尼索地平、奥美沙坦对原发性高血压患者血管内皮功能及其影响因素的作用
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摘要
研究背景
越来越多的证据表明,内皮细胞功能障碍是高血压和动脉粥样硬化的重要发病机制和关键环节。如果抗高血压药物能够在降低血压的同时改善内皮功能障碍,则对于患者症状的改善及长期生活质量是十分重要的。导致血管内皮功能障碍的因素很多。氧化应激和炎症反应对血管内皮功能障碍都有重要的作用。此外,近来发现不对称二甲基精氨酸(ADMA)作为内源性一氧化氮合成酶抑制剂,能够降低一氧化氮(NO)生物利用度导致血管内皮功能障碍。钙离子通道阻滞剂(CCB)尼索地平和血管紧张素Ⅱ受体拮抗剂(ARB)奥美沙坦是临床上常用的降压药物。动物模型和离体实验证实尼索地平通过动员内皮祖细胞到血管腔和增加NO生物利用度改善血管内皮功能障碍,但是否其也能够改善高血压患者中的内皮功能障碍则尚未见报道。奥美沙坦改善血管内皮功能障碍的作用已被报道,但是其具体的机制尚未完全明了。本研究通过检测高血压患者中反映血管内皮功能的指标(NO、内皮素-1(ET-1)和血流介导的舒张功能(FMD)以及血浆ADM A、8-异前列腺素2a (8-iso-PGF2a)(氧化应激指标)和超敏C反应蛋白(hs-CRP)(炎症反应指标)水平,并观察它们在给予尼索地平和奥美沙坦治疗8周后的变化,来评价尼索地平是否能够改善高血压患者血管内皮功能以及探究尼索地平和奥美沙坦影响内皮功能的可能机制。
目的
1.观察本研究中原发性高血压组中是否存在血管内皮功能障碍以及氧化应激、炎症反应和ADMA水平升高。
2.观察尼索地平对血管内皮功能、氧化应激、炎症反应和ADMA水平的影响,探究其影响内皮功能的可能机制。
3.观察奥美沙坦对血管内皮功能、氧化应激、炎症反应和ADMA水平的影响,探究其影响内皮功能的可能机制。
方法
本研究是一个随机、平行对照的临床试验。55例新发现的或不规则服降压药物并已停降压药物1周以上的轻中度原发性高血压患者(140≤收缩压(SBP)<180mmHg和(或)90≤舒张压(DBP)<110mmHg),随机分为2组,分别服用尼索地平(10～20mg/d)、奥美沙坦(20～40mg/d),疗程8周。整个试验资料完整可用于统计分析者共48例,有7例失访。在治疗前和治疗后8周分别测量坐位血压,血浆ADMA、ET-1、8-iso-PGF2α、NO、hs-CRP水平,同时用高分辨率超声检测肱动脉FMD和硝酸甘油介导的血管舒张功能(NMD)评价原发性高血压患者治疗前后的血管舒张功能的变化。本研究同时入选28名血压正常的健康志愿者作为对照组。
结果
本研究结果分为两个部分：
1.原发性高血压患者中除血压高外也存在血管内皮功能障碍、氧化应激、炎症反应、ADMA水平升高
1.1高血压组平均收缩压、舒张压(分别是148.3±9.1,87.8±9.0)明显高于正常血压对照组(分别是110.4±10.5,70.7±8.9),差异具有统计学意义(P<0.01)。
1.2原发性高血压组的血浆NO水平明显低于对照组(P<0.01),而血浆ADM A、ET-1、8-iso-PGF2α、hs-CRP水平则高于正常对照组(P<0.05)。
1.3原发性高血压组FMD百分比与正常对照组相比明显减低(10.43±3.91%vs13.37±5.50%,P<0.05),而硝酸甘油介导的舒张值(NMD)两组之间的差别无统计学意义(13.12±6.36%vs14.70±4.86%,P>0.05)。
2.尼索地平、奥美沙坦对血管内皮功能障碍、氧化应激、炎症反应和ADMA水平的影响
2.1两组在基线水平血压、血浆ADMA、ET-1、NO和8-iso-PGF2a水平以及FMD、NMD无明显差异(P>0.05),但是两组的CRP基线水平有差异(P<0.05),尼索地平组CRP水平高于奥美沙坦组(1.90[0.80-4.30]vs0.80[0.45-1.40])。
2.2两组治疗后收缩压、舒张压均明显下降(P<0.01),心率在两组治疗前后无改变。
2.3两组治疗后FMD百分比升高,血浆ADMA、ET-1水平下降(P<0.05)。两组治疗后血浆NO、8-iso-PGF2α水平、NMD无明显变化(P>0.05)；尼索地平组治疗后血浆CRP水平下降(P<0.05),但是在奥美沙坦组CRP水平变化无统计学意义(P>0.05)。
结论
1.轻、中度原发性高血压患者存在血管内皮细胞功能障碍以及氧化应激、炎症反应、ADMA水平升高。
2.尼索地平和奥美沙坦均能明显降低血浆ADMA和ET-1水平并且改善FMD。此外,尼索地平还具有明显的抗炎作用。治疗8周后,两药均无明显的抗氧化作用及提高NO水平的作用。
3.尼索地平改善FMD可能与其降低ET-1、ADMA和抗炎作用有关；奥美沙坦改善FMD可能与其降低ET-1、ADMA有关。
Background:
More and more evidences show that endothelial dysfunction plays a pivotal role in essential hypertension and arteriosclerosis. If anti-hypertensive drugs are able to not only decrease blood pressure but also improve endothelial dysfunction, it will be beneficial for improving symptoms and long-term life quality of patients. Many factors contribute to endothelial dysfunction. Oxidative stress and inflammation play important roles in the mechanisms of endothelial dysfunction. Moreover, asymmetric dimethylarginine(ADMA), as an endogenous NO synthase inhibitor, and, therefore, is able to decrease nitric oxide(NO) bioavailability to produce endothelial dysfunction. Nisoldipine is a calcium channel blocker, and olmesartan is an angiotensinⅡreceptor blocker(ARB). Nisoldipine and olmesartan are both common anti-hypertensive drugs in clinic. Animal models and ex-vivo experiments have demonstrated that nisoldipine can mobilize endothelial progenitor cells from morrow to vascular lumen and increase NO availability to improve endothelial dysfunction. However, whether nisoldipine is able to improve endothelial dysfunction in