内皮型一氧化氮合酶基因多态性与原发性高血压发病相关性的研究
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摘要
原发性高血压是在我国发病率很高的一种慢性心血管疾病，其病因和发病机制尚不清楚，目前认为高血压是遗传及环境等多种因素共同相互作用的结果。高血压的治疗在我国也存在很多问题，如知晓率、治疗率、控制率低，治疗依从性差，致残及致死率高等等。用于血压控制的五大类一线降压药已被明确写入高血压的诊治指南，但在中国由于受传统观念的影响，有更多的高血压患者会选择中药来控制血压。
用于治疗高血压的中成药制剂也有很多种，虽然种类繁杂，但这些中成药中很多药的主要成分都含有杜仲，以杜仲为主要成分的杜仲平压片作为中成药制剂用于控制血压被很多高血压患者选择和接受，也是目前很经典的一种降压治疗的中成药。基于此，本研究设计了动物实验，研究了经分离提纯的杜仲对SHR血一氧化氮（NO）和内皮素（ET）的影响及其降压效果，并与卡托普利进行了对比。
在动物实验发现杜仲通过对NO及ET的影响发挥其降压作用。但是即使较高剂量的杜仲对大鼠血NO、ET的影响及降压作用也不如卡托普利，由此我们想到，对于原发性高血压患者而言，此结果是否依然存在，因而接下做了本研究的第二部分的临床实验。对比了以杜仲为主要成分的杜仲平压片及同是ACEI类的洛汀新对高血压患者的血NO、ET的影响及降压效果。
NO、ET是与原发性高血压发病相关的一对作用相互拮抗和制约的血管内皮因子，本研究通过临床实验发现如上这两种因子不只与高血压的发病相关，还与高血压的程度及血压的正常节律消失有关，杜仲平压片对高血压患者的血NO、ET的影响及降压作用是不如洛汀新明显的。
由于NO及ET与高血压具有的高度相关性，因此与二者代谢有关的基因必将成为高血压发病相关的重要的候选基因，针对这些基因的研究有望在基因水平对原发性高血压病因加以阐述，并为原发性高血压在基因水平的预防、诊断、治疗提供证据。因此接下来又作了与NO合代谢相关的内皮型一氧化氮合酶基因方面的研究。
本论文主要分为三大部分：
第一部分：杜仲叶树脂提纯工艺优化及其降压作用机制的研究
采用正交实验方法测定不同类型大孔吸附树脂对杜仲叶的纯化效果，通过SHR大鼠测定杜仲叶降压水平来研究杜仲叶树脂提纯工艺优化及其降压作用。经研究发现杜仲叶树脂提取纯化最优工艺为上样药液浓度6mg/ml，选用20%乙醇为洗脱剂，流速控制为3.0柱体积每小时，吸附柱径高比为1：6。杜仲叶提取物能降低SHR大鼠血压，降压相对平稳，且对心率没有明显影响，其降压作用低于卡托普利。同时发现杜仲叶提取物降压作用有可能是通过增加血清一氧化氮（NO）量、降低内皮素（ET）量来得以实现的。
第二部分：原发性高血压患者血清一氧化氮及血浆内皮素水平的研究
应用病例对照研究方法来探讨原发性高血压患者血NO及ET水平的变化，研究此变化与高血压轻重程度、血压节律异常的相关性。对比用药前后24h收缩压(SBP)、舒张压(DBP)平均值及NO、ET及二者比值的改善情况及中成药杜仲平压片与西药洛汀新如上诸值的改善情况，用以指导高血压的治疗。其中高血压病组232例，对照组130例。原发性高血压各组分组依据血压水平、影响预后的因素及靶器官受累程度分为低危、中危、高危组各89、78、65例。将高血压病组按随机分组原则分为中药组与西药组分别为74、69例。以上所有受试者进行血压测定、NO与ET检测、动态血压分析。经数据分析及统计学处理得出以下结果：1、高血压病组与正常对照组比较NO降低而ET升高；2、随原发性高血压的危险度增加NO降低及ET升高以及二者比值下降的幅度有加大趋势；3、随原发性高血压患者正常血压节律性的丧失NO降低及ET升高以及二者比值下降的幅度有加大趋势；4、应用洛汀新治疗后患者的24h收缩压(SBP)、舒张压(DBP)平均值有所下降，NO有所上升而ET相应下降、二者比值也较用药前明显变化，而中药组如上诸值均无明显变化。可见NO、ET是影响血压的重要因素，与原发性高血压的发病、严重程度、血压节律均有一定相关性。而治疗方式中，洛汀新比以杜仲为主的杜仲平压片效果肯定。
第三部分：内皮型一氧化氮合酶基因多态性与原发性高血压发病相关性的研究
采用病例对照研究的方法研究内皮型一氧化氮合酶（eNOS）基因启动子-786位点及第七外显子第894位点多态性与原发性高血压发病的相关性。以215名原发性高血压患者与108名健康中老年人的血白细胞为样本，应用聚合酶链反应-限制性片段长度多态性技术检测两组的eNOS基因启动子-786位点T/C多态性及第七外显子第894位点G/T多态性，比较两组的基因型和等位基因的分布频率。高血压病组内按高血压的危险分层分为低危、中危、高危组各82、72、61例，按血压节律性分为杓型与非杓型组各102、113例，分别比较各组eNOS基因启动子-786位点和第七外显子第894位点的基因型和等位基因的分布频率。通过两基因位点多态性的分布频率研究两基因变异在原发性高血压的发病中是否存在协同作用。