V,et al.Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney[J].Kidney Int,1997,52:1593-1601.
[11]Szuba A,Podgorski M.Asymmetric dimethylarginine(ADMA) a novel cardiovascular risk factor-evidence from epidemiological and prospective clinical trials[J].Pharmacol Rep.2006,58 Suppl:16-20.
[12]Cooke JP.Asymmetrical dimethylarginine:the Uber marker[J].Circulation,2004,109:1813-1818.
[13]Johannes J,Philip JS.Asymmetrical dimethylarginine in renal disease:limits of variation or variation limits[J].Am J Nephrol,2008,28:224-237.
[14]Achan V,Tran C T,Arrigoni F,et al.All-trans-Retinoic acid increases nitric oxide synthesis by endothelial cells:a role for the induction of dimethylarginine imethylaminohydrolase[J].CircRes,2002,90(7):764-769.
[15]Ito A,Tsao PS,Adimoolam S,et al.Novel mechanism for endothelia dysfunctiomdysregulation of dimethylaginine dimethylamiohydrolase[J].Circul -ation,1999,99:3092-3095.
[16]Stuhlinger MC,Tsao PS,Her JH,et al.Homocysteine impairs the nitric oxide synthase pathway:roleofasymmetric dimethylarginine[J].Circulation,2001,104 (21):2569-2575.
[17]Dayoub H,Achan V,Adimoolam S,et al.Dimethylargininedimethylaminohydrolas -eregulates nitric oxide synthesis:genetic and physiological evidence[J].Circulation,2003,108:3042-3047.
[18]Leong T,Zylberstein D,Graham I,et al.Asymmetric Dimethylarginine Independently Predicts Fatal and Nonfatal Myocardial Infarction and Stroke in Women 24-Year Follow-Up of the Population Study of Women in Gothenburg[J].Arterioscler Thromb Vasc Biol ,2008,28:1 -6.
[19]Yoo JH,Lee SC.Elevated levels of plasma homocysteine and asymmetric dimethylarginineinelderly patients with stroke[J].Atherosclerosis,2001,158:425-430.
[20]Wanby P,Teerlink T,Brudin L,et al.Asymmetric dimethylarginine (ADMA) as a risk marker for stroke and TIA in a Swedish population [J].Atherosclerosis,2006,185:271-277.
[21]Kielstein JT,Donnerstag F,Gasper S,et al.ADMA Increases Arterial Stiffness and Decreases Cerebral Blood Flow in Humans.Stroke[J].2006,37:2024-2029.
[22]Kielstein JT,Zoccali C.Asymmetric dimethylarginine:a cardiovascular risk factor and a uremic toxin coming of age[J],Am J Kidney Dis,2005,46:186 -202.
[23]Schnog JB,Teerlink T,van der Dijs FP,et al.Plasma levels of asymmetric dimethylarginine (ADMA),an endogenous nitric oxide synthase inhibitor,are elevated in sickle cell disease[J].Ann Hematol,2005,84:282-286.
[24]Laurent S,Boutouyrie P,Asmar R,et al.Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients[J].Hypertension,2001,37:1236-1241.
[25]Mattace-Raso FU,van der Cammen TJ,Hofman A,et al.Arterial stiffness and risk of coronary heart disease and stroke:the Rotterdam Study[J].Circulation.2006,113:657-663.
[26]Wilkinson IB,Qasem A,McEniery CM,et al.Nitric oxide regulates local arterial distensibility in vivo[J].Circulation,2002,105:213-217.
[27]Segarra G,Medina P,Ballester RM,et al.Effects of some guanidino compounds on human cerebral arteries[J].Stroke,1999,30:2206 -2210.
[28]Faraci FM,Brian JE Jr,Heistad DD.Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase[J].Am J Physiol.1995,269:H1522-H1527.
[29]Iadecola C,Zhang F,Xu X.Role of nitric oxide synthase-containing vascular nerves in cerebrovasodilation elicited from cerebellum [J].Am J Physiol.1993,264:R738-R746.
[30]Jin JS,D'Alecy LG.Central and peripheral effects of asymmetric dimethylarginine,an endogenous nitric oxide synthetase inhibitor [J].J Cardiovasc Pharmacol,1996,28:439-446.
[31]Macrae IM,Dawson DA,Norrie JD,et al.Inhibition of nitric oxide synthesis:effects on cerebral blood flow and glucose utilisation in the rat[J].J Cereb Blood Flow Metab,1993,13:985-992.
[32]Spoelstra-de Man A.M.E,Teerlink T,Brouwer C.B.,et al.No effect of B vitamins on ADMA levels in patients at increased cardiovascular risk[J].Clinical Endocrinology,2006,64 (5):495-501.
[33]Radomski M.W.,Palmer R.M.,Moncada S.Characterization of the L-arginine.nitric oxide pathway in human platelets [J].Br.J.Pharmacol,1990,101:325- 328.
[34]Radomski M.W.,Palmer R.M.,Moncada S.Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium[J].Lancet,1987b:1057 -1058.
[35]Vallance P,Hingorani A.Endothelial nitric oxide in humans in health and disease[J].InternationalJournal of Experimental Pathology,1999,80(6):291-303.
[36]Loscalzo J.Nitric oxide insufficiency,platelet activation,and arterial thrombosis[J].Circ.Res,2001,88:756-762.
[37]Camilletti A,Moretti N,Giacchetti G,et al.Decreased nitric oxide levels and increased calcium content in platelets of hypertensive patients[J].Am.J.Hvpertens.2001,14:382-386.
[38]Moss MB,Brunini TM,Soares de Moura R,et al.Diminished L-arginine bioavailability in hypertension [J].Clin.Sci,2004,107:391-397.
[39]Brunini TMC,Resende AC,Moss MB,et al.L-Arginine availability as a pathological mechanism in essential hypertension,chronic renal and heart failure[J].Vasc.Dis.Prev,2005,2:37-51.