essential hypertensive patients has not yet reported. Effect of olmesartan on endothelial dysfunction has been reported, but the detailed mechanisms in improving endothelial dysfunction are still unclear completely. In this study, biological and functional parameters related to endothelial function (such as NO, endothelin-1(ET-1), flow-mediated vasodilation(FMD)) and the circulating levels of ADMA, hs-CRP (as an inflammatory marker), and 8-isoPGF2a(as an oxidative stress marker), were measured at baseline and eight weeks later, in order to evaluate whether nisoldipine can improve endothelial function in essential hypertensive patients, as well as to explore the potential mechanisms of nisoldipine and olmesartan in influencing endothelial function.
Objective:
1. To observe whether vascular endothelial dysfunction and oxidative stress, inflammation as well as ADMA levels elevation exist in essential hypertensive patients.
2. To observe the effects of nisoldipine on vascular endothelial function, oxidative stress, ADMA as well as inflammation, and to explore the potential mechanisms of it in influencing endothelial function
3. To observe the effects of olmesartan on vascular endothelial function, oxidative stress, ADMA as well as inflammation, and to explore the potential mechanisms of it in influencing endothelial function.
Methods:
GradeⅠorⅡessential hypertension without clinically evident organ damage were recruited if seated arterial blood pressure(after 10 min of rest) was consistently found to be≥140/90mm and<180/110mmHg and they were never treated or reported a history of discontinued pharmacological antihypertensive treatment and withdrawal over 1 weeks at least. According to a randomized, parallel design, fifty-five patients were allocated to nisoldipine(10～20mg/d) or olmesartan (20～40mg/d), the whole treatment was 8-week period.48 patients completed the total study,7 patients failed to complete the study due to lost to follow-up. Sitting blood pressure, plasma ADMA, ET-1, 8-iso-PGF2α, NO and hs-CRP levels were assessed before and after 8-week treatment. In addition, we detected brachial artery FMD and nitroglycerin-mediated vasodilation(NMD) by high-resolution ultrasound in order to evaluate the changes of vascular vasodilation between baseline and 8-week treatment later. Meanwhile,28 normotensive control subjects were evaluated as a control group.
Results:
The results of the study include two parts:
1. Besides high blood pressure, endothelial dysfunction, oxidative stress, inflammatory effect and increasing circulating ADMA levels have become widely recognized in essential hypertensive patients.
1.1 Mean patient BP was 148.3/87.8±9.1/9.0mmHg compared to 110.4/70.7±10.5/8.9mmHg in controls(P<0.01).
1.2 Plasma levels of ADMA、ET-1、8-iso-PGF2α、hs-CRP were significantly higher compared to normotensive control(P<0.05),whereas NO levels was significantly lower(P<0.01).
1.3 FMD was significantly lower in patients compared to controls(10.43±3.91% vsl3.37±5.50%, P<0.05),and NMD was similar in both groups (13.12±6.36% vs14.70±4.86%,P>0.05)
2. Effects of nisoldipine and olmesartan on vascular endothelial dysfunction, oxidative stress, inflammation and ADMA levels.
