非β肾上腺素受体基因多态性对美托洛尔的降血压、心率及升高血脂作用影响的研究
摘要
研究背景
1.美托洛尔在心血管病领域应用广泛,但药物疗效和不良反应存在个体差异,部分患者应用后出现血脂升高。遗传背景是导致个体差异和不良反应的重要原因。以往的研究主要集中在p肾上腺素受体基因多态性上,虽然有阳性,发现但是不能解释所有的差异。
2.人体的α和β肾上腺素受体之间存在着密切的联系。α受体可能影响β受体和阻滞剂的相互作用,肾素-血管紧张素系统是β受体阻滞剂发挥降压作用的途径之一,血管的舒缩状态受血管平滑肌细胞和内皮细胞的调节,上述系统中的基因多态性对pβ体阻滞剂疗效的影响少有研究。
3.甘油三酯代谢(triglyceride,TG)过程中关键酶的活性高低影响TG的浓度,酶活性大小的改变和相关的基因多态性有关,目前已有的研究尚未明确相关酶的基因多态性和美托洛尔升高TG之间的关系。
4.美托洛尔主要由细胞色素酶(cytochrome,CYP)2D6代谢,在中国人中*10多态性是影响酶活性的主要因素,CYP2D6*10和美托洛尔的降血压、心率和升高血脂相关性的研究不多。研究目的
1.研究原发性高血压患者服用美托洛尔8周后,血压心率变化与α肾上腺素受体、肾素-血管紧张素系统中相关蛋白基因多态性的关系。
2.患者血脂变化和代谢关键酶多态性的关系。
3.CYP2D6*10多态性对美托洛尔的降压降心率和血脂升高的影响。
研究方法
1.临床研究
选择2006年5月到2007年3月在阜外心血管病医院门诊就诊的轻至中度原发性高血压患者,服用美托洛尔缓释片95／100mg/天,共8周。评价治疗前后血压、心率、24小时血压监测结果、24小时动态心电图检查结果以及实验室指标(包括血糖、甘油三酯、总胆固醇、高密度脂蛋白、低密度脂蛋白、电解质和肝肾功能等)的变化。
2.基因多态性相关研究
采用聚合酶链-限制性片段长度多态性分析法(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)、直接测序和TaqMan探针的方法分析基因多态性,包括：血管紧张素转换酶(angiotensin-converting enzyme, ACE) I/D、血管紧张素原(angiotensinogen, AGT) G1566T、血管紧张素Ⅱ1型受体(angiotensin receptors, AGTR1) C961T和A1166C、α1D肾上腺素受体A1903T、内收蛋白(adducin,ADD1)G1566T、内皮型一氧化氮合酶(endothelial nitric oxide synthase, eNOS) Glu298Asp、电压依赖-钙离子敏感型钾离子通道蛋白β1亚基(theβ1-subunit of the large-conductance, Ca2+-dependent K+(BK) channel, KCNMB1)的E65K；脂蛋白酯酶(lipoprotein lipase, LPL) HindⅢ和S447X、低密度脂蛋白受体(low density lipoprotein receptor, LDL)C16370T、载脂蛋白A5(apolipoprotein, APOA5) A-1131G多态性和PLIN (perilipin)蛋白C11482T多态性；CYP2D6*10多态性
研究结果
1.影响美托洛尔降压降心率作用的基因多态性
1.1ACE I/D影响24小时平均心率的下降,携带II基因型的患者心率下降了8.7±8.2次／分,携带FD和DD基因型的患者心率下降了5.5±6.3次／分,P=0.045,在纠正了年龄、体重指数和治疗前的血压后,ACE基因I/D多态性仍然与24小时平均心率下降有关。
1.2 eNOS的Glu298Asp影响治疗前后24小时平均收缩压、日间平均收缩压和夜间平均收缩压的下降,GG型患者分别下降了3.3±11.3 mmHg、3.7±11.9 mmHg和3.8±14.9 mmHg,而GT和TT型的患者则分别下降了8.4±8.7 mmHg、5.9±6.2 mmHg和9.9±8.6 mmHg,P值分别为O.021、0.045和0.024。
1.3没有发现AGT G1566T、AGTR1 C961T和A1166C、a 1D肾上腺素受体A1903T、ADD1 G1566T多态性、KCNMB1的E65K与美托洛尔的降压降心率有关。
2.影响美托洛尔血脂升高的基因多态性
2.1 PLIN的C11482T影响美托洛尔引起的TG改变,CC型的TG浓度升高了0.23±1.02 mmol/L,CT型升高了0.26±1.07 mmol/L,TT型升高了1.40±3.21mmol/L,P值是O.045；此外还发现该基因多态性影响治疗前后诊室心率的变化,CC型下降了7.12±9.28次／分,C／T下降了6.8±8.6次／分,TT型下降了-4.0±8.6次／分；P值是0.046。
2.2没有发现LPL的HindⅢ和S447X等位点与TG升高存在关联。
3. CYP2D6*10多态性有影响
有影响治疗前后日间舒张压的变化的趋势,CC型携带者下降6.9±6.8mmHg,CT型下降3.9±6.2 mmHg,TT型下降5.6±6.3 mmHg;两两比较显示,CT型和TT型之间有显著差异(P=0.045)。
研究结论
1.ACE基因I／D多态性和美托洛尔治疗前后24小时平均心率的差值有关,II型下降最明显。
2. eNOS的Glu298Asp多态性和美托洛尔治疗前后24小时平均收缩压、日间平均收缩压和夜间平均收缩压的差值有关,携带T等位基因的患者下降最明显。
3. PLIN的C11482T多态性与美托洛尔治疗前后TG的差值和诊室心率的差值有关,TT型TG升高最多心率下降最小。
4. CYP2D6*10可能和美托洛尔治疗后日间舒张压改变有关。
Background
1. Genetic factor can influence the variability in metoprolol's therapeutic result and adverse effect, many studies focused on the effect ofβ-adrenergic receptor, which a small part of the variability could be derived from.
