摘要
目的:了解阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea-hypopnea syndrome,OSAHS)及阻塞性睡眠呼吸暂停低通气综合征合并高血压病(obstructive sleep apnea-hypopnea associated hypertension,OSAHS+HT)患者血清8-羟基脱氧鸟苷酸(8-hydroxy-2’-deoxyguanosine, 8-OHdG )和锰超氧化物歧化酶( manganese superoxide dismutase,MnSOD)水平的变化。研究两者与OSAHS及OSAHS+HT的关系,旨在探讨OSAHS及OSAHS+HT患者体内氧化损伤及抗氧化情况,以及8-OHdG和MnSOD在OSAHS+HT的病因、发病机制和病情进展中的作用。
方法:随机选择OSAHS患者40例(均为男性),所有患者均有夜间睡眠中打鼾、呼吸暂停及白天嗜睡病史,并经多导睡眠图(polysomnography, PSG)监测确诊,OSAHS的诊断依据中华医学会呼吸病学分会睡眠呼吸疾病学组制定的诊断标准[1],即睡眠呼吸暂停低通气指数(apnea hypopnea index AHI,平均每小时睡眠中的呼吸暂停加上低通气次数)≥5次/h。呼吸暂停指睡眠过程中口鼻呼吸气流均停止10s以上,低通气指睡眠过程中呼吸气流强度较基础水平降低50%以上并伴有血氧饱和度较基础水平下降≥4%。其中无并发症的OSAHS患者20例,年龄29~68(49.40±9.31)岁,体重指数23.11~34.29(29.81±3.38)kg/m2。OSAHS+HT患者20例(均为男性),年龄25~61(43.95±9.17)岁,体重指数22.72~34.60(28.49±3.18)kg/m2,符合OSAHS诊断标准,并达到《中国高血压防治指南》[2]高血压诊断标准,高血压发生晚于OSAHS,且排除肾源性、内分泌性等因素引起的继发性高血压;对照组20例(均为男性),年龄29~67岁(47.55±11.18),体重指数24.02~34.91(28.62±3.27)kg/m2,经询问病史及行Stardust便携式睡眠监测仪初筛检查,排除OSAHS。三组间年龄和体重指数无显著性差异(均p>0.05),并除外吸烟、饮酒、饮食及药物等干扰因素。所有入选者在睡眠呼吸监测结束,晨醒5分钟内抽取空腹静脉血6ml,应用酶联免疫吸附试验检测血清8-OHdG水平,黄嘌呤氧化酶法检测血清MnSOD水平。并记录有关的监测指标,包括睡眠呼吸暂停低通气指数(apnea hypopnea index,AHI)、血氧饱和度(SaO2)<90%占总睡眠时间百分比、睡眠呼吸障碍事件总时间占总睡眠时间百分比、睡眠呼吸障碍事件时最低SaO2及平均最低SaO2、睡眠呼吸障碍事件最长时间。比较正常对照、OSAHS、OSAHS合并HT三组间8-OHdG,MnSOD水平,同时比较OSAHS与OSAHS+HT患者的睡眠呼吸监测指标,三组间8-OHdG,MnSOD比较采用方差分析,两两比较采用q检验。OSAHS与OSAHS+HT患者的睡眠呼吸监测指标比较采用t检验,并将OSAHS、OSAHS+HT患者血清8-OHdG,MnSOD水平与睡眠呼吸监测指标进行直线相关分析。
结果:1.血清8-OHdG,MnSOD水平:正常对照组分别为1.50±1.33ng/ml、12.45±5.15U/ml,OSAHS患者组分别为2.69±2.11ng/ml、10.49±6.60U/ml,OSAHS+HT患者组分别为3.16±2.54ng/ml、7.18±4.34U/ml。OSAHS患者与对照组比较,血清8-OHdG水平升高,血清MnSOD水平降低,均有统计学差异(q分别为7.405,3.934;p<0.01,p<0.01)。OSAHS+HT患者与对照组比较血清8-OHdG升高,血清MnSOD水平降低,差异均有显著性(q分别为10.290,10.579;p<0.01,p<0.01)。OSAHS+HT患者组与OSAHS患者组比较,血清8-OHdG升高,血清MnSOD水平降低,差异均有显著性(q分别为2.885,6.644;p<0.01,p<0.01)。2.与OSAHS患者比较,OSAHS+HT患者的睡眠呼吸监测指标AHI升高、SaO2<90%占总睡眠时间百分比,睡眠呼吸障碍事件总时间占睡眠时间百分比升高,均有统计学差异(t分别为2.95,2.18,2.24;p<0.01,p<0.05,p<0.05),睡眠呼吸障碍事件时最低SaO2降低,平均最低SaO2也降低,且差异有显著性(t分别为2.96,2.33,p<0.05,p<0.05);而睡眠呼吸障碍最长时间在两组间无统计学差异(均为p>0.05)。