2.1 At baseline, blood pressure, ADMA、ET-1、NO,8-iso-PGF2αlevels, FMD, NMD were similar in the two treatment groups(P>0.05), however, baseline CRP levels in nisoldipine group was higher than in olmesartan group(1.90[0.80-4.30] vs0.80[0.45-1.40, P<0.05).
2.2 Clinic sitting blood pressure in both groups decreased significantly after treatments(p<0.01), but heart rate was no change after nisoldipine or olmesartan treatment.
2.3 At the end of the treatment, plasma ADMA and ET-1 levels were significantly decreased and FMD increased in patients receiving nisoldipine or olmesartan (P<0.05). Plasma NO and 8-iso-PGF2a were no change in both groups (P>0.05). There was a significant decrease of plasma hs-CRP only in patients receiving nisoldipine (P<0.05). In both groups, the BA dilator response to glyceryl trinitrate was similar at baseline and was not significantly increased after treatment(P>0.05).
Conclusions:
1. Endothelial dysfunction, oxidative stress, inflammatory effect and increasing circulating ADMA levels have become widely recognized in mild-to-moderate essential hypertensive patients.
2. Nisoldipine and olmesartan both can decrease plasma ADMA and ET-1 levels and improve FMD. Moreover, nisoldipine has significantly anti-inflammatory effect. NO and 8-isoPGF2a levels were no change from baseline to eight-week nisoldipine or olmesartan treatment.
3. The improvements of FMD in nisoldipine may be related to the reduction in ADMA, ET-1 and inflammation; olmesartan may improve FMD by decreasing the levels of ADMA and ET-1.
越来越多的证据表明,内皮细胞功能障碍是高血压和动脉粥样硬化的重要发病机制和关键环节。如果抗高血压药物能够在降低血压的同时改善内皮功能障碍,则对于患者症状的改善及长期生活质量是十分重要的。导致血管内皮功能障碍的因素很多。氧化应激和炎症反应对血管内皮功能障碍都有重要的作用。此外,近来发现不对称二甲基精氨酸(ADMA)作为内源性一氧化氮合成酶抑制剂,能够降低一氧化氮(NO)生物利用度导致血管内皮功能障碍。钙离子通道阻滞剂(CCB)尼索地平和血管紧张素Ⅱ受体拮抗剂(ARB)奥美沙坦是临床上常用的降压药物。动物模型和离体实验证实尼索地平通过动员内皮祖细胞到血管腔和增加NO生物利用度改善血管内皮功能障碍,但是否其也能够改善高血压患者中的内皮功能障碍则尚未见报道。奥美沙坦改善血管内皮功能障碍的作用已被报道,但是其具体的机制尚未完全明了。本研究通过检测高血压患者中反映血管内皮功能的指标(NO、内皮素-1(ET-1)和血流介导的舒张功能(FMD)以及血浆ADM A、8-异前列腺素2a (8-iso-PGF2a)(氧化应激指标)和超敏C反应蛋白(hs-CRP)(炎症反应指标)水平,并观察它们在给予尼索地平和奥美沙坦治疗8周后的变化,来评价尼索地平是否能够改善高血压患者血管内皮功能以及探究尼索地平和奥美沙坦影响内皮功能的可能机制。
目的
1.观察本研究中原发性高血压组中是否存在血管内皮功能障碍以及氧化应激、炎症反应和ADMA水平升高。
2.观察尼索地平对血管内皮功能、氧化应激、炎症反应和ADMA水平的影响,探究其影响内皮功能的可能机制。
3.观察奥美沙坦对血管内皮功能、氧化应激、炎症反应和ADMA水平的影响,探究其影响内皮功能的可能机制。
方法
本研究是一个随机、平行对照的临床试验。55例新发现的或不规则服降压药物并已停降压药物1周以上的轻中度原发性高血压患者(140≤收缩压(SBP)<180mmHg和(或)90≤舒张压(DBP)<110mmHg),随机分为2组,分别服用尼索地平(10～20mg/d)、奥美沙坦(20～40mg/d),疗程8周。整个试验资料完整可用于统计分析者共48例,有7例失访。在治疗前和治疗后8周分别测量坐位血压,血浆ADMA、ET-1、8-iso-PGF2α、NO、hs-CRP水平,同时用高分辨率超声检测肱动脉FMD和硝酸甘油介导的血管舒张功能(NMD)评价原发性高血压患者治疗前后的血管舒张功能的变化。本研究同时入选28名血压正常的健康志愿者作为对照组。
结果
本研究结果分为两个部分：
1.原发性高血压患者中除血压高外也存在血管内皮功能障碍、氧化应激、炎症反应、ADMA水平升高
1.1高血压组平均收缩压、舒张压(分别是148.3±9.1,87.8±9.0)明显高于正常血压对照组(分别是110.4±10.5,70.7±8.9),差异具有统计学意义(P<0.01)。
1.2原发性高血压组的血浆NO水平明显低于对照组(P<0.01),而血浆ADM A、ET-1、8-iso-PGF2α、hs-CRP水平则高于正常对照组(P<0.05)。
1.3原发性高血压组FMD百分比与正常对照组相比明显减低(10.43±3.91%vs13.37±5.50%,P<0.05),而硝酸甘油介导的舒张值(NMD)两组之间的差别无统计学意义(13.12±6.36%vs14.70±4.86%,P>0.05)。
2.尼索地平、奥美沙坦对血管内皮功能障碍、氧化应激、炎症反应和ADMA水平的影响
2.1两组在基线水平血压、血浆ADMA、ET-1、NO和8-iso-PGF2a水平以及FMD、NMD无明显差异(P>0.05),但是两组的CRP基线水平有差异(P<0.05),尼索地平组CRP水平高于奥美沙坦组(1.90[0.80-4.30]vs0.80[0.45-1.40])。
2.2两组治疗后收缩压、舒张压均明显下降(P<0.01),心率在两组治疗前后无改变。
2.3两组治疗后FMD百分比升高,血浆ADMA、ET-1水平下降(P<0.05)。两组治疗后血浆NO、8-iso-PGF2α水平、NMD无明显变化(P>0.05)；尼索地平组治疗后血浆CRP水平下降(P<0.05),但是在奥美沙坦组CRP水平变化无统计学意义(P>0.05)。
结论
1.轻、中度原发性高血压患者存在血管内皮细胞功能障碍以及氧化应激、炎症反应、ADMA水平升高。
2.尼索地平和奥美沙坦均能明显降低血浆ADMA和ET-1水平并且改善FMD。此外,尼索地平还具有明显的抗炎作用。治疗8周后,两药均无明显的抗氧化作用及提高NO水平的作用。
3.尼索地平改善FMD可能与其降低ET-1、ADMA和抗炎作用有关；奥美沙坦改善FMD可能与其降低ET-1、ADMA有关。
Background:
More and more evidences show that endothelial dysfunction plays a pivotal role in essential hypertension and arteriosclerosis. If anti-hypertensive drugs are able to not only decrease blood pressure but also improve endothelial dysfunction, it will be beneficial for improving symptoms and long-term life quality of patients. Many factors contribute to endothelial dysfunction. Oxidative stress and inflammation play important roles in the mechanisms of endothelial dysfunction. Moreover, asymmetric dimethylarginine(ADMA), as an endogenous NO synthase inhibitor, and, therefore, is able to decrease nitric oxide(NO) bioavailability to produce endothelial dysfunction. Nisoldipine is a calcium channel blocker, and olmesartan is an angiotensinⅡreceptor blocker(ARB). Nisoldipine and olmesartan are both common anti-hypertensive drugs in clinic. Animal models and ex-vivo experiments have demonstrated that nisoldipine can mobilize endothelial progenitor cells from morrow to vascular lumen and increase NO availability to improve endothelial dysfunction. However, whether nisoldipine is able to improve endothelial dysfunction in essential hypertensive patients has not yet reported. Effect of olmesartan on endothelial dysfunction has been reported, but the detailed mechanisms in improving endothelial dysfunction are still unclear completely. In this study, biological and functional parameters related to endothelial function (such as NO, endothelin-1(ET-1), flow-mediated vasodilation(FMD)) and the circulating levels of ADMA, hs-CRP (as an inflammatory marker), and 8-isoPGF2a(as an oxidative stress marker), were measured at baseline and eight weeks later, in order to evaluate whether nisoldipine can improve endothelial function in essential hypertensive patients, as well as to explore the potential mechanisms of nisoldipine and olmesartan in influencing endothelial function.
Objective:
1. To observe whether vascular endothelial dysfunction and oxidative stress, inflammation as well as ADMA levels elevation exist in essential hypertensive patients.
2. To observe the effects of nisoldipine on vascular endothelial function, oxidative stress, ADMA as well as inflammation, and to explore the potential mechanisms of it in influencing endothelial function
3. To observe the effects of olmesartan on vascular endothelial function, oxidative stress, ADMA as well as inflammation, and to explore the potential mechanisms of it in influencing endothelial function.
Methods:
GradeⅠorⅡessential hypertension without clinically evident organ damage were recruited if seated arterial blood pressure(after 10 min of rest) was consistently found to be≥140/90mm and<180/110mmHg and they were never treated or reported a history of discontinued pharmacological antihypertensive treatment and withdrawal over 1 weeks at least. According to a randomized, parallel design, fifty-five patients were allocated to nisoldipine(10～20mg/d) or olmesartan (20～40mg/d), the whole treatment was 8-week period.48 patients completed the total study,7 patients failed to complete the study due to lost to follow-up. Sitting blood pressure, plasma ADMA, ET-1, 8-iso-PGF2α, NO and hs-CRP levels were assessed before and after 8-week treatment. In addition, we detected brachial artery FMD and nitroglycerin-mediated vasodilation(NMD) by high-resolution ultrasound in order to evaluate the changes of vascular vasodilation between baseline and 8-week treatment later. Meanwhile,28 normotensive control subjects were evaluated as a control group.