2. Besides P-adrenergic receptor, the polymorphisms in angiotensin-converting enzyme (ACE) and a-adrenergic receptor may affect the antihypertensive response to metoprolol, little is known about their relation.
3. The level of triglyceride (TG) in plasma is determined by enzyme involved in its metabolism, the relationship between the elevated TG induced by metoprolol and the polymorphisms of those enzyme is unclear.
4. Metoprolol is metabolized by CYP2D6, a few of studies investigated the influence of CYP2D6*10 polymorphism on metoprolol's therapeutic result and adverse effect.
Objectives
The aim of the present study was to investigate:1 the association of the polymorphism of ACE and a-adrenergic receptor and proteins in endothelial and smell muscle cells and metoprolol's therapeutic result; and 2 the association of the polymorphism of enzyme involved in TG metabolism and the elevated TG induced by metoprolol; and 3 the influence of CYP2D6*10 polymorphism on metoprolol's therapeutic result and adverse effect.
Methods
Ninety-seven patients with essential hypertension, who visited the FUWAI hospital (from May 2006 to March 2007), received metoprolol (95/100mg once daily) as monotherapy for 8 weeks. Twenty-four hour ambulatory blood pressure monitoring and dynamic electrocardiogram were performed before and after treatment, some biochemical index was measured to assess the influence of metoprolol on metabolism during treatment.
The following single nucleotide polymorphisms (SNPs) were determined by polymerase chain reaction with restriction fragment length polymorphism or gene sequencing:angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) G1566T, angiotensin receptor I (AGTR1) C961T and A1166C, a 1D adrenergic receptor A1903T, endothelial nitric oxide synthase (eNOS) Glu298Asp, theβ1-subunit of the large-conductance, Ca2+-dependent K+(BK) channel (KCNMB1) E65K, Lipoprotein lipase (LPL) HindⅢand S447X, Low density lipoprotein receptor (LDL) C16370T, apolipoprotein (APOA5) A-1131G, PLIN C114829T, CYP2D6 C188T.
Results
1. Association of gene polymorphisms with cardiovascular to metoprolol
1.1 ACE gene I/D had an effect on difference in 24-hour average heart rate during the treatment, patients with ACE geneⅡpolymorphism showed greater reduction in 24-hour average HR than those with ID or DD polymorphisms (8.7±8.2 beats/min vs 5.5±6.3 beats/min,P= 0.045).
1.2 eNOS Glu298Asp influenced the difference in 24-hour average systolic blood press (SBP) and daytime SBP and nocturnal SBP, in patients with GG genotype the fall was 3.3±11.3 mmHg,3.7±11.9 mmHg and 3.8±14.9 mmHg, while in GT and TT genotypes the fall was 8.4±8.7 mmHg,5.9±6.2 mmHg and 9.9±8.6 mmHg (P value was 0.021,0.045 and 0.024).
1.3 The other polymorphisms had no association with the changes in BP and heart rate.
2. Association of gene polymorphisms with the elevated TG induced by metoprolol
1.1 PLIN C1229T influenced the difference in TG during the treatment, patients with TT genotype had the greatest increase in TG than those with CT or CC genotype (1.40±3.21 mmol/L,0.26±1.07 mmol/L and 0.23±1.02 mmol/L, P= 0.045); and changes of heart rate in clinic were influenced by this polymorphism, the difference in TT was-4.0±8.6 beats/min, in CT was 6.8±8.6 beats/min and in CC beats/min was 7.12±9.28 beats/min, P=0.046.
1.2 The other polymorphisms had no association with the changes in TG.
3. The influence of CYP2D6*10 on TG and cardiovascular to metoprolol
A tendency had been observed that the difference in daytime diastolic blood pressure (DBP) was classified by this polymorphism, the reduction was 6.9±6.8 mmHg in CC genotype group,3.9±6.2 mmHg in CT genotype group, and 5.6±6.3 mmHg in TT genotype group. Statistical difference was observed between CT and TT genotype group, P=0.045.