3. OSAHS及OSAHS+HT患者睡眠呼吸各项指标与血清8-OHdG,MnSOD直线相关分析显示:①血清8-OHdG水平与OSAHS、OSAHS+HT患者AHI呈正相关(r=0.974,p<0.01;r=0.765,p<0.01),与SaO2<90%占总睡眠时间百分比呈正相关(r=0.739,p<0.01;r=0.702,p<0.01),与睡眠呼吸障碍事件总时间占睡眠时间百分比呈正相关(r=0.829,p<0.01;r=0.583,p<0.01),与睡眠呼吸障碍事件时最低SaO2呈负相关(r=-0.751,p<0.01;r=-0.560,p<0.05),与平均最低SaO2呈负相关(r=-0.718,p<0.01;r=-0.808,p<0.01)。而与睡眠呼吸障碍最长时间无相关性(r=0.185,p>0.05;r=0.023,p>0.05)。②血清MnSOD水平与OSAHS、OSAHS+HT患者AHI呈负相关(r=-0.806,p<0.01;r=-0.929,p<0.01)。与SaO2<90%占总睡眠时间百分比呈负相关(r=-0.567,p<0.01;r=-0.758,p<0.01),与睡眠呼吸障碍事件总时间占睡眠时间百分比呈负相关(r=-0.738,p<0.01;r=-0.809,p<0.01),与睡眠呼吸障碍事件时最低SaO2正相关(r=0.612,p<0.01;r=0.567,p<0.01),与平均最低SaO2正相关(r=0.518,p<0.05;r=0.742,p<0.01),而与睡眠呼吸障碍最长时间无相关性(r=-0.210,p>0.05;r=-0.099,p>0.05)。
结论:1.除外年龄、体重指数等相关因素的影响,并排除吸烟、饮酒、饮食及药物等干扰因素,OSAHS及OSAHS+HT患者血清8-OHdG较正常对照组水平均升高,其升高的水平与AHI及SaO2<90%占总睡眠时间的百分比呈正相关,与睡眠呼吸障碍事件时最低SaO2、平均最低SaO2呈负相关。表明8-OHdG随OSAHS及OSAHS+HT患者的病情加重而增加。血清MnSOD水平在两组患者较正常对照组均降低,降低的水平均与AHI及SaO2<90%占总睡眠时间的百分比呈负相关,与睡眠呼吸障碍事件时最低SaO2及平均最低SaO2呈正相关,表明MnSOD随OSAHS及OSAHS+HT患者的病情加重而降低。表明其随缺氧的加重而降低。2. MnSOD是线粒体中能催化超氧阴离子发生歧化反应的抗氧化酶,其功能主要是清除氧自由基,保护细胞不受损害。MnSOD水平的稳定对于维持细胞的正常生理功能起着重要作用。8-OHdG是活性氧自由基氧化损伤细胞核DNA或线粒体DNA后形成的产物。MnSOD水平在OSAHS+HT患者较OSAHS患者明显降低,而OSAHS+HT患者较OSAHS患者降低更明显。血清8-OHdG水平明显增高,而OSAHS+HT患者较OSAHS患者升高更明显。说明OSAHS患者无论是否合并高血压,均存在氧化应激及氧化损伤。这种氧化应激所造成的损伤在OSAHS+HT患者中更明显。OSAHS患者已经存在氧化失衡,说明OSAHS患者的氧化应激的发生是独立于或先于高血压的发生而发展的,可能为OSAHS患者发生高血压的原因之一。而多项研究表明氧化应激与多种疾病互为因果。而氧化应激的存在可使自由基增多,也可造成内皮损伤,血管收缩,从而引起高血压病的发生。8-OHdG、MnSOD在阻塞性睡眠呼吸暂停低通气综合征患者血中含量的变化可反映病情的严重程度,了解氧化应激的程度,可指导OSAHS的早期治疗及改善其预后。
Objectives: To investigate the serum 8-OHdG and serum MnSOD concentrations in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) without complications and in those with obsturctive sleep apnea-hypopnea associated hypertension (OSAHS+HT). To evaluate the relationship between three biochemical parameters and OSAHS and OSAHS+HT in order to explore the change of oxidant stress and oxidative DNA damage in patients with OSAHS and OSAHS+HT. To study the role of serum 8-OHdG and serum MnSOD in the pathogenesis and progress of OSAHS+HT.