Results:
The results of the study include two parts:
1. Besides high blood pressure, endothelial dysfunction, oxidative stress, inflammatory effect and increasing circulating ADMA levels have become widely recognized in essential hypertensive patients.
1.1 Mean patient BP was 148.3/87.8±9.1/9.0mmHg compared to 110.4/70.7±10.5/8.9mmHg in controls(P<0.01).
1.2 Plasma levels of ADMA、ET-1、8-iso-PGF2α、hs-CRP were significantly higher compared to normotensive control(P<0.05),whereas NO levels was significantly lower(P<0.01).
1.3 FMD was significantly lower in patients compared to controls(10.43±3.91% vsl3.37±5.50%, P<0.05),and NMD was similar in both groups (13.12±6.36% vs14.70±4.86%,P>0.05)
2. Effects of nisoldipine and olmesartan on vascular endothelial dysfunction, oxidative stress, inflammation and ADMA levels.
2.1 At baseline, blood pressure, ADMA、ET-1、NO,8-iso-PGF2αlevels, FMD, NMD were similar in the two treatment groups(P>0.05), however, baseline CRP levels in nisoldipine group was higher than in olmesartan group(1.90[0.80-4.30] vs0.80[0.45-1.40, P<0.05).
2.2 Clinic sitting blood pressure in both groups decreased significantly after treatments(p<0.01), but heart rate was no change after nisoldipine or olmesartan treatment.
2.3 At the end of the treatment, plasma ADMA and ET-1 levels were significantly decreased and FMD increased in patients receiving nisoldipine or olmesartan (P<0.05). Plasma NO and 8-iso-PGF2a were no change in both groups (P>0.05). There was a significant decrease of plasma hs-CRP only in patients receiving nisoldipine (P<0.05). In both groups, the BA dilator response to glyceryl trinitrate was similar at baseline and was not significantly increased after treatment(P>0.05).
Conclusions:
1. Endothelial dysfunction, oxidative stress, inflammatory effect and increasing circulating ADMA levels have become widely recognized in mild-to-moderate essential hypertensive patients.
2. Nisoldipine and olmesartan both can decrease plasma ADMA and ET-1 levels and improve FMD. Moreover, nisoldipine has significantly anti-inflammatory effect. NO and 8-isoPGF2a levels were no change from baseline to eight-week nisoldipine or olmesartan treatment.
3. The improvements of FMD in nisoldipine may be related to the reduction in ADMA, ET-1 and inflammation; olmesartan may improve FMD by decreasing the levels of ADMA and ET-1.
引文
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and secondary forms of human hypertension. Hypertension,1993,21:929-33.
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[8]ITO A, TSAO PS, ADIMOOLAM S, et al. Novel mechanism for endothelial dysfunction:dysregulation of dimethylarginine dimethylaminohydrolase. Circulation,1999,99(24):3092-3095.
[9]Boger RH, Bode-Boger, SM, et al. Asymmetric dimethylarginine(ADMA):A novel risk factor for endothelial dysfunction-its role in hypercholesterolemia. Criculation, 1998,98(18):1842-1847.
[10]Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases:the role of oxidant stress. Circ Res,2000,87:840-844.
[11]HIGASHI Y, NOMA K, YOSHIZUMI M, et al. Endothelial function and oxidative stress in cardiovascular disease[J]. Circ J,2009,73(3):411-418.
[12]MILNE GL, MUSIEK ES, MORROW JD. F2-isoprostanes as markers of oxidative stress in vivo:an overview[J]. Biomarkers,2005,10 (Suppl 1):10-23.
[13]Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation,2002,106:1439-1441.
[14]Pepine CJ,et al.Comparison of effects of nisoldipine-extended release and amlodipine in patients with systemic Hypertension and chronic stable angima pectoris.Am J Cardiol,2003,91:274-279.
[15]Reinhard Berkels, et al. Nisoldipine increases the bioavailability of endothelial NO. Naunyn-Schmiedeberg's Arch. Pharmacol,2001,364:110-116.
[16]Benndorf RA, et al. Mobilization of putative high-proliferative-potential endothelial colony-forming cells during antihypertensive treatment in patients with essential hypertension. Stem Cells Dev,2007,16:329-338.
[17]Lesley J. Scott, Paul 1. McCormack. Olmesartan medoxomil:a review of its use in the management of hypertension. Drugs,2008,68(9):1239-1272.