经统计学分析得出以下结果：1、eNOS基因启动子-786位点T/T、T/C和C/C基因型在高血压病组中分别为22.79％、50.70％、26.51％，在正常中老年人组中分别为36.11％、52.78％、11.11％，此位点高血压病组与正常中老年人组的基因分布频率差异有显著性。2、eNOS基因第七外显子第894位点G/G、G/T和T/T基因型在高血压病组中分别为69.30％、22.33％、8.37％，在正常中老年人组中分别为82.41％、15.74％、1.85％，此位点高血压病组与正常中老年人组的基因分布频率差异有显著性。3、eNOS基因启动子-786位点T/T、T/C和C/C基因型和第七外显子第894位点G/G、G/T和T/T基因型在原发性高血压低危、中危、高危各组中分布频率无显著差异，如上两位点基因型在依据血压节律的分组中也不存在显著性差异。4、当如上两基因型为CC+TT或TC+TT时，经计算患原发性高血压的OR值明显大于基因型为TT+GG者。可见eNOS基因启动子-786位点及第七外显子第894位点基因多态性与原发性高血压的发病有一定程度的相关性，且eNOS基因启动子-786位点T/T及第七外显子894位点G/G是原发性高血压的保护性基因。两基因变异在原发性高血压的发病中可能有一定程度的协同作用。
1、Studies on resin purification process optimization of eucommia ulmoides oliverand its antihypertensive effect mechanism
Background: Through research it is found that the barks, Oliver, stems, fruits andflowers of Eucommia ulmoides contain various compositions, such as lignin,cycloalkane and phenylpropanoids. The modern pharmacological research shows thatEucommia ulmoides has many functions, such as anti-aging, antitumor and bone cellproliferation. This paper studies the resin purification process optimization conditionsand antihypertensive effect of Eucommia ulmoides Oliver. Materials and Methods:The orthogonal experiment method is adopted to determine the purification effect ofvarious macroporous resin for eucommia ulmoides Oliver, and the SHR model is usedto determine antihypertensive level of eucommia ulmoides Oliver. Results: Theoptimal process of resin extraction and purification of Eucommia ulmoides Oliver isthat the loading liquid concentration is6mg/ml,20%ethanol is used as the eluent, theflow rate control is3.0column volume per hour and the diameter-height ratio ofadsorption column is1:6; the extracts of Eucommia ulmoides Oliver can reduce SHRblood pressure, its antihypertensive effect is relatively stable and has no significantimpact on HR, but the antihypertensive effect is lower than that of control medicinecaptopril. At the same time, the extracts of eucommia ulmoides Oliver cansignificantly increase the content of serum NO and reduce the content of ET.Conclusion: the Eucommia ulmoides Oliver can relax blood vessels, reduce theperipheral resistance, reduce the returned blood volume, and eventually achieve theantihypertensive effect.