Conclusions
1. ACE gene I/D had an effect on difference in 24-hour average heart rate during the treatment with metoprolol.
2. eNOS Glu298Asp (G/T) influenced the difference in 24-hour average systolic blood press (SBP) and daytime SBP and nocturnal SBP.
3. PLIN C11482T influenced the difference in TG and heart rate induced by metoprolol.
4. CYP2D6*10 maybe a genetic marker for change in daytime DBP induced by metoprolol.
1.美托洛尔在心血管病领域应用广泛,但药物疗效和不良反应存在个体差异,部分患者应用后出现血脂升高。遗传背景是导致个体差异和不良反应的重要原因。以往的研究主要集中在p肾上腺素受体基因多态性上,虽然有阳性,发现但是不能解释所有的差异。
2.人体的α和β肾上腺素受体之间存在着密切的联系。α受体可能影响β受体和阻滞剂的相互作用,肾素-血管紧张素系统是β受体阻滞剂发挥降压作用的途径之一,血管的舒缩状态受血管平滑肌细胞和内皮细胞的调节,上述系统中的基因多态性对pβ体阻滞剂疗效的影响少有研究。
3.甘油三酯代谢(triglyceride,TG)过程中关键酶的活性高低影响TG的浓度,酶活性大小的改变和相关的基因多态性有关,目前已有的研究尚未明确相关酶的基因多态性和美托洛尔升高TG之间的关系。
4.美托洛尔主要由细胞色素酶(cytochrome,CYP)2D6代谢,在中国人中*10多态性是影响酶活性的主要因素,CYP2D6*10和美托洛尔的降血压、心率和升高血脂相关性的研究不多。研究目的
1.研究原发性高血压患者服用美托洛尔8周后,血压心率变化与α肾上腺素受体、肾素-血管紧张素系统中相关蛋白基因多态性的关系。
2.患者血脂变化和代谢关键酶多态性的关系。
3.CYP2D6*10多态性对美托洛尔的降压降心率和血脂升高的影响。
研究方法
1.临床研究
选择2006年5月到2007年3月在阜外心血管病医院门诊就诊的轻至中度原发性高血压患者,服用美托洛尔缓释片95／100mg/天,共8周。评价治疗前后血压、心率、24小时血压监测结果、24小时动态心电图检查结果以及实验室指标(包括血糖、甘油三酯、总胆固醇、高密度脂蛋白、低密度脂蛋白、电解质和肝肾功能等)的变化。
2.基因多态性相关研究
采用聚合酶链-限制性片段长度多态性分析法(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)、直接测序和TaqMan探针的方法分析基因多态性,包括：血管紧张素转换酶(angiotensin-converting enzyme, ACE) I/D、血管紧张素原(angiotensinogen, AGT) G1566T、血管紧张素Ⅱ1型受体(angiotensin receptors, AGTR1) C961T和A1166C、α1D肾上腺素受体A1903T、内收蛋白(adducin,ADD1)G1566T、内皮型一氧化氮合酶(endothelial nitric oxide synthase, eNOS) Glu298Asp、电压依赖-钙离子敏感型钾离子通道蛋白β1亚基(theβ1-subunit of the large-conductance, Ca2+-dependent K+(BK) channel, KCNMB1)的E65K；脂蛋白酯酶(lipoprotein lipase, LPL) HindⅢ和S447X、低密度脂蛋白受体(low density lipoprotein receptor, LDL)C16370T、载脂蛋白A5(apolipoprotein, APOA5) A-1131G多态性和PLIN (perilipin)蛋白C11482T多态性；CYP2D6*10多态性
研究结果
1.影响美托洛尔降压降心率作用的基因多态性
1.1ACE I/D影响24小时平均心率的下降,携带II基因型的患者心率下降了8.7±8.2次／分,携带FD和DD基因型的患者心率下降了5.5±6.3次／分,P=0.045,在纠正了年龄、体重指数和治疗前的血压后,ACE基因I/D多态性仍然与24小时平均心率下降有关。
1.2 eNOS的Glu298Asp影响治疗前后24小时平均收缩压、日间平均收缩压和夜间平均收缩压的下降,GG型患者分别下降了3.3±11.3 mmHg、3.7±11.9 mmHg和3.8±14.9 mmHg,而GT和TT型的患者则分别下降了8.4±8.7 mmHg、5.9±6.2 mmHg和9.9±8.6 mmHg,P值分别为O.021、0.045和0.024。
1.3没有发现AGT G1566T、AGTR1 C961T和A1166C、a 1D肾上腺素受体A1903T、ADD1 G1566T多态性、KCNMB1的E65K与美托洛尔的降压降心率有关。
2.影响美托洛尔血脂升高的基因多态性
2.1 PLIN的C11482T影响美托洛尔引起的TG改变,CC型的TG浓度升高了0.23±1.02 mmol/L,CT型升高了0.26±1.07 mmol/L,TT型升高了1.40±3.21mmol/L,P值是O.045；此外还发现该基因多态性影响治疗前后诊室心率的变化,CC型下降了7.12±9.28次／分,C／T下降了6.8±8.6次／分,TT型下降了-4.0±8.6次／分；P值是0.046。
2.2没有发现LPL的HindⅢ和S447X等位点与TG升高存在关联。
3. CYP2D6*10多态性有影响
有影响治疗前后日间舒张压的变化的趋势,CC型携带者下降6.9±6.8mmHg,CT型下降3.9±6.2 mmHg,TT型下降5.6±6.3 mmHg;两两比较显示,CT型和TT型之间有显著差异(P=0.045)。
研究结论
1.ACE基因I／D多态性和美托洛尔治疗前后24小时平均心率的差值有关,II型下降最明显。
2. eNOS的Glu298Asp多态性和美托洛尔治疗前后24小时平均收缩压、日间平均收缩压和夜间平均收缩压的差值有关,携带T等位基因的患者下降最明显。
3. PLIN的C11482T多态性与美托洛尔治疗前后TG的差值和诊室心率的差值有关,TT型TG升高最多心率下降最小。
4. CYP2D6*10可能和美托洛尔治疗后日间舒张压改变有关。
Background
1. Genetic factor can influence the variability in metoprolol's therapeutic result and adverse effect, many studies focused on the effect ofβ-adrenergic receptor, which a small part of the variability could be derived from.