[18]Naya M, Tsukamoto T, Morita K, et al. Olmesartan, but not amlodipine, improves endothelium-dependent coronary dilation in hypertensive patients. J. Am. Coll. Cardiol.2007,50:1144-1149.
[19]丁明超,刑辉,杨娅丽.奥美沙坦对高血压患者颈动脉内膜中层厚度及血管内皮功能的影响.中国临床药理学杂志.2010,26(8)：573-576.
[20]David S, Kumpers P, Lukasz A. Circulating angiopoietin-2 in essential hypertension:relation to atherosclerosis, vascular inflammation, and treatment with olmesartan/pravastatin.
[1]GAO X, ALBERT H, YU H, et al. The Shanghai Changfeng Study:a community-based prospectivecohort study of chronic diseases among middle-aged and elderly:objectives and design. Eur J Epidemiol,2010,25(12):885-893.
[2]SCHULZE F, WESEMANN R, SCWEDHELM E, et al. Determination of asymmetric dimethylarginine (ADMA) sing a novel ELISA assay. Clin Chem Lab Med,2004,42(12):1377-1383.
[3]CELEMAJER DS, SORENSEN KE, GOO CU VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk o f atherosclerosis. Lancet, 1992,340(8828):1111-1115.
[4]CORRETTI MC, ANDERSON TJ, BENJAMIN EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery:a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol,2002,39(2):257-265.
[5]Furchgott RF, Zawadzki JV. The obligatory role of the endothelial cells in the relaxation of arteries smooth muscle by acethylcholine. Nature,1980, 288(5789):373-376.
[6]Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium dependent vascular relaxation in patients with essential hypertension. N Engl J Med,1990,323:22-27.
[7]Taddei S, Virdis A, Mattei P, et al. Defective L-arginine-nitric oxide pathway in offspring of essential hypertensive patients. Circulation,1996,94(6):1298-1303
[8]Virdis A, Ghiadoni L, Sudano I, et al. Endothelial function in hypertension:role of gender. J Hypertens,2002,20(suppl):S11-S16
[9]Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol,2003,42:1149-1160
[10]Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature,1980;288:373.
[11]Drexler H. Hypertension, heart failure, and endothelial function. Am J Cardiol; 1998,82(10A):20s-22s
[12]Ikeda U, Yamamoto K, Maeda Y, et al. Endothelin-1 inhibits nitric oxide synthesis in vascular smooth muscle cells. Hypertension,1997,29(lpt 1):65-69.
[13]Taddei S, Virdis A, Ghiadoni L, et al. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation, 1998,97(22):2222-2229.
[14]Vinoy S. Prasad, et al. Endothelin as a clinical target in the treatment of systemic hypertension. Cardiology in review,2009,17(4):181-191.
[15]Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature,1988,332(6163):411-415.
[16]Felix Bohm,John Pernow.The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovascular Research,2007,76:8-18.
[17]Farhad Amiri,etal. Vascular inflammation in absensce of blood pressure elevation in transgenic murine model overexpressing endothelin-1 in endothelial cells. Jounal of hypertension,2008,26:1102-1109.
[18]Dyah W.Anggrahini,etal.Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation.Cardiovascular Research,2009,82:143-151.
[19]Ohnishi M, Wada A, Tsutamoto T, et al. Endothelin stimulates an endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, in experimental heart failure. Clin. Sci,2002,103:241S-244S.
[20]JOANNIDES R, HAEFELI WE, LINDER L, et al. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation, 1995,91(5):1314-1319.
[21]Gokce N, Holbrook M, Duffy SJ, et al. Effects of race and hypertension on flow-mediated and nitroglycerin-mediated dilation of the brachial artery. Hypertension,2001,38(6):1349-1354.
[22]Kimura Y, Matsumoto M, Deng YB, et al. Impaired endothelial function in hypertensive elderly patients evaluated by high resolution ultrasonography. Canadian journal of cardiology,1999,15(5):563-568
[23]Pohl U, Holtz J, Busse R, Bassenge E. Crucial role of the endothelium in the vasodilator response to flow in vivo. Hypertension,1985,8:37-44
[24]Tagawa T, Imaizumi T, Endo T, et al. Role of nitric oxide in reactive hyperemia in human forearm vessels. Circulation,1994,90:2285-2290.
[25]Sun D, Huang A, Smith CJ, et al. Enhanced release of prostaglandins contributes to flow-induced arteriolar dilatation in eNOS knockout mice. Circ. Res,1999, 85:288-93.
[26]Zizek B, Poredos P. Insulin resistance adds to endothelial dysfunction in hypertensive patients and in normotensive offspring of subjects with essential hypertension. J Intern Med,2001,249(2):189-197.