Methods: Forty males with OSAHS were included randomly in the study and twenty age-matched and body mass index (BMI) -matched healthy men served as control subjects. OSAHS patients with nocturnal snoring, apnea and excessive daytime sleepiness syndrome and control subjetcs without those syndromes underwent overnight polysomnography (PSG) and portal sleep apnea monitoring, respectively. Inclusion criteria for the present study were apnea-hypopnea index (AHI)≥5/h for OSAHS patients and AHI<5/h for control subjects. Apnea was defined as an absence of airflow for≥10s, and hypopnea was defined as a reduction of airflow associated with a reduction of oxygen saturation by 4% from baseline. The AHI was defined as the average of apneic and hypopneic events per sleep hour. All patients with OSAHS were divided into two subgroups:20 OSAHS patients without complications (age= 49.40±9.31, BMI=29.81±3.38kg/m2) and 20 OSAHS+HT patients (age =43.95±9.17, BMI=28.49±3.18kg/m2). Occurrence of hypertension was later than that of OSAHS in patients with OSAHS+HT. Other secondary hypertension (such as renovascular and endocrinic hypertension) were excluded in OSAHS+HT patients. There were no significant differences in age and BMI among control subjects (age=47.55±11.18, BMI=28.62±3.27kg/m2), OSAHS and OSAHS+HT subjects. Smoking, drinking, diets, drugs and other disturbance factors were excluded in this study. Fasting venous blood were obtained from all observed subjects after sleep-breathing monitoring within the following 5 minutes in the next morning. The serum 8-OHdG concentrations were measured by ELISA, the serum MnSOD contents were detected by xanthine oxidase method, respectively. Differences in serum 8-OHdG and MnSOD among three groups were assessed by using one-way analysis of variance and further multiple comparisons were performed with SNK-q test. Sleep-breathing parameters of patients with OSAHS without complications were compared with those of patients with OSAHS+HT by using student’s two- tailed t test. Furthermore, linear correlations were performed between three biochemical parameters and sleep-breathing parameters of patients with OSAHS and OSAHS+HT, respectively.
Results: 1. the serum 8-OHdG and serum MnSOD concentrations were 1.50±1.33ng/ml、12.45±5.15U/ml in control subjects, were 2.69±2.11ng/ml、10.49±6.60U/ml,in patients with OSAHS and 3.16±2.54ng/ml、7.18±4.34 U/ml in patients with OSAHS+HT, respectively. The serum 8-OHdG concentrations were higher, serum MnSOD concentrations were lower in patients with OSAHS compared with those in control subjects. There were statistical significances (q=7.405, 3.934, respectively; p<0.01). There were similar results in patients with OSAHS+HT compared with those in control subjects and significant differences were found (q=10.290, 10.579, respectively; p<0.01). Compared with OSAHS patients, there was a decreased trend of serum MnSOD concentrations in the patients with OSAHS+HT, but this difference reached statistical significance (q=2.885, 6.644, respectively; p<0.01). 2. Compared with OSAHS patients, both AHI and percentage of sleep time below 90% oxygen saturation (SaO2<90%) and percentage of sleep time the total duration of apnea/hyponea were higher in OSAHS+HT patients (t=2.95, 2.18, 2.24, repectively; p<0.01), both the lowest SaO2 and average the lowest SaO2 were lower in OSAHS+HT patients (t=2.96, p<0.05; t=2.33, p<0.05). But there were no differences in the longest duration of apnea/hypopnea between two subgroups(p>0.05). 