2. Besides P-adrenergic receptor, the polymorphisms in angiotensin-converting enzyme (ACE) and a-adrenergic receptor may affect the antihypertensive response to metoprolol, little is known about their relation.
3. The level of triglyceride (TG) in plasma is determined by enzyme involved in its metabolism, the relationship between the elevated TG induced by metoprolol and the polymorphisms of those enzyme is unclear.
4. Metoprolol is metabolized by CYP2D6, a few of studies investigated the influence of CYP2D6*10 polymorphism on metoprolol's therapeutic result and adverse effect.
Objectives
The aim of the present study was to investigate:1 the association of the polymorphism of ACE and a-adrenergic receptor and proteins in endothelial and smell muscle cells and metoprolol's therapeutic result; and 2 the association of the polymorphism of enzyme involved in TG metabolism and the elevated TG induced by metoprolol; and 3 the influence of CYP2D6*10 polymorphism on metoprolol's therapeutic result and adverse effect.
Methods
Ninety-seven patients with essential hypertension, who visited the FUWAI hospital (from May 2006 to March 2007), received metoprolol (95/100mg once daily) as monotherapy for 8 weeks. Twenty-four hour ambulatory blood pressure monitoring and dynamic electrocardiogram were performed before and after treatment, some biochemical index was measured to assess the influence of metoprolol on metabolism during treatment.
The following single nucleotide polymorphisms (SNPs) were determined by polymerase chain reaction with restriction fragment length polymorphism or gene sequencing:angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) G1566T, angiotensin receptor I (AGTR1) C961T and A1166C, a 1D adrenergic receptor A1903T, endothelial nitric oxide synthase (eNOS) Glu298Asp, theβ1-subunit of the large-conductance, Ca2+-dependent K+(BK) channel (KCNMB1) E65K, Lipoprotein lipase (LPL) HindⅢand S447X, Low density lipoprotein receptor (LDL) C16370T, apolipoprotein (APOA5) A-1131G, PLIN C114829T, CYP2D6 C188T.
Results
1. Association of gene polymorphisms with cardiovascular to metoprolol
1.1 ACE gene I/D had an effect on difference in 24-hour average heart rate during the treatment, patients with ACE geneⅡpolymorphism showed greater reduction in 24-hour average HR than those with ID or DD polymorphisms (8.7±8.2 beats/min vs 5.5±6.3 beats/min,P= 0.045).
1.2 eNOS Glu298Asp influenced the difference in 24-hour average systolic blood press (SBP) and daytime SBP and nocturnal SBP, in patients with GG genotype the fall was 3.3±11.3 mmHg,3.7±11.9 mmHg and 3.8±14.9 mmHg, while in GT and TT genotypes the fall was 8.4±8.7 mmHg,5.9±6.2 mmHg and 9.9±8.6 mmHg (P value was 0.021,0.045 and 0.024).
1.3 The other polymorphisms had no association with the changes in BP and heart rate.
2. Association of gene polymorphisms with the elevated TG induced by metoprolol
1.1 PLIN C1229T influenced the difference in TG during the treatment, patients with TT genotype had the greatest increase in TG than those with CT or CC genotype (1.40±3.21 mmol/L,0.26±1.07 mmol/L and 0.23±1.02 mmol/L, P= 0.045); and changes of heart rate in clinic were influenced by this polymorphism, the difference in TT was-4.0±8.6 beats/min, in CT was 6.8±8.6 beats/min and in CC beats/min was 7.12±9.28 beats/min, P=0.046.