[27]Ceriello A. Possible role of oxidative stress in the pathogenesis of hypertension. Diabetes Care,2008,31 (suppl 2):S181-S184
[28]Lassegue B, Griendling KK. Reactive oxygen species in hypertension; An update. Am J Hypertens,2004,17:852-860
[29]Pedro-Botet J, Covas MI, Martin S, Rubies-Prat J. Decreased endogenous antioxidant enzymatic status in essential hypertension. J Hum Hypertens,2000, 14:343-345
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[1]BENNDORF RA, APPEL D. Telmisartan improves endothelial function in patients with essential hypertension[J]. J Cardiovasc Pharmacol,2007, 50(4):367-371.
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[27]HIGASHI Y, NOMA K, YOSHIZUMI M, et al. Endothelial function and oxidative stress in cardiovascular disease[J]. Circ J,2009,73(3):411-418.
[28]Bragulat E, Larrousse M, Coca A, Delasierra A. Effect of long-term irbesartan treatment on endothelium-dependent vasodilation in essential hypertensive patients. British journal of biomedical science,2003,60:191-196.
[29]Hirofumi T, Jiko Y, Yutaka K, et al. Effect of telmisartan on forearm postischemic hyperemia and serum asymmetric dimethylarginine levels. Am. J. Hypertens,2007, 20:1305-1311.
[30]ANNA F P, ULISSE G, CHIARA S, et al. Nebivolol treatment reduces serum levels of asymmetric dimethylarginine and improves endothelial dysfunction in essential hypertensive patients. Am. J. Hypertens,2008,21:1251-1257.
[31]Farhad Amiri,etal. Vascular inflammation in absensce of blood pressure elevation in transgenic murine model overexpressing endothelin-1 in endothelial cells. Jounal of hypertension,2008,26:1102-1109.
[32]Ohnishi M, Wada A, Tsutamoto T, et al. Endothelin stimulates an endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, in experimental heart failure. Clin. Sci,2002,103:241S-244S.
[33]Bohm F, Ahlborg G, Pernow J. Endothelin-1 inhibits endotheliumdependent vasodilatation in the human forearm:reversal by ETA receptor blockade in patients with atherosclerosis. Clin Sci (Lond),2002,102:321-7.
[34]Bohm F, Settergren M, Pernow J. Vitamin C blocks vascular dysfunction and release of interleukin-6 induced by endothelin-1 in humans in vivo. Atherosclerosis, 2007,190:408-15.
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[2]Ganz P, Vita JA. Testing endothelial vasomotor function:nitric oxide, a multipotent molecule. Circulation,2003,108:2049-2053.
[3]Cardillo C, et al. Role of endothelin in the increased vascular tone of patients with
essential hypertension. Hypertension,1999,33 (2):753
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and secondary forms of human hypertension. Hypertension,1993,21:929-33.
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[8]ITO A, TSAO PS, ADIMOOLAM S, et al. Novel mechanism for endothelial dysfunction:dysregulation of dimethylarginine dimethylaminohydrolase. Circulation,1999,99(24):3092-3095.
[9]Boger RH, Bode-Boger, SM, et al. Asymmetric dimethylarginine(ADMA):A novel risk factor for endothelial dysfunction-its role in hypercholesterolemia. Criculation, 1998,98(18):1842-1847.
[10]Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases:the role of oxidant stress. Circ Res,2000,87:840-844.
[11]HIGASHI Y, NOMA K, YOSHIZUMI M, et al. Endothelial function and oxidative stress in cardiovascular disease[J]. Circ J,2009,73(3):411-418.
[12]MILNE GL, MUSIEK ES, MORROW JD. F2-isoprostanes as markers of oxidative stress in vivo:an overview[J]. Biomarkers,2005,10 (Suppl 1):10-23.
[13]Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation,2002,106:1439-1441.
[14]Pepine CJ,et al.Comparison of effects of nisoldipine-extended release and amlodipine in patients with systemic Hypertension and chronic stable angima pectoris.Am J Cardiol,2003,91:274-279.
[15]Reinhard Berkels, et al. Nisoldipine increases the bioavailability of endothelial NO. Naunyn-Schmiedeberg's Arch. Pharmacol,2001,364:110-116.
[16]Benndorf RA, et al. Mobilization of putative high-proliferative-potential endothelial colony-forming cells during antihypertensive treatment in patients with essential hypertension. Stem Cells Dev,2007,16:329-338.
[17]Lesley J. Scott, Paul 1. McCormack. Olmesartan medoxomil:a review of its use in the management of hypertension. Drugs,2008,68(9):1239-1272.
[18]Naya M, Tsukamoto T, Morita K, et al. Olmesartan, but not amlodipine, improves endothelium-dependent coronary dilation in hypertensive patients. J. Am. Coll. Cardiol.2007,50:1144-1149.
[19]丁明超,刑辉,杨娅丽.奥美沙坦对高血压患者颈动脉内膜中层厚度及血管内皮功能的影响.中国临床药理学杂志.2010,26(8)：573-576.