[40]Meirelles LR,Mendes-Ribeiro AC,Santoro MM,et al.Inhibitory effects of endogenous L-arginine analogues on nitric oxide synthesis in platelets:role in platelet hyperaggregability in hypertension[J].Clinical and Experimental Pharmacology and Physiology,2007,34 (12):1267-1271.
[41]Brunini TMC,Moss MB,Siqueira MAS,et al.Inhibition of L-arginine transport in platelets by asymmetric dimethylarginine and N-monomethyl-L-arginine:effects of arterial hypertension[J].Clin Exp Pharmacol Physiol,2004,31:738-740.
[42]Camilletti A,Moretti N,Giacchetti G,et al.Decreased nitric oxide levels and increased calcium content in platelets of hypertensive patients[J].Am.J.Hypertens,2001,14:382-386.
[43]Boger RH,Bode-Boger SM,Thiele W,et al.Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease [J],Circulation,1997,95:2068-2074.
[44]Celermajer DS,Sorensen KE,Spiegelhalter DJ,et al.Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women[J].J Am Coll Cardiol,1994,24:471-476.
[45]Valkonen VP,Paaiva H,Salonen JT,et al.Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine [J].Lancet ,2001,358:2127-2128.
[46]Miyazaki H,Matsuoka H,Cooke JP,et al.Endogenous nitric oxide synthase inhibitor:a novel marker of atherosclerosis[J].Circulation,1999,99:1141-1146.
[47]Kielstein JT,Donnerstag F,Gasper S,et al.ADMA Increases Arterial Stiffness and Decreases Cerebral Blood Flow in Humans [J].Stroke,2006,37:2024-2029.
[48]Jin JS,D'Alecy LG.Central and peripheral effects of asymmetric dimethylarginine,an endogenous nitric oxide synthetase inhibitor[J].J Cardiovasc Pharmacol,1996,28:439-446.
[49]B(o|¨)ger RH,Sydow K,Borlak J,et al.LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells:involvement of S-adenosylmethionine-dependent methyltransferases[J].Circ Res,2000,87:99-105.
[50]B(o|¨)ger RH,Bode-B(o|¨)ger SM,Szuba A,et al.Asymmetric dimethylarginine a novel risk factor for endothelial dysfunction its role in hypercholesterolemia.[J].Circulation 1998;98:1842-1847.
[51]Suwaidi JA,Hamasaki S,Higano ST,et al.Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction[J].Circulation,2000,101(9):948-954.
[52]Heitzer T,Schlinzig T,Krohn K,Meinertz T.Endothelial dysfunction,oxidative stress,and risk of cardiovascular events in patients with coronary artery disease.Circulation 2001,104:2673-8.
[53]Mittermayer F,Krzyzanowska K,Exner M,et al.Asymmetric Dimethylarginine Predicts Major Adverse Cardiovascular Events in Patients With AdvancedPeripheral Artery Disease[J].Arterioscler Thromb Vasc Biol,2006,26:2536-2540.
[54]Perticone F,Sciacqua A,Maio R,et al.Asymmetric Dimethylarginine,L-Arginine,and Endothelial Dysfunction in Essential Hypertension[J].J Am Coll Cardiol,2005,46:518-523.
[55]张卫茹,陈本美,熊燕等.原发性高血压患者降压治疗前后血清非对称性二甲基精氨酸浓度的变化[J].中南大学学报(医学版),2005,30(1):57-59.
[56]Kielstein JT,Burcu I,Solveig S,et al.Cardiovascular effects of systemic nitricoxide synthase inhibition with asymmetricaldimethy largininen humans[J].Circulation,2004,109:172-177.
[57]叶任高,陆在英.内科学[M].第六版.北京:人民卫生出版社,2004:250-250.
[58]SzolnokiZ,Havasi V,Bene J,et al.Endothelial nitric oxide syntgene interactions and the risk of ischaernin stroke[J].Acta Neurol Scand,2005,Ⅲ(1):20-23.
[59]Hou L,Osei Hyiaman D,Yu H,et al.Association of a 27——bp repeat polymorphism in eNOS gene with ischemic stroke in Chinese patients[J],Neurology,2001,56(4):490-496.
[60]Aicher A,Heeschen C,Mildner-Rihm C,et al.Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells[J].NatMed.2003,9:1370-1376.
[61]朴翔宇,陶定波.内皮细胞型一氧化氮合酶基因多态性与血管性疾病的关系[J ].国外医学脑血管疾病分册,2002,10(4):305-307.
[62]Martinez-Ruiz A,Villanreva L,Orduna C,et al.S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities.Proc Natl Acad Sci USA.2005.102(24):8525-8530.
[63]Koti RS,Tsui J,Lobos E,et al.Nitric oxide synthase distribution and expression with ischemic preconditioning of the rat liver[J].FASEB J,2005,19(9):1155-1157
[64]帅杰,叶建宁,高广正.前脑缺血再灌注海马CAI区神经元死亡与一氧化氮的关系.中国临床康复,2004,8(1):70-71.
[65]Aichner A,Heeschen C,Mildner-Rihm C,et al.Essential role of endothelial nitric oxide synthase for the mobilization of stem and progenitor and progenitor cells[J].Nat Med,2003,9(11):1370-1376.
[66]曲晓义,金惠铭.血管内皮祖细胞与缺血性心血管病的血管新生[J],中国病理生理杂志,2003,19(3):412-414.
[67]Laufs U.Beyond lipid-lowering:effects of statins on endothelial nitric oxide[J].Eur J Clin Pharmacol,2003,58(11):719-731.
[68]Elbaz A,Poirier O,Moulin T,et al.Association between the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthase gene and brain infarction.[J].Stroke.2000,31(7):1634-1639.
[69]Miyamoto Y,Saito Y,Kajiyama N,et al.Endothelial Nitric Oxide Synthase Gene Is Positively Associated With Essential Hypertension[J].Hypertension,1998,32:3-8.