3. The linear correlations were found between three biochemical parameters and sleep-breathing parameters in patients with OSAHS and OSAHS+HT as follows:①The serum 8-OHdG levels were correlated positively with AHI both in OSAHS and OSAHS+HT patients (r=0.974, p<0.01; r=0.765, p<0.01), were correlated positively with SaO2<90% (r=0.739, p<0.01; r=0.702, p<0.01), were correlated positively with percentage of sleep time the total duration of apnea/hyponea (r=0.829, p<0.01; r=0.583, p<0.01), were correlated negatively with the lowest SaO2 (r=-0.751, p<0.01; r=-0.560, p<0.05) and were correlated negatively with average the lowest SaO2 (r=-0.718, p<0.01; r=-0.808, p<0.01). The correlations were not found between the longest dutation of apnea/hypopnea and levels of three biochemical parameters in patients with OSAHS and OSAHS+HT. (r=0.185, p>0.05; r=0.023, p>0.05).②The correlations between serum MnSOD and sleep-breathing parameters were not as same as those of 8-OHdG. MnSOD levels levels were correlated negatively with AHI both in OSAHS and OSAHS+HT patients (r=-0.806, p<0.01; r=-0.929, p<0.01), were correlated negatively with SaO2<90% both in OSAHS and OSAHS+HT patients (r=-0.567, p<0.01; r=-0.758, p<0.01), were correlated negatively with percentage of sleep time the total duration of apnea/hyponea (r=-0.738, p<0.01; r=-0.809, p<0.01), were correlated positively with the lowest SaO2 (r=0.612, p<0.01; r=0.567, p<0.01), and were correlated positively with average the lowest SaO2 (r=0.518, p<0.05; r=0.742, p<0.01). And there were no correlations with the longest dutation of apnea/hypopnea (r=-0.210, p > 0.05; r=-0.099, p>0.05).
Conclusions: 1. Despite controlling for age, BMI and excluding disturbance factors such as smoking, drinking, diets and drugs, the resum 8-OHdG concentrations in patients with OSAHS and OSAHS+HT were higher than those in control subjects. The resum 8-OHdG levels were correlated positively to both AHI and SaO2<90% and were correlated negatively to both the lowest SaO2 and average the lowest SaO2 . which showed a strong correlation between 8-OHdG increasing with the degree of hypoxemia. Both the MnSOD levels in patients with OSAHS and OSAHS+HT were lower than those in control subjects. MnSOD levels were correlated negatively to AHI and SaO2<90% and correlated positively to the lowest SaO2 and average the lowest SaO2 , which showed a strong correlation between MnSOD reducing with the degree of hypoxemia. 2. MnSOD,as an important antioxidant enzyme in mitochondria,which can catalyze the dismutation of superoxide ion,and protect the cells from oxidative damage.It is important that the stable level of MnSOD maitaining the normal physiology function of the cells. The content of 8-hydroxydeoxyguanosine (8-OHdG) by which the cellular DNA damage caused by active oxygen species. The serum MnSOD contents in patients with OSAHS+HT was lower than those in patients with OSAHS. The serum 8-OHdG contents in patients with OSAHS+HT was higher than those in patients with OSAHS.Our study demonstrated the change of oxidative /anti- oxidative imbalance between oxidative stress and oxidative DNA damage in patients with OSAHS no matter with or without hypertension. The imbalance of oxidative /anti- oxidative was more obvious in patients with OSAHS+HT. Our study documents the existence of oxidative damage in OSAHS, which suggests that important oxidative stress of OSAHS occur independent of , and possibly prior to, the development of systemic hypertension. Several studies showed oxidative stress was significantly correlated with many of disease. The information of the severity of sleep disordered breathing and the degree of oxidative stress can be obtained by measuring the change of two biochemical parameters, which has important value to advice the early treatment and to improve the prognosis.
