国产卡维地洛的降压疗效及对高血压病患者血浆NO、ET的影响
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摘要
前言
高血压病是现代社会的多发病，常见病，是导致心、脑血管等疾病的重要危险因素。高血压病的发病机理复杂，其中包括遗传因素、交感神经活性增强、肾素血管紧张素活性异常，以及血管内皮功能失调等，尚有许多因素未完全清楚。纠正血管内皮细胞功能失调是研制抗高血压药物的新思路和有发展前途方向的。卡维地洛是一种非选择性β受体阻断剂，可完全性阻断α_1、β_1和β_2受体而无内源性拟交感活性，大剂量时兼有钙拮抗作用。其扩张血管作用主要通过阻断α_1受体而产生。卡维地洛具有很强的抗氧自由基、抑制脂质过氧化、抑制氧自由基相关的损伤，并可抑制血管平滑肌的细胞增殖、改善胰岛素抵抗、降低肾灌注压而不影响肾血流，改善肾功能。本实验旨在探讨国产卡维地洛的降压疗效及其对高血压患者血浆NO、ET的影响。
实验方法
入选80例高血压患者按随机配对原则分入卡维地洛组(a组)及阳性对照组络德(b组)，以10mg日一次口服为起始剂量，每周随访一次血压、心率，如血压未降至正常，降压药可逐渐加量，总疗程8周，第八周随访两次。其中40例病人在用药前及总疗程结束后采取晨空腹肘正中静脉血，采用亚硝酸还原法测定血浆一氧化氮，采用放射免疫技术测定血浆内皮素，10例正常健康组对照组测定血浆一氧化氮及内皮素。
计数资料采用X~2检验，血压、心率、血浆NO、ET等计量资料以±s表示，比较采用t检验。
实验结果
两种国产卡维地洛均具有理想的降压疗效，卡维地洛组血压
由 165．28。11．69／98．90。9．95nunHg下降为 142．98。15．87／
85．41。8．22 nunHg，总有效率为 85％，络德组血压由 166．54 t
13．24／97．56。11．41 nunHg下降为140．77ti2．98／sl．23。8．58
mxnHg，总有效率为84．6％，两药降压疗效无差异；两组高血压患
者用药前后心率均下降，卡维地洛组由76．50 S 8．21 w分下降
为66．03。5．27 w分（P＜o．01），络德组由76．＊6。8．协议分下
降为67．24。6．64 a分（P＜o．01），两组患者心率下降无差异瞩
＞0．05人两组高血压患者的血浆一氧化氮分别为61．25 12．ZI
umol／L和 63．38。15．32umol／L，均低于正常对照组 86＊互 t20．且二
umo＊L（P＜o．05L两组药物均可升高一氧化氮，卡维地洛组上升
至76．呼上万．31 urno＊L（P＜0．oj），络德组上升至四．21 14．56
＜＜O＊L（P＜0．05）。两组患者血浆内皮素分别为二10．27。23．17
P矿M和 114．38。31．22P吵M均高于正常对照组 55．47。11．10
Pg／Inl汀＜0刀厂，两组药物均可降低血浆内皮素水平，卡维地洛
下降至论．＊。15．15p少血（P＜O．05），络德组下降至74．71。
23．39pg／Inl瞩＜0．05人两组药物的不良反应较轻，仅有一例患者
因球结膜充血退出试验，其余轻微头痛、干咳，均可耐受。
讨 论
高血压病是现代社会的常见病与多发病，是引起心脑血管疾
病的重要危险因素。对血压的有效控制，可明显降低心、脑血管病
事件的发生。本研究结果显示两种国产卡维地洛均具有较好的降
压效果，卡维地洛组与络德组的总有效率分别为85．0％和84．
·2·
6％，两组差异无统计学意义，提示卡维地洛和络德均具有良好的
降压作用，与国内文献报道相符。卡维地洛是一种非选择性兼具
血管扩张作用的p受体阻滞剂，它可完全性阻滞p；丹。及a；受
体，a；中阻滞作用一动10，无内源性拟交感活性。其降压作用是
通过直接扩张周围血管及间接抑制肾素一血管紧张素一醛固酮系
统而产生的，而无反射性心动过速，考虑与其p肾上腺素受体阻
滞作用有关。尽管其有钙桔抗作用，但钙桔抗作用要求的浓度至
少30倍于其a；一肾上腺素受体桔抗作用所需要的浓度。常规浓
度下，卡维地洛的钙离子桔抗作用并不起扩血管降压作用。两种
国产卡维地洛均降低心率，且降心率作用无显著差异。本研究中
不良反应较低，主要为头晕、头痛，症状轻，无需停药。仅一例有球
结膜充血，停药后好转。
目前研究证实，高血压的发生、发展与内皮细胞功能和结构上
的变化相关，而高血压状态又可能进一步加重血管内皮细胞及血
管平滑肌细胞功能和结构的损伤。其中血浆ET扑O是血管内皮
细胞合成的一对具有持抗效应的血管活性物质，在血管平滑肌功
能及血管张力的调节中具有重要作用。NO为内皮细胞受刺激而
由L一精氨酸产生的原子团，为内皮源性血管舒张因子；ET是一
种由ZI个氨基酸组成的血管活性多肽，是目前所知作用最强的长
效血管收缩剂，为内皮源性收缩因子，二者是重要的内皮功能调解
因子0O可直接使血管平滑肌舒张在T可使血管平滑肌收缩。在
高血压病人，血浆NO水平下降，血浆ET水平升高，说明血管内皮