2、Studies on the levels of plasma endothelin and serum nitric oxide inhypertensive patients
Objective：To investigate the levels of plasma endothelin, serum nitric oxide andNO/ET in hypertensive patients. To find the relationship between the levels of plasmaendothelin, serum nitric oxide and NO/ET with the extent of Essential Hypertensionand circadian rhythm of blood pressure in hypertensive patients. To find on the levelsof plasma endothelin, serum nitric oxide and NO/ET in hypertensive patients aftertreated by Duzhong pingya tablet and Lotensin. Methods：Levels of plasmaendothelin, serum nitric oxide and NO/ET were detected in hypertensive patients (n=232) and normal controls (n=130). In hypertensive patients there were89patientsof low risk,78patients of risk and65patients of high risk. Ambulatory blood pressuremonitoring for24h were done with hypertensive patients.74hypertensive patientswere treated by lotensin and69patients were treated by Duzhong pingya tablet fortwo weeks. Plasma endothelin, serum nitric oxide and NO/ET were detected after twoweeks’ treating in hypertensive patients. Ambulatory blood pressure monitoring for24h were done again at the same time. Results：In hypertensive patients the level ofplasma endothelin is higher than that of normal controls. While the level of serumnitric oxide is lower and NO/ET is much lower than that of normal controls. Asignificant difference was seen in the levels of plasma endothelin, serum nitric oxideand NO/ET between the two groups. The changes of these three levels were muchmore significant when the risk of hypertension was increasing and the changing ofblood pressure rhythm from dipper blood pressure group (n=109) to non-dipper bloodpressure group (n=123). To the levels of SBP, DBP, plasma endothelin, serum nitricoxide and NO/ET Lotensin (n=66) had significant effects after two weeks’ treating inhypertensive patients but no effects were seen in the group (n=70) treated by Duzhongpingya tablet. Conclusion：The levels of plasma endothelin, serum nitric oxide andNO/ET have something to do with not only morbility of Essential Hypertension butalso the extent of Essential Hypertension and the changing of blood pressure rhythm.To the levels of SBP, DBP, plasma endothelin, serum nitric oxide and NO/ET Lotensinhas more significant effects on Essential Hypertension than that of Duzhong pingyatablet after weeks’treating.
3、Relationship between genetic polymorphism of endothelial nitric oxidesynthase gene and essential hypertension