[70]张建成等.高血压患者循环一氧化氮和内皮素平衡变化的临床意义[J].福建医科大学学报,1998,32(1):58-61.
[71]俞国华.一氧化氮和内皮素在高血压病中的作用[J].中国病理生理杂志, 1998,14(6):659.
[72]VasaM,B reitschopf K,Zeiher AM,et al.N itric oxide activates telomerase and delays endothelial cell senescence[J].Circ Res,2000,87(7):540-542.
[73]Perticone F,Sciacqua A,Maio R,et al.Asymmetric Dimethylarginine,L-Arginine,and Endothelial Dysfunction in Essential Hypertension[J].J Am Coll Cardiol,2005,46:518-523.
[74]张卫茹,陈本美,熊燕等.原发性高血压患者降压治疗前后血清非对称性二甲基精氨酸浓度的变化[J].中南大学学报(医学版),2005,30(1):57-59.
[75]Meinitzer A,Seelhorst U,Wellnitz Bet al.Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease(the Ludwigshafen Risk and Cardiovascular Health study[J].Clin Chem,2007,53(2):273-283.
[76]Berard E.Metabolism and regulation of nitric oxide:a hard to control mediator [J].Arch Pediatr,2006,4407:1004-1011.
[77]张天锡,孙青芳,田恒力,等.局灶脑缺血后早、晚期一氧化氮合成酶的活性变化[J].临床神科病学,1996,4(4):187-189.
[78]林卫红,张淑琴,胡伟红.脑梗死急性期及恢复期血浆一氧化氮及相关因素测定分析[J].中风与神经疾病杂志,1997,14(4):225-226.
[79]张洪.一氧化氮与神经系统疾病[J].临床神经病学杂志,2000,13(2):124-126
[80]王晓娟.一氧化氮与脑缺血再灌注损伤[J].国外医学·老年医学分册,2000,21(3):114-117.
[81]Schmidt-Lucke C,Rossig L,Fichtlscherer S,Vasa M,et al.Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events:proof of concept for the clinical importance of endogenous vascular repair[J].Ci rculation.2005,111:2981-2987.
[82]Royall JA,Kooy NW,Beckman JS,et al.Nitric oxide-related oxidants in acute lung injury[J].New Horizons,2005,3(1):113-122.
[83]Shigeru N.Interaction between inducible nitric oxide synthase and cyclooxygen -ase after cerebral ischemia[J].Proc Natl Acad Sci,1998,95:10966-10971.
[84]Estrada C,Defelipe J.Nitric oxide producing neurons in the neocorex[J].Cereb Cortex,1998,8(3):193-203.
[85]Iadecola C,Xu X,Zhang FY,et al.Marked induction ofcalcicum independent nitric oxide synthase activity after focal cerebral ischemia[J].J Cereb Bloow Flow Metab,1995,15:52-55.
[86]江文,黄远桂.一氧化氮合酶与局灶性脑缺血[J].中风与神经疾病杂志,1998,15(6):375-377.
[87]Karsten Sydow,Thomas M(u|¨)nzel.ADMA and oxidative stress[J].Atheros.2003,4(1):41-51.
[88]De Gennaro Colonna V,Bonomo S,Ferrario P,et al.Asymmetric methylarginine (ADMA) induces vascular endothelium impairment andaggravates post-ischemic ventricular dysfunction in rats[J].Eur JPharmacol,2007,557(2-3):178-185.
[89]Dayal S,Lentz SR:ADMA and hyperhomocysteinemia[J].Vasc Med,2005,10(1) S27-S33.
[90]Stuhlinger MC,Abbasi F,Chu JW,et al.Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor[J].JAMA,2002,287,1420-1426.
[91]Sydow K,Mondon CE,Cooke JP:Insulin resistance:potential role of the endoge -nous nitric oxide synthase inhibitor ADMA[J].Vasc Med,2005,10,Suppl 1:S35-S43.
[92]Dayal S,Lentz S R.ADMA and hyperhomocysteinemia[J].Vascular Medicine 2005,10:S27-33.
[93]Juonala M,Viikari JS,Alfthan G,et al.Brachial artery flow-mediated dilation and asymmetrical dimethylarginine in the cardiovascular risk in young Finns study[J].Circulation,2007,116(12):1367-1373.
[94]Schmidt-Lucke C,Rossig L,Fichtlscherer S,Vasa M,et al.Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events:proof of concept for the clinical importance of endogenous vascular repair[J].Circulation.2005,111:2981-2987.
[95]Aicher A,Heeschen C,Mildner-Rihm C,et al.Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells[J].Nat Med.2003,9:1370-1376.
[96]Thum T,Tsikas T,Stein S,et al.Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine[J].J Am Coll Cardiol.2005;46:1693-1701.
[97]Andrzej Szuba,Maciej Podg(?)rski.Asymmetric dimethylarginine(ADMA) a Novel cardiovascular risk factor-evidence from epidemiological and prospective clinical trials[J].Pharmmaological Reports 2006.58.suppl.16-20
[98]Wlodek A,Dlugosz I,Sandereoek PA,et al.Agreement between the clinical Oxfordshire Community Stroke Project classifieation and CT findings in Poland[J].Eur J Neurol,2004,11(2):91-96.
[99]Dewey H.Macdonell R,Donnan G,et al.Interrater reliability of stroke subtype classification by neurologists and nurses within acommunity—based stroke incid -ence study[J].J Clin Neurosci,2001,8(1):14-17.
[100]李振东,朱良付,杨智云,等.脑梗死急性期OCSP分型的效度评价[J].中国神经精神疾病杂志,2004,30(1):17-20.
[101]Qiao J,Cao HM,Ju Xe,et al.Prediction of the long term functional prognosis of patients with cerebral infarction by the classification of oxfordshirecommunity stroke project[J].中国临床康复.2005,9(9):182-183.