功能受损。
本实验
Essential hypertension is very common in modern society and is one of the dangerous factors of causing cardiocerebrovascullar disease. The aetiology of hypertension is very complex, including heteridity, the increase of sympathetic nervous system tone, the abnomality of HAS and the vascular endothelial dysfunction. There are a lot of fac-tors which are unclear. Correcting vascular endothelial dysfunction is a new idea and a promising direction in studing antihypertension drug. Carvedilol is a nonselective (β - adrenoreceptor blocker, it can block αt - adrenoreceptor, βl - adrenoreceptor and β2 ~ adrenoreceptor completely. It has no the intrinsic sympathomimetic activity and it has Ca2+ -channel blockade activity at high dose. Its vasodilation effect mainly through α - adrenoreceptor blockade. Carvedilol has strong function of anti ?oxygen free radicals. It inhibits Liposuperoxidation, the injury of oxygen free radicals and the growth of vascular smooth muscle cell. It improves insulin resistance, decreases renal pressure without affecting renal blood flow. The aim of this experiment is to discuss the antihypertensive effect and the effect on the hypertension patients'plasma endothelium and nitric oxide of Carvedilol.
Methods
80 essential hypertension patients were double blind randomized assigned to two group - Carvedilol group ( a group) and Luode group ( b group). The original dose is 10 mg once a day. In a double blind control trial for eight weeks, the blood pressure and heart rate were re-cord once a week. The dose of Carvedilol was increased gradully when the blood pressure was not controlled to normal. We follow - up twice in the 8 th week. The venous blood were detected in 40 patients in the morning before and after the treatment. Plasma nitric oxide were de-tected by colorimeteric method, and plasma ET were detected by the radio - immunoassay(RIA) method. Plasma NO and ET were detec-ted in 10 normal control subjects.
For categorical data, x2 test is used. For count data, such as blood pressure, heart rate, plasma NO and ET were analysized by t lest.