[20]David S, Kumpers P, Lukasz A. Circulating angiopoietin-2 in essential hypertension:relation to atherosclerosis, vascular inflammation, and treatment with olmesartan/pravastatin.
[1]GAO X, ALBERT H, YU H, et al. The Shanghai Changfeng Study:a community-based prospectivecohort study of chronic diseases among middle-aged and elderly:objectives and design. Eur J Epidemiol,2010,25(12):885-893.
[2]SCHULZE F, WESEMANN R, SCWEDHELM E, et al. Determination of asymmetric dimethylarginine (ADMA) sing a novel ELISA assay. Clin Chem Lab Med,2004,42(12):1377-1383.
[3]CELEMAJER DS, SORENSEN KE, GOO CU VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk o f atherosclerosis. Lancet, 1992,340(8828):1111-1115.
[4]CORRETTI MC, ANDERSON TJ, BENJAMIN EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery:a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol,2002,39(2):257-265.
[5]Furchgott RF, Zawadzki JV. The obligatory role of the endothelial cells in the relaxation of arteries smooth muscle by acethylcholine. Nature,1980, 288(5789):373-376.
[6]Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium dependent vascular relaxation in patients with essential hypertension. N Engl J Med,1990,323:22-27.
[7]Taddei S, Virdis A, Mattei P, et al. Defective L-arginine-nitric oxide pathway in offspring of essential hypertensive patients. Circulation,1996,94(6):1298-1303
[8]Virdis A, Ghiadoni L, Sudano I, et al. Endothelial function in hypertension:role of gender. J Hypertens,2002,20(suppl):S11-S16
[9]Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol,2003,42:1149-1160
[10]Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature,1980;288:373.
[11]Drexler H. Hypertension, heart failure, and endothelial function. Am J Cardiol; 1998,82(10A):20s-22s
[12]Ikeda U, Yamamoto K, Maeda Y, et al. Endothelin-1 inhibits nitric oxide synthesis in vascular smooth muscle cells. Hypertension,1997,29(lpt 1):65-69.
[13]Taddei S, Virdis A, Ghiadoni L, et al. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation, 1998,97(22):2222-2229.
[14]Vinoy S. Prasad, et al. Endothelin as a clinical target in the treatment of systemic hypertension. Cardiology in review,2009,17(4):181-191.
[15]Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature,1988,332(6163):411-415.
[16]Felix Bohm,John Pernow.The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovascular Research,2007,76:8-18.
[17]Farhad Amiri,etal. Vascular inflammation in absensce of blood pressure elevation in transgenic murine model overexpressing endothelin-1 in endothelial cells. Jounal of hypertension,2008,26:1102-1109.
[18]Dyah W.Anggrahini,etal.Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation.Cardiovascular Research,2009,82:143-151.
[19]Ohnishi M, Wada A, Tsutamoto T, et al. Endothelin stimulates an endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, in experimental heart failure. Clin. Sci,2002,103:241S-244S.
[20]JOANNIDES R, HAEFELI WE, LINDER L, et al. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation, 1995,91(5):1314-1319.
[21]Gokce N, Holbrook M, Duffy SJ, et al. Effects of race and hypertension on flow-mediated and nitroglycerin-mediated dilation of the brachial artery. Hypertension,2001,38(6):1349-1354.
[22]Kimura Y, Matsumoto M, Deng YB, et al. Impaired endothelial function in hypertensive elderly patients evaluated by high resolution ultrasonography. Canadian journal of cardiology,1999,15(5):563-568
[23]Pohl U, Holtz J, Busse R, Bassenge E. Crucial role of the endothelium in the vasodilator response to flow in vivo. Hypertension,1985,8:37-44
[24]Tagawa T, Imaizumi T, Endo T, et al. Role of nitric oxide in reactive hyperemia in human forearm vessels. Circulation,1994,90:2285-2290.
[25]Sun D, Huang A, Smith CJ, et al. Enhanced release of prostaglandins contributes to flow-induced arteriolar dilatation in eNOS knockout mice. Circ. Res,1999, 85:288-93.
[26]Zizek B, Poredos P. Insulin resistance adds to endothelial dysfunction in hypertensive patients and in normotensive offspring of subjects with essential hypertension. J Intern Med,2001,249(2):189-197.
[27]Ceriello A. Possible role of oxidative stress in the pathogenesis of hypertension. Diabetes Care,2008,31 (suppl 2):S181-S184
[28]Lassegue B, Griendling KK. Reactive oxygen species in hypertension; An update. Am J Hypertens,2004,17:852-860
[29]Pedro-Botet J, Covas MI, Martin S, Rubies-Prat J. Decreased endogenous antioxidant enzymatic status in essential hypertension. J Hum Hypertens,2000, 14:343-345
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