[102]Boger RH.The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor[J].Circ Res,2003,59:824-833.
[103]杨永宗,杨和平,戴爱国,等.L-精氨酸/一氧化氮抗动脉粥样硬化的作用及机制[J].中国动脉硬化杂志,1997,5(3):258-264.
[104]Tsikas D,Boger RH,Sandmann J,etal.Endogenous nitric oxide synthase inhibito -rs are responsible for the l-arginine paradox[J].FEBSLett,2000,478(1-2):1-5.
[105]Holven KB,Haugstad TS,Holm T,et al.Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine inhyperhomocy -stein aemicsubjects[J].BrJNutr,2003,89(3):359.
[106]TeerlinkT,NeeleSJ,DeJongS,etal.Oestrogen replacement therapy lowers plasma levels of asymmetric dimethylarginine in healthy postmenopausal men[J]Clin Sci(Lond),2003,105(1):67.
[1]Osanai T,Saitoh M,Sasaki S,et al.Effect of shear stress on asymmetric dimethylarginine release from vascular endothelial cells [J].Hypertension,2003,42(5):985～990.
[2]Boger RH,Lentz SR,Bode-Boger SM,et al.Elevation of asymmetrical dimethylarginine mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans [J].Clin Sci(Lond),2001,100(2):161-167.
[3]Boger RH,Bode-Boger SM,Tsao PS,et al.An endogenous inhibitor of nitric oxide synthase regulates endothelial ashesiveness for monocytes[J].J Am Coll Cardiol ,2000,36(7):2287-2295.
[4]Xiao HB,Yang ZC,Jia SJ,et al.Effect of asymmetric dimethylarginine on atherogenesis and eyrthrocyte deformability in apolipoprotein E deficient mice[J].Life Sci ,2007,81(1):l-7.
[5]Toth J,Raze A,Kaminiski PM,et al.Asymmetrical dimethylarginine inhibits shear stress-induced nitric oxide release and elicits superoxide-mediated increase in arteriolar tone [J].Hypertension ,2007,49(3):563-568.
[6]Kielstein JT,Impraim B,Simmel S,et al.Csrfiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans[J].Circulation ,2004,109(25):e327.
[7]De Gennaro Colonna V,Bonomo S,Ferrario P,et al.Asymmetrical dimethylarginine (ADMA) induces vascular endothelium impairment and aggravates post-ischemic ventricular dysfunction in rats[J].Eur J Pharmacol ,2007,557(2-3):178-185.
[8]Schulze F,Lenzen H,Hanefeld C,et al.Asymmetrical dimethylarginine is an independent risk factor for coronary heart disease:results from the multicenter Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC) study[J].Am Heart J,2006,152 (3):493.el-8.
[9]Lentz SR,Rodionow RN,Dayal S.Hyperhomocysteinemia ,endothelial dysfunction ,and cardiovascular risk factor:the potential role of ADMA[J].Atheroscler Suppl,2003,4(4):61-65.
[10]Valkonen VP ,Paiva H,Salonen JT,et al.Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine[J].Lacent,2001,358(9299):2127-2128.
[11]Maas R,Schulze F,Baumert J,et al.Asymmetrical dimethylarginine ,smoking,and risk of coronary heart disease in apparently healthy men:prospective analysis from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung inder Region Augsburg study and experimental data[J].Clin Chem,2007,53(4):693-701.
[12]Kielstein JT,Donnerstag F,Gasper S,et al.ADMA increases arterial stiffness and decreases blood flow in humans[J].Stroke,2006,37(8):2024-2029.
[13]Tanaka N,Katayama Y,Katasumata T,et al.Effects of longterm administration of HMG-CoA reductase inhibitor ,atovastatin ,on stroke events and local cerebral blood flow in stroke -prone spontaneously hypertensive rats [J].Brain Res,2007,1169:125-132.
[14]Yoo JH,Lee SC.Elevated levels of plasma homocysteine and asymmetrical dimethylarginine in elderly patients with stroke [J].Atheroscolerosis,2001,158(2):425-430.
[15]Wanby P,Teerlink T,Brudin L,et al.Asymmetrical dimethylarginine (ADMA) as a risk marker for stroke and TIA in a Swedish population [J].Atheroscolerosis,2006,185(2):271-277.
[16]Khali U,Hassan A,Vallance P,et al.Asymmetrical dimethylarginine in cerebral small vessel disease [J].Stroke ,2007,38(2):411-413.
[17]Tan B,Jiang DJ,Huang H,et al Taurine protects against low-density lipoprotein-induced endothelial dysfunction by the DDAH/ADMA pathway.[J].Vascul Phamacol.2007 May;46(5):338-345.
[18]Holven KB,Haugstad TS,Holm T,et al.Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects[J].BrJNutr,2003,89 (3):359.
[19]Tsikas D,Boger RH,Sandmann J.Endogenous nitric oxide synthase inhibitors are responsible for the 1-arginine paradox[J].FEBSLett ,2000,478(1-2):1.
[20]TeerlinkT,NeeleSJ,DeJongS,et al.Oestrogen replacement therapy lowers plasma levels of asymmetric dimethylarginine in healthy postmenopausal women[J].ClinSci(Lond),2003,105(1):67.
[2]Boger R H,Bode-Boger SM.Asymmetric dimenthylarginine,derangemengts of the endothelial nitric oxide synthase pathway,and cardiovascular disease[J].Semin Thromb Hemost,2000,26(5):539-545.
[3]叶任高,陆在英.内科学[M].第六版.北京:人民卫生出版社,2004:247.
[4]王维治,罗祖明.神经病学[M].第5版.北京:人民卫生出版社,2005:134.
[5]Yoo JH,Lee SC.Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke[J].Atherosclerosis,2001,158:425-430.