引文
1 阻塞性睡眠呼吸暂停低通气综合征诊治指南(草案) 中华结核和呼吸杂志,2002,25(4):195-198
2 中国高血压防治指南修订委员会.中国高血压防治指南.2005 年修订版[J].高血压杂志,2005,134(增刊):2-41
3 Nickenig G,Harrison DG. The AT(1)-type angiotensin receptorin oxidative stress and at herogenesis :part I : oxidative stress andat herogenesis. Circulation . 2002 ,105 (3):393-396
4 Zalba G, San Jose G, Moreno M , et al . Oxidative stress in arterial hypertension :role of NAD(P) H oxidase. Hypertension .2001 ,38(6):1395-1399
5 Sorescu D , Griendling KK. Reactive oxygen species , mitochondria ,and NAD( P) H oxidases in the development and progression of heart failure. Congest Heart Fail . 2002 , 8 : 132-140
6 Chan P. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab. 2001 , 21 (1):2-14
7 Schulz R , Mahmoudi S , Hattar K, et al . Enhanced release of superoxide f rom polymorphonuclear neutrophils in obstructive sleep apnea : impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med. 2000 , 162(2Pt1):566-570
8 Dyugovskaya L, Lavie P ,Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med.2002 ,165(7) :934-939
9 Christou K,Moulas AN , Pastaka C ,et al . Antioxidant capacity in obstructive sleep apnea patients. Sleep Med . 2003 ,4 (3):225-228
10 Motoo Yamauchi, Hiroshi Nakano, MD, PhD; Junko Maekawa, MD, PhD; et al.Oxidative Stress in Obstructive Sleep Apnea* Chest. 2005,127(5):1674-1679
11 Young T,Palta M,Dempsey J,et al.The occurrence of sleep-disordered breathing among middle-aged adults.N Engl J Med.1993,328(17):1230-1235
12 Young T,Peppard PE.Gottlieb DJ.Epidemiology of obstructive sleep apnea:a population health perspective.AmJ Respair Crit Care Med.2002,165(9):1217-1239
13 Kim J,In K,You S ,et al.Prevalence of sleep-disordered breathing inmiddle-aged Korean men and women.Am J Respair Crit Care Med.2004,170(10):1108-1113
14 上海市医学会呼吸病学分会睡眠呼吸疾病学组。上海市30 岁以上人群阻塞性睡眠暂停低通气综合症流行病学调查,中华结核和呼吸杂志,2003,26(5):268-272
15 黄席珍.睡眠呼吸障碍诊治进展与国内16年来的经验[J].中华结核和呼吸杂志,1999,21(8):463
16 Bounhoure J P , Galinier M , Didier A , et al1 Sleep apnea syndromes and cardiovascular disease [ J ] . Bull Acad NatlMed. 2005 , 189 (3) : 445-459
17 Peppard PE,Young T,Palta M,et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med.2000,342(19):1378-1384
18 Robinsn GV , St radling RJ . Obstructive sleep pnoeahyppnoea syndrome and hypertension [ J ] . Thorax . 2004 ,59 (12) : 1089-1094
19 Harman D. Aging : a theory based on free radical and radiation chemistry[J ] . J Gerontol.1956 ,11 (3) :298-300.
20 McCord JM , Fridovich I. Superoxide dismutase : An enzymic function for eryt hrocuprein ( hemocuprein) [ J ] . J Biol Chem .1969 ,25 ,244 (22) :6049-6055
21 Prabha Qs. Das UN , Kotat kar R. Free radical generation , lipid peroxidation and essential fatty acids in uncontrolled essential hypertension [ J ] . Prostaglandins Leukot EssentFatty Acids .1990,41 (1) :27-33
22 Lacy F ,O’Connor DT ,Schmid2Schonbein GW. Plasma hydrogen peroxide production in hypertensives and normotensive subjects at genetics risk of hypertension [ J ] . J Hypertens.1998 ,16 (3) :291-303
23 段艳杰,张 辉,郑永刚原发性高血压患者血清SOD 和MDA 及NO 检测的临床意义.实用医技杂志[J]2006 ,13(11):1856-1857
24 孙广辉、宁玉琴、韦荷英.原发性高血压患者超氧化物歧化酶及其同工酶的研究.中国循环杂志,1994,9(4):203-205
25 Negishi H,Ikeda K, Kuga S,et al.The relation of oxidative DNA damage to hypertension and other cardiovascular risk factors in Tanzania. J Hypertens. 2001,19(3Pt1):529-533