1.2 The other polymorphisms had no association with the changes in TG.
3. The influence of CYP2D6*10 on TG and cardiovascular to metoprolol
A tendency had been observed that the difference in daytime diastolic blood pressure (DBP) was classified by this polymorphism, the reduction was 6.9±6.8 mmHg in CC genotype group,3.9±6.2 mmHg in CT genotype group, and 5.6±6.3 mmHg in TT genotype group. Statistical difference was observed between CT and TT genotype group, P=0.045.
Conclusions
1. ACE gene I/D had an effect on difference in 24-hour average heart rate during the treatment with metoprolol.
2. eNOS Glu298Asp (G/T) influenced the difference in 24-hour average systolic blood press (SBP) and daytime SBP and nocturnal SBP.
3. PLIN C11482T influenced the difference in TG and heart rate induced by metoprolol.
4. CYP2D6*10 maybe a genetic marker for change in daytime DBP induced by metoprolol.
引文
1 Evans WE, Relling MV. Pharmacogenomics:translating functional genomics into rational therapeutics. Science 1999; 286:487-491.
2李娜等β肾上腺素受体和G蛋白的基因多态性与美托洛尔药效学和血脂升高的相关性研究
3 Saino A, Pomidossi G, Perondi R, Valentini R, Rimini A, Di Francesco L, Mancia G. Intracoronary angiotensin Ⅱ potentiates coronary sympathetic vasoconstrictions in humans. Circulation 1997; 96:148-153.
4 Saino A, Pomidossi G, Perondi R, Morganti A, Turolo L, Mancia G Modulation of sympathetic coronary vasoconstriction by cardiac rennin angiotensin system in human coronary artery disease. Circulation 2000; 101:2277-2283
5 Karin Malmqvist, K. Peter Ohman, Lars Lind, Fredrik Nystrom, and Thomas Kahan Long-Term Effects of Irbesartan and Atenolol on the Renin-Angiotensin-Aldosterone System in Human Primary Hypertension J Cardiovasc PharmacolTM 2003;42:719-726
6 Blumenfeld JD, Sealey JE, Mann SJ, et al. Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensinaldosterone system in normotensive and hypertensive subjects. Am J Hypertens.1999;12:451-459.
7 Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.
8 Zhu X, McKenzie CA, Forrester T, Nickerson DA, Broeckel U, Schunkert H, Doering A, Jacob HJ, Cooper RS, Rieder MJ. Localization of a small genomic region associated with elevated ACE. Am J Hum Genet 2000; 67:1144-1153.
9 Bei Sun, Ekaterina Kintsurashvili, Deborah Ona, Ivana Ignjacev-Lazich, Irene Gavras, and Haralambos Gavras. Inhibition of the α 1D-Adrenergic Receptor Gene by RNA interference (RNAi) in Rat Vascular Smooth Muscle Cells and its effects on other adrenergic receptors. Vascul Pharmacol.2007 May; 46(5):367-372.
10张幼怡韩启德(α1与β肾上腺素受体间的交互作用基础医学与临床1997,17：241-245
11余细勇林曙光肾上腺素受体亚型的调节及其交互作用国外医学·生理、病理科学与临床手册1998.18(2)125-129
12 Skomedal T, et al. Both alpha and beta adrenoceptor-mediated components contribute to final inotropic response to norepinephrine in rat heart J Pharmacol Exp Ther,1988,247:1204
13 Tanoue A, Nasa Y, Koshimizu Shinoura H, Oshikawa S, KawaiT, et al. The alpha (1 D)- adrenergic receptor directly regulates arterial blood pressure via vasoconstriction. J Clin Invest 2002:109:765-75.
14 Akito Tanoue, Masahiro Koba, Shigeki Miyawaki, Taka-aki Koshimizu, Chihiro Hosoda, Sayuri Oshikawa, Gozoh Tsujimoto Role of the α1D-Adrenegric Receptor in the Development of Salt-Induced Hypertension. Hypertension.2002;40:101-106.
15李艳芳 张幼怡 吕志珍 韩启德长期饮用普萘洛尔对大鼠心脏α1肾上腺素受体亚型数量的影响中国药理学与毒理学杂志1996年11月：11：281-284
16 S Nonen, H Okamoto,Y Fujio, Y Takemoto, M Yoshiyama, T Hamaguchi, Y Matsui, J Yoshikawa, A Kitabatake and J Azuma. Polymorphisms of norepinephrine transporter and adrenergic receptor alD are associated with the response to β-blockers in dilated cardiomyopathy. The Pharmacogenomics Journal (2008) 8,78-84
17 Wellman GC, Cartin L, Eckman DM, Stevenson AS, Saundry CM, Lederer WJ, Nelson MT. Membrane depolarization, elevated Ca(2+) entry, and gene expression in cerebral arteries of hypertensive rats. Am J Physiol Heart Circ Physiol 2001; 281:H2559-H2567.