[6]Wanby P,Teerlink T,Brudin L,et al.Asymmetric dimethylarginine(ADMA) as a risk marker for stroke and TIA in a Swedish population[J].Atherosclerosis,2006,185:271-277.
[7]Luscher TF,Barton M.Biology of the endothelium[J].ClinCardiol,1997,20(11):3-10.
[8]Boger RH.The emerging role of asymmetric dimethylarginine as a novel car diovascular risk factor[J].Circ Res,2003,59:824-833.
[9]Teerlink T.ADMA metabolism and clearance[J].Vascular Medicine 2005,10:S73-81.
[10]Tojo A,Welch WJ,Bremer V,et al.Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney[J].Kidney Int,1997,52:1593-1601.
[11]Szuba A,Podgorski M.Asymmetric dimethylarginine(ADMA) a novel cardiovascular risk factor-evidence from epidemiological and prospective clinical trials[J].Pharmacol Rep.2006,58 Suppl:16-20.
[12]Cooke JP.Asymmetrical dimethylarginine:the Uber marker[J].Circulation,2004,109:1813-1818.
[13]Johannes J,Philip JS.Asymmetrical dimethylarginine in renal disease:limits of variation or variation limits[J].Am J Nephrol,2008,28:224-237.
[14]Achan V,Tran C T,Arrigoni F,et al.All-trans-Retinoic acid increases nitric oxide synthesis by endothelial cells:a role for the induction of dimethylarginine imethylaminohydrolase[J].CircRes,2002,90(7):764-769.
[15]Ito A,Tsao PS,Adimoolam S,et al.Novel mechanism for endothelia dysfunctiomdysregulation of dimethylaginine dimethylamiohydrolase[J].Circul -ation,1999,99:3092-3095.
[16]Stuhlinger MC,Tsao PS,Her JH,et al.Homocysteine impairs the nitric oxide synthase pathway:roleofasymmetric dimethylarginine[J].Circulation,2001,104 (21):2569-2575.
[17]Dayoub H,Achan V,Adimoolam S,et al.Dimethylargininedimethylaminohydrolas -eregulates nitric oxide synthesis:genetic and physiological evidence[J].Circulation,2003,108:3042-3047.
[18]Leong T,Zylberstein D,Graham I,et al.Asymmetric Dimethylarginine Independently Predicts Fatal and Nonfatal Myocardial Infarction and Stroke in Women 24-Year Follow-Up of the Population Study of Women in Gothenburg[J].Arterioscler Thromb Vasc Biol ,2008,28:1 -6.
[19]Yoo JH,Lee SC.Elevated levels of plasma homocysteine and asymmetric dimethylarginineinelderly patients with stroke[J].Atherosclerosis,2001,158:425-430.
[20]Wanby P,Teerlink T,Brudin L,et al.Asymmetric dimethylarginine (ADMA) as a risk marker for stroke and TIA in a Swedish population [J].Atherosclerosis,2006,185:271-277.
[21]Kielstein JT,Donnerstag F,Gasper S,et al.ADMA Increases Arterial Stiffness and Decreases Cerebral Blood Flow in Humans.Stroke[J].2006,37:2024-2029.
[22]Kielstein JT,Zoccali C.Asymmetric dimethylarginine:a cardiovascular risk factor and a uremic toxin coming of age[J],Am J Kidney Dis,2005,46:186 -202.
[23]Schnog JB,Teerlink T,van der Dijs FP,et al.Plasma levels of asymmetric dimethylarginine (ADMA),an endogenous nitric oxide synthase inhibitor,are elevated in sickle cell disease[J].Ann Hematol,2005,84:282-286.
[24]Laurent S,Boutouyrie P,Asmar R,et al.Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients[J].Hypertension,2001,37:1236-1241.
[25]Mattace-Raso FU,van der Cammen TJ,Hofman A,et al.Arterial stiffness and risk of coronary heart disease and stroke:the Rotterdam Study[J].Circulation.2006,113:657-663.
[26]Wilkinson IB,Qasem A,McEniery CM,et al.Nitric oxide regulates local arterial distensibility in vivo[J].Circulation,2002,105:213-217.
[27]Segarra G,Medina P,Ballester RM,et al.Effects of some guanidino compounds on human cerebral arteries[J].Stroke,1999,30:2206 -2210.
[28]Faraci FM,Brian JE Jr,Heistad DD.Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase[J].Am J Physiol.1995,269:H1522-H1527.
[29]Iadecola C,Zhang F,Xu X.Role of nitric oxide synthase-containing vascular nerves in cerebrovasodilation elicited from cerebellum [J].Am J Physiol.1993,264:R738-R746.
[30]Jin JS,D'Alecy LG.Central and peripheral effects of asymmetric dimethylarginine,an endogenous nitric oxide synthetase inhibitor [J].J Cardiovasc Pharmacol,1996,28:439-446.
[31]Macrae IM,Dawson DA,Norrie JD,et al.Inhibition of nitric oxide synthesis:effects on cerebral blood flow and glucose utilisation in the rat[J].J Cereb Blood Flow Metab,1993,13:985-992.
[32]Spoelstra-de Man A.M.E,Teerlink T,Brouwer C.B.,et al.No effect of B vitamins on ADMA levels in patients at increased cardiovascular risk[J].Clinical Endocrinology,2006,64 (5):495-501.
[33]Radomski M.W.,Palmer R.M.,Moncada S.Characterization of the L-arginine.nitric oxide pathway in human platelets [J].Br.J.Pharmacol,1990,101:325- 328.
[34]Radomski M.W.,Palmer R.M.,Moncada S.Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium[J].Lancet,1987b:1057 -1058.
[35]Vallance P,Hingorani A.Endothelial nitric oxide in humans in health and disease[J].InternationalJournal of Experimental Pathology,1999,80(6):291-303.
[36]Loscalzo J.Nitric oxide insufficiency,platelet activation,and arterial thrombosis[J].Circ.Res,2001,88:756-762.