Objective：To detect the relationship between genetic polymorphism of endothelialnitric oxide synthase （eNOS）gene and essential hypertension．Methods：Polymorphism of the promoter region-786thsite T/C and894thsite G/T of eNOSgene were detected by polymerase chain reaction-restriction fragment lengthpolymorphism in hypertensive patients (n=215) and normal controls (n=108)．Inhypertensive patients there were82patients of low risk,72of risk and61of high risk.At the same time hypertensive patients were divided into dipper blood pressure group (n=102) and non-dipper blood pressure group (n=113) by the change of bloodpressure rhythm. OR and95%CI were studied to find the interaction betweenpolymorphisms of both two sides which we studied．Results： To eNOS promoterregion-786，the frequencies of TT, TC and CC genotype were22.79％,50.70％and26.51％in hypertensive patients and36.11％,52.78％and11.11％in normalcontrols．A significant difference was seen in the distribution frequency in the twogroups of hypertensive patients and normal controls．To the894thsite of the seventhextron of eNOS the frequencies of GG, GT and TT genotype were69.30％,22.33％and8.37％in hypertensive patients and82.41％,15.74％and1.85％in normalcontrols．Asignificant difference was also seen in the two groups.To promoter region-786and the894th site of the seventh extron of eNOS no significant difference wereseen when the risk of hypertension was increasing and the blood pressure rhythm waschanging from dipper to non-dipper blood pressure. When the genotypes of the twosites were CC and TT or TC and TT the OR of morbility of essential hypertensionwere much higher than that when they are TT and GG．Conclusion：Polymorphismsof the promoter region-786T/C and894thsite G/T of eNOS gene have something todo with morbility of essential hypertension but have nothing to do with the extent andthe change of blood pressure rhythm of essential hypertension．Genotypes TT of thepromoter region-786and GG of894thsite of eNOS gene may have some protectiveeffect against essential hypertension．There may exist some interaction betweenpolymorphisms of the two sites we studied．
用于治疗高血压的中成药制剂也有很多种，虽然种类繁杂，但这些中成药中很多药的主要成分都含有杜仲，以杜仲为主要成分的杜仲平压片作为中成药制剂用于控制血压被很多高血压患者选择和接受，也是目前很经典的一种降压治疗的中成药。基于此，本研究设计了动物实验，研究了经分离提纯的杜仲对SHR血一氧化氮（NO）和内皮素（ET）的影响及其降压效果，并与卡托普利进行了对比。
在动物实验发现杜仲通过对NO及ET的影响发挥其降压作用。但是即使较高剂量的杜仲对大鼠血NO、ET的影响及降压作用也不如卡托普利，由此我们想到，对于原发性高血压患者而言，此结果是否依然存在，因而接下做了本研究的第二部分的临床实验。对比了以杜仲为主要成分的杜仲平压片及同是ACEI类的洛汀新对高血压患者的血NO、ET的影响及降压效果。
NO、ET是与原发性高血压发病相关的一对作用相互拮抗和制约的血管内皮因子，本研究通过临床实验发现如上这两种因子不只与高血压的发病相关，还与高血压的程度及血压的正常节律消失有关，杜仲平压片对高血压患者的血NO、ET的影响及降压作用是不如洛汀新明显的。
由于NO及ET与高血压具有的高度相关性，因此与二者代谢有关的基因必将成为高血压发病相关的重要的候选基因，针对这些基因的研究有望在基因水平对原发性高血压病因加以阐述，并为原发性高血压在基因水平的预防、诊断、治疗提供证据。因此接下来又作了与NO合代谢相关的内皮型一氧化氮合酶基因方面的研究。
本论文主要分为三大部分：
第一部分：杜仲叶树脂提纯工艺优化及其降压作用机制的研究
采用正交实验方法测定不同类型大孔吸附树脂对杜仲叶的纯化效果，通过SHR大鼠测定杜仲叶降压水平来研究杜仲叶树脂提纯工艺优化及其降压作用。经研究发现杜仲叶树脂提取纯化最优工艺为上样药液浓度6mg/ml，选用20%乙醇为洗脱剂，流速控制为3.0柱体积每小时，吸附柱径高比为1：6。杜仲叶提取物能降低SHR大鼠血压，降压相对平稳，且对心率没有明显影响，其降压作用低于卡托普利。同时发现杜仲叶提取物降压作用有可能是通过增加血清一氧化氮（NO）量、降低内皮素（ET）量来得以实现的。
第二部分：原发性高血压患者血清一氧化氮及血浆内皮素水平的研究