26 Lavie L. Obst ructive sleep apnoea syndrome2an oxidative stress disorder . Sleep Med Rev .2003 ,7 (1) :35-51.
27 Kara T,Narkiewicz K,Somers VK. Chemoreflexes- physiology and clinical implications.Acta Physiol Scand. 2003,177(3):377-384
28 Wu LL, Chiou CC, Chang PY, et al. Urinary 8-OHdG: amarker of oxidative stress to DNA and a risk factor forcancer, atherosclerosis and diabetics[J] . Clin Chim Acta.2004,339(1- 2):1- 9
29 Babior BM. NADPH oxidase: an update. Blood. 1999,93(5):1464 –1476
30 李海燕, 赵秋良, 韩晓攀等.阻塞性睡眠呼吸暂停综合征患者自由基损伤与高血压的关系[J]山东大学耳鼻喉眼学报,2006,20(6):527-529
31 Huie RE , Padmaja S. The reaction of nitric oxide with superoxide[J ] . Free Radic Res Commun . 1993 , 18(4) : 195 - 199
32 Beckman J S , Koppenol WH. Nitric oxide , superoxide , and peroxynitrite : the good ,the bad ,the ugly[J ] . Am J Physiol.1996 ,271(5Pt1):C1424~C1437
33 Chu Y, Iida S, L und DD, et al. Gene transfer of extracellular superoxide dismutase reduces arterial p ressure in spontaneously hypertensive rats: role of heparin-binding domain [J ]. Circ Res.2003, 92(4): 461-468
34 D ikalova A , Clempus R,L assegue B, et al. Noxl overexp ression potentiates angiotensin ê -induced hypertension and vscular smooth muscle hypertrophy in transgenic mice [J ]. Circulation.2005, 112(17): 2668-2676
1 Catherwood MA, Powell LA, Anderson P, et al. Glucose-induced oxidative stress in mesangial cells. Kidney Int .2002, 61(2):599-608
2 Bonnefont-Rousselot D, Bastard JP, Jaudon MC, et al. Consequences of the diabetic status on the oxidant/ antioxidant balance. Diabetes Metab. 2000, 26(3): 163-176
3 Halliwell B , Gutteridge J . Free radicals in biology and medicine Third edition [J ] . Oxford University Press . 1999 , 617~783
4 McCord JM , Fridovich I. Superoxide dismutase : Anenzymic function for erythrocuprein ( hemocuprein) [ J ] . J Biol Chem. 1969 ,25 ,244 (22) :6049-6055
5 Borgstahl GE ,Parge HE ,Hickey MJ , et al . The structure of human mitochondrial manganese superoxide dismutase reveals a novel tetrameric interface of two 4-helix bundles [J ]. Cell ,1992 ,71(1) :107 - 118
6 Shimoda-Matsubayashi S , Hattori T , Matsumine H , et al. MnSOD activity and protein in a patient with chromosome
6-linked autosomal recessive parkinsonism in comparison with Parkinson disease and control. Neurology . 1997 , 49 (5) : 1257-1261
7 RosenblumJ S , Gilula NB , Lerner RA. On signal sequence polymorphisms and diseases of distribution. Proc Natl Acad Sci USA. 1996 ,93 : 4471-4473
8 SEVERIN I,JONDEAU A,DAHBI L.2,4-Diaminotoluene (2,4-DAT)-induced DNA damage,DNA repair and micronucleus formation in the human hepatoma cell line HepG2[J]. Toxicology. 2005, 213(1-2): 138-146
9 Umegaki K,Hashimoto M,Yamasaki H ,etal. Docosahexae- noic acid supplementation-increases oxidative damage in bone marrow DNA in aged rats and its relation to antioxida - nt vitamins.Free Radical Res. 2001, 34(4): 427-435
10 柯跃斌,徐苑苑,谭春荣,等.饮食业四类人群DNA 氧化损伤尿8 - 羟基脱氧鸟苷水平分析[J]. 中国热带医学2005 ,5(3) :441-443
11 Chen X,Touyz PM,Park JB,et al.Antioxidant effects ofvitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR.Hypertension.2001,38(3 Pt 2):606-611