18 Davare MA, Avdonin V, Hall DD, Peden EM, Burette A,Weinberg RJ,Horne MC, Hoshi T, Hell JW (2001) A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2. Science 293:98-101
19 Brown SM, Bentcheva-Petkova LM, Liu L, Hristov KL, Chen M, Kellett WF, Meredith AL, Aldrich RW, Nelson MT, Petkov GV.β-Adrenergic relaxation of mouse urinary bladder smooth muscle in the absence of large-conductance Ca2+-activated K+channel. Am J Physiol Renal Physiol.2008 Oct;295(4):F1149-57
20 Pluger S, Faulhaber J, Furstenau M, Lohn M, Waldschutz R, Gollasch M, et al. Mice with disrupted BK channel betal subunit gene feature abnormal Ca(2+) spark/STOC coupling and elevated blood pressure. Circ Res 2000; 87:E53-E60.
21 Brenner R, Perez GJ, Bonev AD, Eckman DM, Kosek JC, Wiler SW, et al. Vasoregulation by the betal subunit of the calcium-activated potassium channel. Nature 2000; 407:870-876.
22 Fernandez-Fernandez JM, Tomas M, Vazquez E, Orio P, Latorre R, Senti M, et al. Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. J Clin Invest 2004; 113:1032-1039.
23 Senti M, Fernandez-Fernandez JM, Tomas M, Vazquez E, Elosua R, Marrugat J, Valverde MA. Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk. Circ Res 2005.
24 Kelley-Hedgepeth A, Peter I, Kip K, Montefusco M, Kogan S, Cox D, Ordovas J, Levy D, Reis S, Mendelsohn M, Housman D, Huggins G. The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with beta-blockade. Journal of Human Hypertension (2008) 22,512-515
25Yosimura M, Yasue H, Nakayama M, et al. Amissense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese [J]. Hum Genet,1998,103:65-69.
26 Hingorani AD. Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep,2003,5:19-25.
27 Wang X L, Mahaney M C, Sim A S, Wang J, Wang J, BlangeroJ, Almasy L, Badenhop R B, W ilcken D E Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels. Arterioscler Thromb Vobc Biol.1997,17(11):3147-3153.
28 Y Miyamoto Y, Saito Y, Kajiyama N, Yoshimura M, Shimasaki Y, Nakayama M, Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertens,1998,32(1):3-8.
29 asujima M, Tsutaya S, Shoji M Endothelial nitric oxide synthase gene polymorphism and hypertension Rinsho Byori,1998,46(12):1199- 1204.
30李东宝,华琦.皮林.内皮型一氧化氮合酶基因G894T多态性与原发性高血 压的相关关系。高血压杂志,2004,12(4)：326—330.
31 Jachymova M, Horky K, Bultas J, et al. Association of the Glu298Asp polymorphism in the endothelial nitric oxide synthase gene with essential hypertension resistant to conventional therapy[J]. Biochem Biophys Res Commun, 2001,284:426-430.
32 Tuomo R, Treva R, Louis P, etal. NOS3 Glu298Asp genotype and blood pressure response to endurance training. The HERITAGE family study[J]. Hypertension, 2000,36:885-889.
33 Kim JS Endothelial nitric oxide synthase Glu298Asp gene polymorphism is associated with hypertensive response to exercise in well-controlled hypertensive patients. Yonsei Med J.2007 Jun 30;48(3):389-95
34 Greenberg, A. S., J. J. Egan, S. A. Wek, N. B. Garty, E. J. Blanchette-Mackie, and C. Londos.1991. Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets. J. Biol. Chem. 266:11341-11346.
35 Brasaemle, D. L., Rubin, B., Harten, I. A., Gruia-Gray, J., Kimmell, A. R. and Londos, C. (2000) Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J. Biol. Chem.275,38486-38493
36 Martinez-Botas, J., Anderson, J. B., Tessier, D., Lapiilonne, A., Chang, B. H.-J., Quast, M. J., Gorenstein, D., Chen, K..-H. and Chan, L. (2000) Absence of perilipin results in leanness and reverses obesity in Leprdb/db mice. Nat. Genet.26,474-479
37Tansey, J. T., Sztalryd, C., Gruia-Gray, J., Roush, D. L., Zee, J. V., Gavrilova, O., Reitman, M. L., Deng, C.-X., Li, C., Kimmel, A. R. and Londos, C. (2001) Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc. Natl. Acad. Sci. U.S.A.98, 6494-6499
38 Clifford, G. M., Londos, C., Kraemer, F. B., Vernon, R. G. and Yeaman, S. J. (2000) Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation of rat adipocytes. J. Biol. Chem.275,5011-5015
39 Martinez-Botas, J., Anderson, J.B., Tessier, D., Lapillonne, A., Chang, B.H., Quast, M.J., Gorenstein, D., Chen, K.H. and Chan, L. (2000) Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. Nat. Genet. 26,474-479
40 Tansey, J.T., Sztalryd, C., Gruia-Gray, J., Roush, D.L., Zee, J.V., Gavrilova, O., Reitman,. (2001) Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity.Proc. Natl. Acad. Sci. U.S.A.98,6494-6499
41 Mottagui-Tabar S, Ryden M, Lofgren P, Faulds G, Hoffstedt J, Brookes AJ et al. Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis. Diabetologia 2003; 46:789-797.