Results
Carvedilol had ideal antihypertensive effect (165. 28 ?1. 69/ 98.90 ?9. 95mmHg vs 142. 98 ?15. 87/85. 41 ?8. 22 mmHg in a group, P <0.01; 166.54 ?13.24/97.56 ?11.41 mmHg vs 140.77 ?12. 98/81.23 ?.58 mmHg, P <0. 01) ,total effective rate was 85% in a group and 84. 6% in b group respectively. Heart rate declined significantly (76.50 ?. 21bpm vs 66.03 ?. 27 bpm in a group, P <0.01;76.46?.04 bpm vs67.24?.64 bpm, P<0.01). Before treatment plasma nitric oxide in essential hypertension patients is lower
than in normal control (61. 25 ?12. 21 umol/L vs 86. 21 ?20. 12 umol/L, P <0.05; 63. 38 ?15. 32 umol/L vs 86. 21 ?0.12 umol/ L;P<0. 05). After treatment, plasma nitric oxide increased signifi-cantly (76. 48 ?15.31 umol/L in a group, P <0. 05; 79. 21 ?14. 56 umol/L in b group, P<0.05). Before treatment plasma endothelium was higher in hypertension patients than in normal control (110.27 ?23. 17 pg/ml vs 54. 47 ?11. 10 in a group, P < 0. 01; 114. 38 ?31. 22pg/ml vs 54. 47 ?11. 10 in b group, P <0. 01). It decreases significantly after treatment (78. 49 ?15. 15 pg/ml in a group, P < 0.05; 74.71 ?3.39 pg/ml in b group, P <0.05) . Side effects in Cervedilol such as headache, dizziness, cough were slight, except that one patient discontinued the experiment because of eyeball con-junctiva congestion.
Discussion
Hypertension is very common in modem, society. It is one of the important and dangerous factors of causing cardiocerebrovascular dis-ease. Effectively controlling blood pressure can obviously decrease cardio - cerebral accidence. The result of the study indicate that the two native Carvedilol both have ideal antihypertensive effect. Total ef-fective rate of carvedilol and Luode group are 85.0% and 84. 6% re-spectively. The difference of the two groups has no statistic signifi-cance. These indicate that Carvedilol and Luode have ideal antihyper-tension effect. Carvedilol is a kind of nonselective (3 -
高血压病是现代社会的多发病，常见病，是导致心、脑血管等疾病的重要危险因素。高血压病的发病机理复杂，其中包括遗传因素、交感神经活性增强、肾素血管紧张素活性异常，以及血管内皮功能失调等，尚有许多因素未完全清楚。纠正血管内皮细胞功能失调是研制抗高血压药物的新思路和有发展前途方向的。卡维地洛是一种非选择性β受体阻断剂，可完全性阻断α_1、β_1和β_2受体而无内源性拟交感活性，大剂量时兼有钙拮抗作用。其扩张血管作用主要通过阻断α_1受体而产生。卡维地洛具有很强的抗氧自由基、抑制脂质过氧化、抑制氧自由基相关的损伤，并可抑制血管平滑肌的细胞增殖、改善胰岛素抵抗、降低肾灌注压而不影响肾血流，改善肾功能。本实验旨在探讨国产卡维地洛的降压疗效及其对高血压患者血浆NO、ET的影响。
实验方法
入选80例高血压患者按随机配对原则分入卡维地洛组(a组)及阳性对照组络德(b组)，以10mg日一次口服为起始剂量，每周随访一次血压、心率，如血压未降至正常，降压药可逐渐加量，总疗程8周，第八周随访两次。其中40例病人在用药前及总疗程结束后采取晨空腹肘正中静脉血，采用亚硝酸还原法测定血浆一氧化氮，采用放射免疫技术测定血浆内皮素，10例正常健康组对照组测定血浆一氧化氮及内皮素。
计数资料采用X~2检验，血压、心率、血浆NO、ET等计量资料以±s表示，比较采用t检验。
实验结果
两种国产卡维地洛均具有理想的降压疗效，卡维地洛组血压
由 165．28。11．69／98．90。9．95nunHg下降为 142．98。15．87／