12 Hirooka Y,Eshima K,Setoguchi S,et al.Vitamin C improves attenuated angiotension II-induced endothelium-dependent vasodilation in human forearm vessels.hypertens Res. 2003; 26(12):953-959
13 Ulker S,Mckeown PP,Bayraktutan U.Vitamins Reverse Endothedial Dysfunction Through Regulation of eNOSand NAD(P)H oxidase Activities.Hypertension. 2003, 41 (3): 534-539
14 Engler MM,Engler MB,Malloy MJ,et al.Antioxidant Vitamine C and E Improve Endothelial Function in Children With Hyperlipidemia:Endothelial Assessment of Risk from Lipids in Youth(EARLY)Trial.Circulation. 2003,108(9):1059-1063
15 Franco Mdo C,Akamine EH,Oliveira AM,et al.Vitamins C and E improve endothelial dysfunction in intrsuterine- undemourished rats by decreasing vascular superoxide anion concentration J Cardiovasc Pharmacol. 2003,42(2): 211-217
16 Negishi H,Ikeda K, Kuga S,et al.The relation of oxidative DNA damage to hypertension and other cardiovascular risk factors in Tanzania. J Hypertens. 2001,19(3Pt2):529-533
17 Juyong Lee; Mejeong Lee; Jeong-Uk ,et al.Carvedilol Reduces Plasma 8-Hydroxy-2'-Deoxyguanosine in Mild toModerate Hypertension.Hypertension. 2005,45(5):986-990
18 段艳杰,张 辉,郑永刚原发性高血压患者血清SOD 和MDA 及NO 检测的临床意义。实用医技杂志[J],2006 ,13(11):1856-1857
19 凌亦凌,黄善生,谷振勇. 过氧亚硝基阴离子的细胞代谢及病理损伤作用[J ] . 生理科学进展,1999 ,30 (1) :71-73
20 David J ,Rosario S ,Barry C ,et al. Peroxynitrite inhibits leukocyte endothelial cell interactions and protects against ischemia reperfusion injury in rats [ J ] . J Clin Invest. 1997 ,99 ( 4) : 684-691
21 Mui-J sers RB , Folkerts G, Henricks PA , et al. Peroxynitrite : a two-metabolite of nitric oxide[J ] . Life Sci .1997 ,60 (21) :1833-1845
22 Young T,Palta M,Dempsey J,et al.The occurrence of sleep-disordered breathing among middle-aged adults.N Engl J Med.1993,328(17):1230-1235
23 Young T,Peppard PE.Gottlieb DJ.Epidemiology of obstructive sleep apnea:a population health perspective.Am J Respair Crit Care Med.2002,165(9):1217-1239
24 Kim J,In K,You S ,et al.Prevalence of sleep-disordered breathing in middle-aged Korean men and women.Am J Respair Crit Care Med.2004,170(10):1108-1113
25 上海市医学会呼吸病学分会睡眠呼吸疾病学组.上海市30 岁以上人群阻塞性睡眠暂停低通气综合症流行病学调查,中华结核和呼吸杂志,2003,26(5):268-272
26 黄席珍.睡眠呼吸障碍诊治进展与国内16年来的经验[J].中华结核和呼吸杂志,1999,21(8):463
27 Bounhoure J P , Galinier M , Didier A , et al. Sleep apnea syndromes and cardiovascular disease [ J ] . Bull Acad NatlMed . 2005 , 189 (3) : 445-459
28 Robinsn GV , St radling RJ . Obstructive sleep pnoeahyppnoea syndrome and hypertension [ J ] . Thorax. 2004 ,59 (12) : 1089-1094
29 中华医学会呼吸病学分会睡眠呼吸疾病学组. 阻塞性睡眠呼吸暂停综合征诊治指南(草案) [ J ]. 中华结核和呼吸杂志, 2002, 25 (4) : 195-198
30 Hla KM,Young TB,Bidwell T,et al.Sleep apnea and hypertension.A population-based study.Ann Intern Med. 1994,120(5):382-388
31 Lavie P,Herer P,Hoffstein V.Obstructive sleep apnea syndrome as a risk factor for hypertion:population study.BMJ.2000,320(7233):479-482
32 Peppard PE, Young T, Palta M.Prospective study of the association between sleep- disordered breathing and hypertension [J].N Engl J Med.2000, 342( 19) : 1378-1384
33 Silverberg DS,o ksenberg A.Are sleep-related breathing disorders important contributing factors to the production of essential hypertension?Curr Hypertens Rep. 2001, 3: 209-215