[37]Camilletti A,Moretti N,Giacchetti G,et al.Decreased nitric oxide levels and increased calcium content in platelets of hypertensive patients[J].Am.J.Hvpertens.2001,14:382-386.
[38]Moss MB,Brunini TM,Soares de Moura R,et al.Diminished L-arginine bioavailability in hypertension [J].Clin.Sci,2004,107:391-397.
[39]Brunini TMC,Resende AC,Moss MB,et al.L-Arginine availability as a pathological mechanism in essential hypertension,chronic renal and heart failure[J].Vasc.Dis.Prev,2005,2:37-51.
[40]Meirelles LR,Mendes-Ribeiro AC,Santoro MM,et al.Inhibitory effects of endogenous L-arginine analogues on nitric oxide synthesis in platelets:role in platelet hyperaggregability in hypertension[J].Clinical and Experimental Pharmacology and Physiology,2007,34 (12):1267-1271.
[41]Brunini TMC,Moss MB,Siqueira MAS,et al.Inhibition of L-arginine transport in platelets by asymmetric dimethylarginine and N-monomethyl-L-arginine:effects of arterial hypertension[J].Clin Exp Pharmacol Physiol,2004,31:738-740.
[42]Camilletti A,Moretti N,Giacchetti G,et al.Decreased nitric oxide levels and increased calcium content in platelets of hypertensive patients[J].Am.J.Hypertens,2001,14:382-386.
[43]Boger RH,Bode-Boger SM,Thiele W,et al.Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease [J],Circulation,1997,95:2068-2074.
[44]Celermajer DS,Sorensen KE,Spiegelhalter DJ,et al.Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women[J].J Am Coll Cardiol,1994,24:471-476.
[45]Valkonen VP,Paaiva H,Salonen JT,et al.Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine [J].Lancet ,2001,358:2127-2128.
[46]Miyazaki H,Matsuoka H,Cooke JP,et al.Endogenous nitric oxide synthase inhibitor:a novel marker of atherosclerosis[J].Circulation,1999,99:1141-1146.
[47]Kielstein JT,Donnerstag F,Gasper S,et al.ADMA Increases Arterial Stiffness and Decreases Cerebral Blood Flow in Humans [J].Stroke,2006,37:2024-2029.
[48]Jin JS,D'Alecy LG.Central and peripheral effects of asymmetric dimethylarginine,an endogenous nitric oxide synthetase inhibitor[J].J Cardiovasc Pharmacol,1996,28:439-446.
[49]B(o|¨)ger RH,Sydow K,Borlak J,et al.LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells:involvement of S-adenosylmethionine-dependent methyltransferases[J].Circ Res,2000,87:99-105.
[50]B(o|¨)ger RH,Bode-B(o|¨)ger SM,Szuba A,et al.Asymmetric dimethylarginine a novel risk factor for endothelial dysfunction its role in hypercholesterolemia.[J].Circulation 1998;98:1842-1847.
[51]Suwaidi JA,Hamasaki S,Higano ST,et al.Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction[J].Circulation,2000,101(9):948-954.
[52]Heitzer T,Schlinzig T,Krohn K,Meinertz T.Endothelial dysfunction,oxidative stress,and risk of cardiovascular events in patients with coronary artery disease.Circulation 2001,104:2673-8.
[53]Mittermayer F,Krzyzanowska K,Exner M,et al.Asymmetric Dimethylarginine Predicts Major Adverse Cardiovascular Events in Patients With AdvancedPeripheral Artery Disease[J].Arterioscler Thromb Vasc Biol,2006,26:2536-2540.
[54]Perticone F,Sciacqua A,Maio R,et al.Asymmetric Dimethylarginine,L-Arginine,and Endothelial Dysfunction in Essential Hypertension[J].J Am Coll Cardiol,2005,46:518-523.
[55]张卫茹,陈本美,熊燕等.原发性高血压患者降压治疗前后血清非对称性二甲基精氨酸浓度的变化[J].中南大学学报(医学版),2005,30(1):57-59.
[56]Kielstein JT,Burcu I,Solveig S,et al.Cardiovascular effects of systemic nitricoxide synthase inhibition with asymmetricaldimethy largininen humans[J].Circulation,2004,109:172-177.
[57]叶任高,陆在英.内科学[M].第六版.北京:人民卫生出版社,2004:250-250.
[58]SzolnokiZ,Havasi V,Bene J,et al.Endothelial nitric oxide syntgene interactions and the risk of ischaernin stroke[J].Acta Neurol Scand,2005,Ⅲ(1):20-23.
[59]Hou L,Osei Hyiaman D,Yu H,et al.Association of a 27——bp repeat polymorphism in eNOS gene with ischemic stroke in Chinese patients[J],Neurology,2001,56(4):490-496.
[60]Aicher A,Heeschen C,Mildner-Rihm C,et al.Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells[J].NatMed.2003,9:1370-1376.
[61]朴翔宇,陶定波.内皮细胞型一氧化氮合酶基因多态性与血管性疾病的关系[J ].国外医学脑血管疾病分册,2002,10(4):305-307.
[62]Martinez-Ruiz A,Villanreva L,Orduna C,et al.S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities.Proc Natl Acad Sci USA.2005.102(24):8525-8530.
[63]Koti RS,Tsui J,Lobos E,et al.Nitric oxide synthase distribution and expression with ischemic preconditioning of the rat liver[J].FASEB J,2005,19(9):1155-1157
[64]帅杰,叶建宁,高广正.前脑缺血再灌注海马CAI区神经元死亡与一氧化氮的关系.中国临床康复,2004,8(1):70-71.
[65]Aichner A,Heeschen C,Mildner-Rihm C,et al.Essential role of endothelial nitric oxide synthase for the mobilization of stem and progenitor and progenitor cells[J].Nat Med,2003,9(11):1370-1376.