85．41。8．22 nunHg，总有效率为 85％，络德组血压由 166．54 t
13．24／97．56。11．41 nunHg下降为140．77ti2．98／sl．23。8．58
mxnHg，总有效率为84．6％，两药降压疗效无差异；两组高血压患
者用药前后心率均下降，卡维地洛组由76．50 S 8．21 w分下降
为66．03。5．27 w分（P＜o．01），络德组由76．＊6。8．协议分下
降为67．24。6．64 a分（P＜o．01），两组患者心率下降无差异瞩
＞0．05人两组高血压患者的血浆一氧化氮分别为61．25 12．ZI
umol／L和 63．38。15．32umol／L，均低于正常对照组 86＊互 t20．且二
umo＊L（P＜o．05L两组药物均可升高一氧化氮，卡维地洛组上升
至76．呼上万．31 urno＊L（P＜0．oj），络德组上升至四．21 14．56
＜＜O＊L（P＜0．05）。两组患者血浆内皮素分别为二10．27。23．17
P矿M和 114．38。31．22P吵M均高于正常对照组 55．47。11．10
Pg／Inl汀＜0刀厂，两组药物均可降低血浆内皮素水平，卡维地洛
下降至论．＊。15．15p少血（P＜O．05），络德组下降至74．71。
23．39pg／Inl瞩＜0．05人两组药物的不良反应较轻，仅有一例患者
因球结膜充血退出试验，其余轻微头痛、干咳，均可耐受。
讨 论
高血压病是现代社会的常见病与多发病，是引起心脑血管疾
病的重要危险因素。对血压的有效控制，可明显降低心、脑血管病
事件的发生。本研究结果显示两种国产卡维地洛均具有较好的降
压效果，卡维地洛组与络德组的总有效率分别为85．0％和84．
·2·
6％，两组差异无统计学意义，提示卡维地洛和络德均具有良好的
降压作用，与国内文献报道相符。卡维地洛是一种非选择性兼具
血管扩张作用的p受体阻滞剂，它可完全性阻滞p；丹。及a；受
体，a；中阻滞作用一动10，无内源性拟交感活性。其降压作用是
通过直接扩张周围血管及间接抑制肾素一血管紧张素一醛固酮系
统而产生的，而无反射性心动过速，考虑与其p肾上腺素受体阻
滞作用有关。尽管其有钙桔抗作用，但钙桔抗作用要求的浓度至
少30倍于其a；一肾上腺素受体桔抗作用所需要的浓度。常规浓
度下，卡维地洛的钙离子桔抗作用并不起扩血管降压作用。两种
国产卡维地洛均降低心率，且降心率作用无显著差异。本研究中
不良反应较低，主要为头晕、头痛，症状轻，无需停药。仅一例有球
结膜充血，停药后好转。
目前研究证实，高血压的发生、发展与内皮细胞功能和结构上
的变化相关，而高血压状态又可能进一步加重血管内皮细胞及血
管平滑肌细胞功能和结构的损伤。其中血浆ET扑O是血管内皮
细胞合成的一对具有持抗效应的血管活性物质，在血管平滑肌功
能及血管张力的调节中具有重要作用。NO为内皮细胞受刺激而
由L一精氨酸产生的原子团，为内皮源性血管舒张因子；ET是一
种由ZI个氨基酸组成的血管活性多肽，是目前所知作用最强的长
效血管收缩剂，为内皮源性收缩因子，二者是重要的内皮功能调解
因子0O可直接使血管平滑肌舒张在T可使血管平滑肌收缩。在
高血压病人，血浆NO水平下降，血浆ET水平升高，说明血管内皮
功能受损。
本实验
Essential hypertension is very common in modern society and is one of the dangerous factors of causing cardiocerebrovascullar disease. The aetiology of hypertension is very complex, including heteridity, the increase of sympathetic nervous system tone, the abnomality of HAS and the vascular endothelial dysfunction. There are a lot of fac-tors which are unclear. Correcting vascular endothelial dysfunction is a new idea and a promising direction in studing antihypertension drug. Carvedilol is a nonselective (β - adrenoreceptor blocker, it can block αt - adrenoreceptor, βl - adrenoreceptor and β2 ~ adrenoreceptor completely. It has no the intrinsic sympathomimetic activity and it has Ca2+ -channel blockade activity at high dose. Its vasodilation effect mainly through α - adrenoreceptor blockade. Carvedilol has strong function of anti ?oxygen free radicals. It inhibits Liposuperoxidation, the injury of oxygen free radicals and the growth of vascular smooth muscle cell. It improves insulin resistance, decreases renal pressure without affecting renal blood flow. The aim of this experiment is to discuss the antihypertensive effect and the effect on the hypertension patients'plasma endothelium and nitric oxide of Carvedilol.