42 Qi L, Corella D, Sorli JV, Portoles O, Shen H, Coltell O et al. Genetic variation at the perilipin (PLIN) locus is associated with obesity-related phenotypes in White women. Clin Genet 2004; 66:299-310.
43 Weili Yan, Shufeng Chen, Jianfeng Huang, Yan Shen, Boqin Qiang, and Dongfeng Gu Polymorphisms in PLIN and Hypertension Combined with Obesity and Lipid Profiles in Han Chinese Obes Res.2004; 12:1733-1737.
44 van der Vliet H N, Sammels M G, Leegwater A C, Levels J H, Reitsma P H, Boers W, Chamuleau R A. Apolipoprotein AV a novel apolipoprotein associated with an early phase of liver regeneration. J Bio Chem,2001,276:44512-44520
45刘琼,赵水平.APOA5单克隆抗体的制备及其临床初步应用[J].医学临床研究,2006；23(2)：153-6.
46 Remen Apolipoprotein AV:low concentration, high impact. Arterioscler Thromb Vasc Biol 2005,25(12) 2445-2447
47 Pennacchio LA. Rubin EM. Apolipoprotein A5. a newly identified gene that affects plasma triglyceride levels in human s an d mice. Arterioseler Thromb Vasc Biol,2003.23:529-534.
48 Olofeson SO. ApoA-V:the regulation of a regulator of plasma triglyceride. Arterioscler Thromb Vasc Biol 2005,25(6) 1097-99
49李国平,陈保生载脂蛋白家族新成员：载脂蛋白A5基因研究进展.中国动脉硬化杂志2004,112(2)：229-232
50 Nowak M. Helleboid-Chapman A, Jakel H, et al. Insulin-mediated down regulation of apolipoprotein A5 gene expression through the phosphatidylinositol 3-kinase pathway:rule of upstream stimulatory factor [J). Mol Cell Biol,2005; 25(4): 1537-43
51 Seda O, Sedova L New apolipoprotein AV:comparative genomics meets metabolism Physiol Res,2003,52:141- 146.
52 Baum L. Tomlinson B. Thomas GN. ApoA5-1131T> C polymorphism is associated with triglyceride levels in Chinese men. Clin Genet.2oo3.63:377-379.
53 Lai CQ, Tai ES, Tan CE, et al. The APOA5 locus is a strong determinant of plasma triglyceride concentrations across ethnic groups in Singapore. J Lipid Res, 2003,44:2365-2373.
54 Nabika T, Nasre n S, Kobayashi S, Masuda J The genetic effect of the apoprotein AV gene on the serum triglyceride level in Japanese. Atherosclerosis 2002,165: 201-204.)
55 Pasalic D, Sertic J, Kunovic B, et al. Lipoprotein lipase gene polymorphism and lipid profile in patients with hypertriglycerdemia. Clinical Sciences.2001; 42: 517.22
56 Tu X, Tu J, W en X, Wang J, Zhang D. A study of lipoprotein lipase gene intron 8 polymorphisms in Chinese Han race essential hypertension patients. Int J Cardiol, 2005,99(2):263-267.
57Hendemon HE, Kastelein JJ, Zwinderman AH, et al. Lipoprotein lipase activity is decreased in a large cohort of patients with coronary artery disease and is associated with changes in lipids and lipoproteins. J Lipid Res,1999.40:735-743.
58Wittrnp HH, Nordestgaard BG Stefensen R, Jensen G Tybjaerg-Hansen A. Effect of gender on phenotypic expression of the S447X mutation in LPL:the Copenhagen city heart study. Atherosclerosis,2002,165(1):119 - 126.
59官国东 徐恩 王小娟 许寅宏 邱少东 脂蛋白脂酶Ser447Ter基因多态性与动脉硬化性脑梗死的相关研究中华医学遗传学杂志2006年10月第23卷第5期519-523页
60 Regardh, C.G.& Johnsson, G. Clinical pharmacokinetics of metoprolol. Clin. Pharmacokinet (1980).5,557-569.
61 Lennard, M.S., Silas, J.H., Freestone, S., Ramsay, L.E., Tucker, G.T.& Woods, H.F. Oxidation phenotype-a major determinant of metoprolol metabolism and response. N. Engl. J. Med(1982).307,1558-1560.)
62 Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity Of CYP2D6 in Chinese. Drug Metab Dispos 1999; 27(3):385-80
63 Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus:characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol.1994 Sep;46(3):452-9.
64Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. Drug Metab Dispos.1999 27(3):385-8.
65 Garcia-Barcelo M, Chow LY, Chiu HF, Wing YK, Lee DT, Lam KL, Waye MM. Genetic analysis of the CYP2D6 locus in a Hong Kong Chinese population. Clin Chem 2000,46(1):18-23.