[66]曲晓义,金惠铭.血管内皮祖细胞与缺血性心血管病的血管新生[J],中国病理生理杂志,2003,19(3):412-414.
[67]Laufs U.Beyond lipid-lowering:effects of statins on endothelial nitric oxide[J].Eur J Clin Pharmacol,2003,58(11):719-731.
[68]Elbaz A,Poirier O,Moulin T,et al.Association between the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthase gene and brain infarction.[J].Stroke.2000,31(7):1634-1639.
[69]Miyamoto Y,Saito Y,Kajiyama N,et al.Endothelial Nitric Oxide Synthase Gene Is Positively Associated With Essential Hypertension[J].Hypertension,1998,32:3-8.
[70]张建成等.高血压患者循环一氧化氮和内皮素平衡变化的临床意义[J].福建医科大学学报,1998,32(1):58-61.
[71]俞国华.一氧化氮和内皮素在高血压病中的作用[J].中国病理生理杂志, 1998,14(6):659.
[72]VasaM,B reitschopf K,Zeiher AM,et al.N itric oxide activates telomerase and delays endothelial cell senescence[J].Circ Res,2000,87(7):540-542.
[73]Perticone F,Sciacqua A,Maio R,et al.Asymmetric Dimethylarginine,L-Arginine,and Endothelial Dysfunction in Essential Hypertension[J].J Am Coll Cardiol,2005,46:518-523.
[74]张卫茹,陈本美,熊燕等.原发性高血压患者降压治疗前后血清非对称性二甲基精氨酸浓度的变化[J].中南大学学报(医学版),2005,30(1):57-59.
[75]Meinitzer A,Seelhorst U,Wellnitz Bet al.Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease(the Ludwigshafen Risk and Cardiovascular Health study[J].Clin Chem,2007,53(2):273-283.
[76]Berard E.Metabolism and regulation of nitric oxide:a hard to control mediator [J].Arch Pediatr,2006,4407:1004-1011.
[77]张天锡,孙青芳,田恒力,等.局灶脑缺血后早、晚期一氧化氮合成酶的活性变化[J].临床神科病学,1996,4(4):187-189.
[78]林卫红,张淑琴,胡伟红.脑梗死急性期及恢复期血浆一氧化氮及相关因素测定分析[J].中风与神经疾病杂志,1997,14(4):225-226.
[79]张洪.一氧化氮与神经系统疾病[J].临床神经病学杂志,2000,13(2):124-126
[80]王晓娟.一氧化氮与脑缺血再灌注损伤[J].国外医学·老年医学分册,2000,21(3):114-117.
[81]Schmidt-Lucke C,Rossig L,Fichtlscherer S,Vasa M,et al.Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events:proof of concept for the clinical importance of endogenous vascular repair[J].Ci rculation.2005,111:2981-2987.
[82]Royall JA,Kooy NW,Beckman JS,et al.Nitric oxide-related oxidants in acute lung injury[J].New Horizons,2005,3(1):113-122.
[83]Shigeru N.Interaction between inducible nitric oxide synthase and cyclooxygen -ase after cerebral ischemia[J].Proc Natl Acad Sci,1998,95:10966-10971.
[84]Estrada C,Defelipe J.Nitric oxide producing neurons in the neocorex[J].Cereb Cortex,1998,8(3):193-203.
[85]Iadecola C,Xu X,Zhang FY,et al.Marked induction ofcalcicum independent nitric oxide synthase activity after focal cerebral ischemia[J].J Cereb Bloow Flow Metab,1995,15:52-55.
[86]江文,黄远桂.一氧化氮合酶与局灶性脑缺血[J].中风与神经疾病杂志,1998,15(6):375-377.
[87]Karsten Sydow,Thomas M(u|¨)nzel.ADMA and oxidative stress[J].Atheros.2003,4(1):41-51.
[88]De Gennaro Colonna V,Bonomo S,Ferrario P,et al.Asymmetric methylarginine (ADMA) induces vascular endothelium impairment andaggravates post-ischemic ventricular dysfunction in rats[J].Eur JPharmacol,2007,557(2-3):178-185.
[89]Dayal S,Lentz SR:ADMA and hyperhomocysteinemia[J].Vasc Med,2005,10(1) S27-S33.
[90]Stuhlinger MC,Abbasi F,Chu JW,et al.Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor[J].JAMA,2002,287,1420-1426.
[91]Sydow K,Mondon CE,Cooke JP:Insulin resistance:potential role of the endoge -nous nitric oxide synthase inhibitor ADMA[J].Vasc Med,2005,10,Suppl 1:S35-S43.
[92]Dayal S,Lentz S R.ADMA and hyperhomocysteinemia[J].Vascular Medicine 2005,10:S27-33.
[93]Juonala M,Viikari JS,Alfthan G,et al.Brachial artery flow-mediated dilation and asymmetrical dimethylarginine in the cardiovascular risk in young Finns study[J].Circulation,2007,116(12):1367-1373.
[94]Schmidt-Lucke C,Rossig L,Fichtlscherer S,Vasa M,et al.Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events:proof of concept for the clinical importance of endogenous vascular repair[J].Circulation.2005,111:2981-2987.
[95]Aicher A,Heeschen C,Mildner-Rihm C,et al.Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells[J].Nat Med.2003,9:1370-1376.
[96]Thum T,Tsikas T,Stein S,et al.Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine[J].J Am Coll Cardiol.2005;46:1693-1701.
[97]Andrzej Szuba,Maciej Podg(?)rski.Asymmetric dimethylarginine(ADMA) a Novel cardiovascular risk factor-evidence from epidemiological and prospective clinical trials[J].Pharmmaological Reports 2006.58.suppl.16-20
[98]Wlodek A,Dlugosz I,Sandereoek PA,et al.Agreement between the clinical Oxfordshire Community Stroke Project classifieation and CT findings in Poland[J].Eur J Neurol,2004,11(2):91-96.