Methods
80 essential hypertension patients were double blind randomized assigned to two group - Carvedilol group ( a group) and Luode group ( b group). The original dose is 10 mg once a day. In a double blind control trial for eight weeks, the blood pressure and heart rate were re-cord once a week. The dose of Carvedilol was increased gradully when the blood pressure was not controlled to normal. We follow - up twice in the 8 th week. The venous blood were detected in 40 patients in the morning before and after the treatment. Plasma nitric oxide were de-tected by colorimeteric method, and plasma ET were detected by the radio - immunoassay(RIA) method. Plasma NO and ET were detec-ted in 10 normal control subjects.
For categorical data, x2 test is used. For count data, such as blood pressure, heart rate, plasma NO and ET were analysized by t lest.
Results
Carvedilol had ideal antihypertensive effect (165. 28 ?1. 69/ 98.90 ?9. 95mmHg vs 142. 98 ?15. 87/85. 41 ?8. 22 mmHg in a group, P <0.01; 166.54 ?13.24/97.56 ?11.41 mmHg vs 140.77 ?12. 98/81.23 ?.58 mmHg, P <0. 01) ,total effective rate was 85% in a group and 84. 6% in b group respectively. Heart rate declined significantly (76.50 ?. 21bpm vs 66.03 ?. 27 bpm in a group, P <0.01;76.46?.04 bpm vs67.24?.64 bpm, P<0.01). Before treatment plasma nitric oxide in essential hypertension patients is lower
than in normal control (61. 25 ?12. 21 umol/L vs 86. 21 ?20. 12 umol/L, P <0.05; 63. 38 ?15. 32 umol/L vs 86. 21 ?0.12 umol/ L;P<0. 05). After treatment, plasma nitric oxide increased signifi-cantly (76. 48 ?15.31 umol/L in a group, P <0. 05; 79. 21 ?14. 56 umol/L in b group, P<0.05). Before treatment plasma endothelium was higher in hypertension patients than in normal control (110.27 ?23. 17 pg/ml vs 54. 47 ?11. 10 in a group, P < 0. 01; 114. 38 ?31. 22pg/ml vs 54. 47 ?11. 10 in b group, P <0. 01). It decreases significantly after treatment (78. 49 ?15. 15 pg/ml in a group, P < 0.05; 74.71 ?3.39 pg/ml in b group, P <0.05) . Side effects in Cervedilol such as headache, dizziness, cough were slight, except that one patient discontinued the experiment because of eyeball con-junctiva congestion.