应用病例对照研究方法来探讨原发性高血压患者血NO及ET水平的变化，研究此变化与高血压轻重程度、血压节律异常的相关性。对比用药前后24h收缩压(SBP)、舒张压(DBP)平均值及NO、ET及二者比值的改善情况及中成药杜仲平压片与西药洛汀新如上诸值的改善情况，用以指导高血压的治疗。其中高血压病组232例，对照组130例。原发性高血压各组分组依据血压水平、影响预后的因素及靶器官受累程度分为低危、中危、高危组各89、78、65例。将高血压病组按随机分组原则分为中药组与西药组分别为74、69例。以上所有受试者进行血压测定、NO与ET检测、动态血压分析。经数据分析及统计学处理得出以下结果：1、高血压病组与正常对照组比较NO降低而ET升高；2、随原发性高血压的危险度增加NO降低及ET升高以及二者比值下降的幅度有加大趋势；3、随原发性高血压患者正常血压节律性的丧失NO降低及ET升高以及二者比值下降的幅度有加大趋势；4、应用洛汀新治疗后患者的24h收缩压(SBP)、舒张压(DBP)平均值有所下降，NO有所上升而ET相应下降、二者比值也较用药前明显变化，而中药组如上诸值均无明显变化。可见NO、ET是影响血压的重要因素，与原发性高血压的发病、严重程度、血压节律均有一定相关性。而治疗方式中，洛汀新比以杜仲为主的杜仲平压片效果肯定。
第三部分：内皮型一氧化氮合酶基因多态性与原发性高血压发病相关性的研究
采用病例对照研究的方法研究内皮型一氧化氮合酶（eNOS）基因启动子-786位点及第七外显子第894位点多态性与原发性高血压发病的相关性。以215名原发性高血压患者与108名健康中老年人的血白细胞为样本，应用聚合酶链反应-限制性片段长度多态性技术检测两组的eNOS基因启动子-786位点T/C多态性及第七外显子第894位点G/T多态性，比较两组的基因型和等位基因的分布频率。高血压病组内按高血压的危险分层分为低危、中危、高危组各82、72、61例，按血压节律性分为杓型与非杓型组各102、113例，分别比较各组eNOS基因启动子-786位点和第七外显子第894位点的基因型和等位基因的分布频率。通过两基因位点多态性的分布频率研究两基因变异在原发性高血压的发病中是否存在协同作用。经统计学分析得出以下结果：1、eNOS基因启动子-786位点T/T、T/C和C/C基因型在高血压病组中分别为22.79％、50.70％、26.51％，在正常中老年人组中分别为36.11％、52.78％、11.11％，此位点高血压病组与正常中老年人组的基因分布频率差异有显著性。2、eNOS基因第七外显子第894位点G/G、G/T和T/T基因型在高血压病组中分别为69.30％、22.33％、8.37％，在正常中老年人组中分别为82.41％、15.74％、1.85％，此位点高血压病组与正常中老年人组的基因分布频率差异有显著性。3、eNOS基因启动子-786位点T/T、T/C和C/C基因型和第七外显子第894位点G/G、G/T和T/T基因型在原发性高血压低危、中危、高危各组中分布频率无显著差异，如上两位点基因型在依据血压节律的分组中也不存在显著性差异。4、当如上两基因型为CC+TT或TC+TT时，经计算患原发性高血压的OR值明显大于基因型为TT+GG者。可见eNOS基因启动子-786位点及第七外显子第894位点基因多态性与原发性高血压的发病有一定程度的相关性，且eNOS基因启动子-786位点T/T及第七外显子894位点G/G是原发性高血压的保护性基因。两基因变异在原发性高血压的发病中可能有一定程度的协同作用。
1、Studies on resin purification process optimization of eucommia ulmoides oliverand its antihypertensive effect mechanism
Background: Through research it is found that the barks, Oliver, stems, fruits andflowers of Eucommia ulmoides contain various compositions, such as lignin,cycloalkane and phenylpropanoids. The modern pharmacological research shows thatEucommia ulmoides has many functions, such as anti-aging, antitumor and bone cellproliferation. This paper studies the resin purification process optimization conditionsand antihypertensive effect of Eucommia ulmoides Oliver. Materials and Methods:The orthogonal experiment method is adopted to determine the purification effect ofvarious macroporous resin for eucommia ulmoides Oliver, and the SHR model is usedto determine antihypertensive level of eucommia ulmoides Oliver. Results: Theoptimal process of resin extraction and purification of Eucommia ulmoides Oliver isthat the loading liquid concentration is6mg/ml,20%ethanol is used as the eluent, theflow rate control is3.0column volume per hour and the diameter-height ratio ofadsorption column is1:6; the extracts of Eucommia ulmoides Oliver can reduce SHRblood pressure, its antihypertensive effect is relatively stable and has no significantimpact on HR, but the antihypertensive effect is lower than that of control medicinecaptopril. At the same time, the extracts of eucommia ulmoides Oliver cansignificantly increase the content of serum NO and reduce the content of ET.Conclusion: the Eucommia ulmoides Oliver can relax blood vessels, reduce theperipheral resistance, reduce the returned blood volume, and eventually achieve theantihypertensive effect.