[99]Dewey H.Macdonell R,Donnan G,et al.Interrater reliability of stroke subtype classification by neurologists and nurses within acommunity—based stroke incid -ence study[J].J Clin Neurosci,2001,8(1):14-17.
[100]李振东,朱良付,杨智云,等.脑梗死急性期OCSP分型的效度评价[J].中国神经精神疾病杂志,2004,30(1):17-20.
[101]Qiao J,Cao HM,Ju Xe,et al.Prediction of the long term functional prognosis of patients with cerebral infarction by the classification of oxfordshirecommunity stroke project[J].中国临床康复.2005,9(9):182-183.
[102]Boger RH.The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor[J].Circ Res,2003,59:824-833.
[103]杨永宗,杨和平,戴爱国,等.L-精氨酸/一氧化氮抗动脉粥样硬化的作用及机制[J].中国动脉硬化杂志,1997,5(3):258-264.
[104]Tsikas D,Boger RH,Sandmann J,etal.Endogenous nitric oxide synthase inhibito -rs are responsible for the l-arginine paradox[J].FEBSLett,2000,478(1-2):1-5.
[105]Holven KB,Haugstad TS,Holm T,et al.Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine inhyperhomocy -stein aemicsubjects[J].BrJNutr,2003,89(3):359.
[106]TeerlinkT,NeeleSJ,DeJongS,etal.Oestrogen replacement therapy lowers plasma levels of asymmetric dimethylarginine in healthy postmenopausal men[J]Clin Sci(Lond),2003,105(1):67.
[1]Osanai T,Saitoh M,Sasaki S,et al.Effect of shear stress on asymmetric dimethylarginine release from vascular endothelial cells [J].Hypertension,2003,42(5):985～990.
[2]Boger RH,Lentz SR,Bode-Boger SM,et al.Elevation of asymmetrical dimethylarginine mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans [J].Clin Sci(Lond),2001,100(2):161-167.
[3]Boger RH,Bode-Boger SM,Tsao PS,et al.An endogenous inhibitor of nitric oxide synthase regulates endothelial ashesiveness for monocytes[J].J Am Coll Cardiol ,2000,36(7):2287-2295.
[4]Xiao HB,Yang ZC,Jia SJ,et al.Effect of asymmetric dimethylarginine on atherogenesis and eyrthrocyte deformability in apolipoprotein E deficient mice[J].Life Sci ,2007,81(1):l-7.
[5]Toth J,Raze A,Kaminiski PM,et al.Asymmetrical dimethylarginine inhibits shear stress-induced nitric oxide release and elicits superoxide-mediated increase in arteriolar tone [J].Hypertension ,2007,49(3):563-568.
[6]Kielstein JT,Impraim B,Simmel S,et al.Csrfiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans[J].Circulation ,2004,109(25):e327.
[7]De Gennaro Colonna V,Bonomo S,Ferrario P,et al.Asymmetrical dimethylarginine (ADMA) induces vascular endothelium impairment and aggravates post-ischemic ventricular dysfunction in rats[J].Eur J Pharmacol ,2007,557(2-3):178-185.
[8]Schulze F,Lenzen H,Hanefeld C,et al.Asymmetrical dimethylarginine is an independent risk factor for coronary heart disease:results from the multicenter Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC) study[J].Am Heart J,2006,152 (3):493.el-8.
[9]Lentz SR,Rodionow RN,Dayal S.Hyperhomocysteinemia ,endothelial dysfunction ,and cardiovascular risk factor:the potential role of ADMA[J].Atheroscler Suppl,2003,4(4):61-65.
[10]Valkonen VP ,Paiva H,Salonen JT,et al.Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine[J].Lacent,2001,358(9299):2127-2128.
[11]Maas R,Schulze F,Baumert J,et al.Asymmetrical dimethylarginine ,smoking,and risk of coronary heart disease in apparently healthy men:prospective analysis from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung inder Region Augsburg study and experimental data[J].Clin Chem,2007,53(4):693-701.
[12]Kielstein JT,Donnerstag F,Gasper S,et al.ADMA increases arterial stiffness and decreases blood flow in humans[J].Stroke,2006,37(8):2024-2029.
[13]Tanaka N,Katayama Y,Katasumata T,et al.Effects of longterm administration of HMG-CoA reductase inhibitor ,atovastatin ,on stroke events and local cerebral blood flow in stroke -prone spontaneously hypertensive rats [J].Brain Res,2007,1169:125-132.
[14]Yoo JH,Lee SC.Elevated levels of plasma homocysteine and asymmetrical dimethylarginine in elderly patients with stroke [J].Atheroscolerosis,2001,158(2):425-430.
[15]Wanby P,Teerlink T,Brudin L,et al.Asymmetrical dimethylarginine (ADMA) as a risk marker for stroke and TIA in a Swedish population [J].Atheroscolerosis,2006,185(2):271-277.
[16]Khali U,Hassan A,Vallance P,et al.Asymmetrical dimethylarginine in cerebral small vessel disease [J].Stroke ,2007,38(2):411-413.
[17]Tan B,Jiang DJ,Huang H,et al Taurine protects against low-density lipoprotein-induced endothelial dysfunction by the DDAH/ADMA pathway.[J].Vascul Phamacol.2007 May;46(5):338-345.
[18]Holven KB,Haugstad TS,Holm T,et al.Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects[J].BrJNutr,2003,89 (3):359.
[19]Tsikas D,Boger RH,Sandmann J.Endogenous nitric oxide synthase inhibitors are responsible for the 1-arginine paradox[J].FEBSLett ,2000,478(1-2):1.
[20]TeerlinkT,NeeleSJ,DeJongS,et al.Oestrogen replacement therapy lowers plasma levels of asymmetric dimethylarginine in healthy postmenopausal women[J].ClinSci(Lond),2003,105(1):67.