Discussion
Hypertension is very common in modem, society. It is one of the important and dangerous factors of causing cardiocerebrovascular dis-ease. Effectively controlling blood pressure can obviously decrease cardio - cerebral accidence. The result of the study indicate that the two native Carvedilol both have ideal antihypertensive effect. Total ef-fective rate of carvedilol and Luode group are 85.0% and 84. 6% re-spectively. The difference of the two groups has no statistic signifi-cance. These indicate that Carvedilol and Luode have ideal antihyper-tension effect. Carvedilol is a kind of nonselective (3 -
引文
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9 Anderson T J, Meredith IT, Charbonneau F, etal, Endotheliumdependent coronary vasomotion relates to the susceptibility of oxidation in humans. Circulation, 1996,93(9):1647～1650
10 Boulanger CM, Desta B, Clozel JP, et al. Chronic treatment with the Ca~(2+) channel inhibitor RO40-5967 potentiates the endothelium-dependent relaxationsin the aorta of the hypertensive salt sensitive Dahl rat. Blood Press, 1994,3(3):193～196
11 Kohuo H, Yasunar K, Mawyakawa K et al. plasma immunoreactive endothelin in essential hypertension. AmJMed, 1990; 88: 614
12 Hehuamei, Vascular endothelial dysfunction and Hypertension, Foreign Medical Sciences section on pharmacy 1999Apri; 26(2) 79～84
13 Ynagiswa M, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature,1998;322:411
14 Shaipe N, Doujhty R. Epidemiolujy of heart failure and ventricular dysfunction Lancet, 1998,352(suppl):3～7
15 Cowie Mr, Mosterd A, Wood DAet al. The epidemiology of heart failure. EurHeartJ, 1997,18:208～225
16 Ho KKL,Anderson KM, Kannel WB, et al. Survival after onset of congestive heart failure in Framingham Heart Study subjects. Circulation, 1993,88:107～105
17 Frishman WH. Drugtherapy-Carvedilol. Drugtheraty, 1998,339:1759
18 Ruffolo RR Jr, Feuerstein GZ, Ohlstein EH. Recent observations with β-adrenoceptorblockade-Beneficial effects in hypertension and heart failure. Am J Hypertens, 1998,11:9s-14s.
19 Krum H, Sackner-Bernstein JD, Goldsmith R, etal. Doubleblind, placebo-controlled study of the longterm efficacy of carvedilol in severe chronic heart failure. Circulation, 1995,92: 1499-1506
20 Shcphcrd JT, Zvonimirs. Endothelium derived vasoactivate factor endothelium dependent relaxation. Hypertension, 1991, 181 Suppl 37:36
21 Lgnarro LJ, Buja GM, Wood KS, et al. Endothelium derived relaxing factor produced and released from artery and veins nitric oxide. Proc Natl Acad Sci USA, 1997,84:9265-9269
22 Palmer RMJ, Ferviage AG, Moncada S. Nitric Oxide release accounts for the biological activity of endothelium derived relaxing. Nature, 1987,327:524-526
23 Tamirisa P, Frishman WH, Kumar A. Endothelin and endothelin antagonism. Role in cardiovascular health and disease[J]. Am Heart J,1995,130(3pt1):601
24 汤健，唐朝枢，杨军，等．内皮素[M]．北京：中国医科大学中国协和医科大学联合出版社，1993：246
25 吾柏铭，迟东升，洪小苏，等．高血压病患者血浆内皮素变化与硝苯地平缓释剂对其影响[J]．中华内科杂志，1998，38(8)：531
26 陈伯钧、陈晓伟等，络德与美托洛尔治疗原发性高血压的疗效比较．临床心血管病杂志，2001；17(9)：17-19
27 何苗地，络德治疗轻中度高血压的临床疗效观察，临床心血管病杂志，2001；17(9)：39-40．
28 吕艳青，周际安，曾繁典．卡维地洛的药理及临床研究进展．中国新药与临床杂志，1997，18(4)：236-238
2 De Meyer G R, Herman A G. Vascular endothelial dysfunction. Prog Cardiovasc Dis, 1997,39 (4):325～342
3 Ferro C J, Webb D J. Endothelial dysfunction and hypertension. Drugs,1997,53 (Suppll):30～41