34 Lavie P ,Silverberg D ,Oksenberg A ,et al. Obstructive sleep apnea and hypertension:from correlative to causative relationship [J ].J Clin Hypertens .2001 ,3 :296-301
35 Grote L , Hedne J , Peter J H . Mean blood pressure , pul sepressure and grade of hypertension in untreated hypertension .patients with sleep related breathing disorder [ J ] .J Hypertens . 2001 , 19 (4) : 683-690
36 Lologan AG, Perilikowski SM,Mente A, et al. High p revalence of unrecognized sleep apnea in drug resistant hypertension. J Hypertens.2001,19(12): 2271-2277
37 Sharabi Y ,Scope A,Cherney N,et al.Diastolic blood pressure is the first to rise in association with early subclinical obstructive sleep apnea:lessons from periodic examination screening[J].Am J Hyper.2003,16(3):236-239
38 Davies CWH,Crosby JH,Mullins RL,et al.Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnea and normal matched control subjects[J].Thorax.2000,55(9):736-740
39 Sanner BM ,Tepel M,Markmann A,et al.Effect of continous positive airway pressure therapy on 24-hour blood pressure in patients with obstructive sleep apnea syndrome[J].Am J Hyper.2002,15(3):251-257
40 Loredo J S , Ancoli -Israel S , Dimsdale J E. Sleep quality and blood pressure dipping in obstructive sleep apnea[J ]. Am J Hypertens.2001 ,14(9Pt1) :887 -892
41 Sharabi Y ,Scope A ,Chorney N ,et al. Diastolic blood pressure is the first to rise in association with early subclinical obstructive sleep apnea : lessons from periodicexamination screening [J ]. Am J Hypertens. 2003 , 16(3) : 236 -239
42 陈宝元. 睡眠呼吸疾病与高血压研究进展[J ]. 实用诊断与治疗杂志, 2004 , 11 (6) : 467
43 耿玉青.持续正压通气辅助治疗高血压并发睡眠呼吸暂停综合征的临床研究.临床肺科杂志,2007,12(8):826-827
44 李莉,黄建风,谢晋湘,等. 睡眠呼吸暂停综合症.中华心血管病杂志, 2001, 9: 524 - 526
45 Motoo Yamauchi, MD; Hiroshi Nakano, MD, PhD; Junko Maekawa, MD, PhD; et al.Oxidative Stress in Obstructive Sleep Apnea* Chest. 2005;127(5):1674-1679
46 Cooke, MS, Evans, MD, Dizdaroglu, M, et al. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 2003,17(10):1195-1214
47 Schulz, R, Mahmoudi, S, Hattar, K, et al Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea: impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med .2000,162(2Pt1):566-570
48 Halliwell, B Can oxidative DNA damage be used as a biomarker of cancer risk in humans? Problems, resolutions and preliminary results from nutritional supplementation studies. Free Radic Res. 1998,29:469-486
49 Christou, K, Moulas, AN, Pastaka, C, et al Antioxidant capacity in obstructive sleep apnea patients. Sleep Med .2003,4(3):225-228
50 Carpagnano, GE, Kharitonov, SA, Resta, O, et al 8-Isoprostane, a marker of oxidative stress, is increased in exhaled breath condensate of patients with obstructive sleep apnea after night and is reduced by continuous positive airway pressure therapy. Chest. 2003 , 124 (4): 1386-1392
51 Lavie, L, Vishnevsky, A, Lavie, P Evidence for lipid peroxidation in obstructive sleep apnea. Sleep. 2004, 27(1):123-128
52 McCord, JM The evolution of free radicals and oxidative stress. Am J Med 2000,108(8):652-659
53 Shan X, Chi L, Ke Y,et al. Manganese superoxide dismutase protects mouse cortical neurons from chronic intermittent hypoxia-mediated oxidative damage. Neurobiol Dis. 2007 ,28(2):206-215
54 李海燕, 赵秋良, 韩晓攀.阻塞性睡眠呼吸暂停综合征患者自由基损伤与高血压的关系.山东大学耳鼻喉眼学报 2006,20(6):527-529