2、Studies on the levels of plasma endothelin and serum nitric oxide inhypertensive patients
Objective：To investigate the levels of plasma endothelin, serum nitric oxide andNO/ET in hypertensive patients. To find the relationship between the levels of plasmaendothelin, serum nitric oxide and NO/ET with the extent of Essential Hypertensionand circadian rhythm of blood pressure in hypertensive patients. To find on the levelsof plasma endothelin, serum nitric oxide and NO/ET in hypertensive patients aftertreated by Duzhong pingya tablet and Lotensin. Methods：Levels of plasmaendothelin, serum nitric oxide and NO/ET were detected in hypertensive patients (n=232) and normal controls (n=130). In hypertensive patients there were89patientsof low risk,78patients of risk and65patients of high risk. Ambulatory blood pressuremonitoring for24h were done with hypertensive patients.74hypertensive patientswere treated by lotensin and69patients were treated by Duzhong pingya tablet fortwo weeks. Plasma endothelin, serum nitric oxide and NO/ET were detected after twoweeks’ treating in hypertensive patients. Ambulatory blood pressure monitoring for24h were done again at the same time. Results：In hypertensive patients the level ofplasma endothelin is higher than that of normal controls. While the level of serumnitric oxide is lower and NO/ET is much lower than that of normal controls. Asignificant difference was seen in the levels of plasma endothelin, serum nitric oxideand NO/ET between the two groups. The changes of these three levels were muchmore significant when the risk of hypertension was increasing and the changing ofblood pressure rhythm from dipper blood pressure group (n=109) to non-dipper bloodpressure group (n=123). To the levels of SBP, DBP, plasma endothelin, serum nitricoxide and NO/ET Lotensin (n=66) had significant effects after two weeks’ treating inhypertensive patients but no effects were seen in the group (n=70) treated by Duzhongpingya tablet. Conclusion：The levels of plasma endothelin, serum nitric oxide andNO/ET have something to do with not only morbility of Essential Hypertension butalso the extent of Essential Hypertension and the changing of blood pressure rhythm.To the levels of SBP, DBP, plasma endothelin, serum nitric oxide and NO/ET Lotensinhas more significant effects on Essential Hypertension than that of Duzhong pingyatablet after weeks’treating.
3、Relationship between genetic polymorphism of endothelial nitric oxidesynthase gene and essential hypertension
Objective：To detect the relationship between genetic polymorphism of endothelialnitric oxide synthase （eNOS）gene and essential hypertension．Methods：Polymorphism of the promoter region-786thsite T/C and894thsite G/T of eNOSgene were detected by polymerase chain reaction-restriction fragment lengthpolymorphism in hypertensive patients (n=215) and normal controls (n=108)．Inhypertensive patients there were82patients of low risk,72of risk and61of high risk.At the same time hypertensive patients were divided into dipper blood pressure group (n=102) and non-dipper blood pressure group (n=113) by the change of bloodpressure rhythm. OR and95%CI were studied to find the interaction betweenpolymorphisms of both two sides which we studied．Results： To eNOS promoterregion-786，the frequencies of TT, TC and CC genotype were22.79％,50.70％and26.51％in hypertensive patients and36.11％,52.78％and11.11％in normalcontrols．A significant difference was seen in the distribution frequency in the twogroups of hypertensive patients and normal controls．To the894thsite of the seventhextron of eNOS the frequencies of GG, GT and TT genotype were69.30％,22.33％and8.37％in hypertensive patients and82.41％,15.74％and1.85％in normalcontrols．Asignificant difference was also seen in the two groups.To promoter region-786and the894th site of the seventh extron of eNOS no significant difference wereseen when the risk of hypertension was increasing and the blood pressure rhythm waschanging from dipper to non-dipper blood pressure. When the genotypes of the twosites were CC and TT or TC and TT the OR of morbility of essential hypertensionwere much higher than that when they are TT and GG．Conclusion：Polymorphismsof the promoter region-786T/C and894thsite G/T of eNOS gene have something todo with morbility of essential hypertension but have nothing to do with the extent andthe change of blood pressure rhythm of essential hypertension．Genotypes TT of thepromoter region-786and GG of894thsite of eNOS gene may have some protectiveeffect against essential hypertension．There may exist some interaction betweenpolymorphisms of the two sites we studied．
引文
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