4 Schiffrin EL, Deng LY, Sventek P, et al. Expression of endothelin-1 gene in small arteries in human essential hypertension. J Hypertens, 1996,14 (Suppll):s290
5 Tschudi M R, MesarosS, Luseher T F, et al. Direct in situ measurement of nitric oxide in mesenteric resistance arteries. Increased decomposion by superoxide in hypertension. Hypertension, 1996,27(1):32～35
6 Van de Voorde J, Leusen I. Endothelium dependent and independent relaxation of aortic rings from hypertensive rats. Am J Physiol,1996,270(19):H711～H717
7 Schiffrin EL, Intengan H D, Thibault G, et al. Clinical significance of endothelin in cardiovascular disease. Curr Op in Cardiol, 1997,12(4):354-367
8 Campese VM, Amarm, Anjalic, etal. Effect of L-arginine on systemic and renal haemodynamics in salt-sensitive with essential hypertension J H um Hypertens, 1997, 11(8):527～532
9 Anderson T J, Meredith IT, Charbonneau F, etal, Endotheliumdependent coronary vasomotion relates to the susceptibility of oxidation in humans. Circulation, 1996,93(9):1647～1650
10 Boulanger CM, Desta B, Clozel JP, et al. Chronic treatment with the Ca~(2+) channel inhibitor RO40-5967 potentiates the endothelium-dependent relaxationsin the aorta of the hypertensive salt sensitive Dahl rat. Blood Press, 1994,3(3):193～196
11 Kohuo H, Yasunar K, Mawyakawa K et al. plasma immunoreactive endothelin in essential hypertension. AmJMed, 1990; 88: 614
12 Hehuamei, Vascular endothelial dysfunction and Hypertension, Foreign Medical Sciences section on pharmacy 1999Apri; 26(2) 79～84
13 Ynagiswa M, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature,1998;322:411
14 Shaipe N, Doujhty R. Epidemiolujy of heart failure and ventricular dysfunction Lancet, 1998,352(suppl):3～7
15 Cowie Mr, Mosterd A, Wood DAet al. The epidemiology of heart failure. EurHeartJ, 1997,18:208～225
16 Ho KKL,Anderson KM, Kannel WB, et al. Survival after onset of congestive heart failure in Framingham Heart Study subjects. Circulation, 1993,88:107～105
17 Frishman WH. Drugtherapy-Carvedilol. Drugtheraty, 1998,339:1759
18 Ruffolo RR Jr, Feuerstein GZ, Ohlstein EH. Recent observations with β-adrenoceptorblockade-Beneficial effects in hypertension and heart failure. Am J Hypertens, 1998,11:9s-14s.
19 Krum H, Sackner-Bernstein JD, Goldsmith R, etal. Doubleblind, placebo-controlled study of the longterm efficacy of carvedilol in severe chronic heart failure. Circulation, 1995,92: 1499-1506
20 Shcphcrd JT, Zvonimirs. Endothelium derived vasoactivate factor endothelium dependent relaxation. Hypertension, 1991, 181 Suppl 37:36
21 Lgnarro LJ, Buja GM, Wood KS, et al. Endothelium derived relaxing factor produced and released from artery and veins nitric oxide. Proc Natl Acad Sci USA, 1997,84:9265-9269
22 Palmer RMJ, Ferviage AG, Moncada S. Nitric Oxide release accounts for the biological activity of endothelium derived relaxing. Nature, 1987,327:524-526
23 Tamirisa P, Frishman WH, Kumar A. Endothelin and endothelin antagonism. Role in cardiovascular health and disease[J]. Am Heart J,1995,130(3pt1):601
24 汤健，唐朝枢，杨军，等．内皮素[M]．北京：中国医科大学中国协和医科大学联合出版社，1993：246
25 吾柏铭，迟东升，洪小苏，等．高血压病患者血浆内皮素变化与硝苯地平缓释剂对其影响[J]．中华内科杂志，1998，38(8)：531
26 陈伯钧、陈晓伟等，络德与美托洛尔治疗原发性高血压的疗效比较．临床心血管病杂志，2001；17(9)：17-19
27 何苗地，络德治疗轻中度高血压的临床疗效观察，临床心血管病杂志，2001；17(9)：39-40．
28 吕艳青，周际安，曾繁典．卡维地洛的药理及临床研究进展．中国新药与临床杂志，1997，18(4)：236-238