66 Ji L, Pan S, Wu J, Marti-Jaun J, Hersberger M.. Genetic polymorphisms of CYP2D6 in Chinese mainland. Chin Med J (Engl).2002 Dec; 115(12):1780-4.
67Gao Y, Zhang Q. Polymorphisms of the GSTM1 and CYP2D6 genes associated with susceptibility to lung cancer in Chinese. Mutat Res,1999,444(2):441-449
68Taguchi M, Nozawa T, Kameyama T, Inoue H, Takesono C, Mizukami A, Hashimoto Y.. Effect of CYP2D6*10 on pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients. Eur J Clin Pharmacol.2003 Sep;59(5-6):385-8.
69 Huang J., Chuang S.K., Cheng C.L., Lai M.L. Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes. Clin. Pharmacol. Ther. (1999)65 402-407.
70 Huang J., Chuang S.K., Cheng C.L., Lai M.L. Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes. Clin. Pharmacol. Ther. (1999)65 402-407.
71 Agema WR, Jukema JW, Zwinderman AH, Wall EE van der:A metaanalysis of the angiotensin-converting enzyme gene polymorphism and restenosis after percutaneous transluminal coronary revascularization:evidence for publication bias. Am Heart J 2002,144:760-768.
72 Danser AH, Schalekamp MA, Bax WA, Brink AM van den, Saxena PR, Riegger GA, Schunkert H:Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation 1995,92:1387-1388.
73 Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.
74 Zhu X, McKenzie CA, Forrester T, Nickerson DA, Broeckel U, Schunkert H, Doering A, Jacob HJ, Cooper RS, Rieder MJ. Localization of a small genomic region associated with elevated ACE. Am J Hum Genet 2000; 67:1144-1153.
75 Kurland L, Melhus H, Karlsson J, Kahan T, Malmqvist K, Ohman KP, et al. Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin Ⅱ receptor type 1 antagonist treatment in hypertensive patients. J Hypertens 2001; 19:1783-4787.
76 Schelleman H, Klungel OH, van Duijn CM, Witteman JC, Hofman A, de Boer A, et al. Drug-Gene Interaction Between the Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Antihypertensive Therapy. Ann Pharmacother 2006; 40:212-218.
77 Schelleman H, Stricker BH, Verschuren WM, de Boer A, Kroon AA, de Leeuw PW, et al. Interactions between five candidate genes and antihypertensive drug therapy on blood pressure. Pharmacogenomics J 2006; 6:22-26.
78 Suonsyrja T, Hannila-Handelberg T, Fodstad H, Donner K, Kontula K, Hiltunen TP. Renin-Angiotensin System and α-Adducin Gene Polymorphisms and Their Relation to Responses to Antihypertensive Drugs:Results From the GENRES Study. Am J Hypertens 2009; 22:169-175
79 Kolloch R, Legler UF, Champion A, Cooper-Dehoff RM, Handberg E, Zhou Q, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease:findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J 2008; 29:1327-1334.
80 Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol 2008; 101:865-869.
81 Shepherd JT, Mancia G. Reflex control of the human cardiovascular system. Rev Physiol Biochem Pharmacol 1986; 105:1-99.
82 Parati G, Saul JP, Di Rienzo M, Mancia G. Spectral analysis of blood pressure and heart failure variability in evaluating cardiovascular regulation. Hypertension 1995; 25:1276-1286.
83 Mancia G, Daffonchio A, Di Rienzo M, Ferrari AU, Grassi G. Methods to quantify sympathetic cardiovascular influences. Eur Heart J 1998; 19:F7-F13.
84 Montgomery HE, Marshall R, Hemingway H, et al. Human gene for physical performance. Nature 1998;393:221-2
85 Heled Yuval, Daniel S. Moran, Liran Mendel, Arie Laor, Elon Pras, and Yair Shapiro. Human ACE I/D polymorphism is associated with individual differences in exercise heat tolerance. J Appl Physiol 97:72-76,2004
86 Euan A. Ashley, Attila Kardos, Ewan S. Jack, Walter Habenbacher, Mathew Wheeler, Young M. Kim, Jeffrey Froning, Jonathan Myers, Gregory Whyte, PHD, Victor Froelicher, Pamela Douglas Angiotensin-Converting Enzyme Genotype Predicts Cardiac and Autonomic Responses to Prolonged Exercise J Am Coll Cardiol 2006;48:523-31
87 1996 Heart rate variability:standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 93:1043-1065
88 Kupper NH, Willemsen G, van den Berg M, de Boer D, Posthuma D, Boomsma DI, de Geus EJ. Heritability of ambulatory heart rate variability. Circulation 2004; 110:2792-2796.
89 Singh JP, Larson MG, O'Donnell CJ, Tsuji H, Evans JC, Levy D. Heritability of heart rate variability:the Framingham Heart Study. Circulation 1999;99:2251-2254.
90 Andreas Busjahn, Andreas Voss, Hans Knoblauch, Margit Knoblauch, Eva Jeschke, Niels Wessel, Ju'rgen Bohlender, Jesse McCarron, BS, Hans-Dieter Faulhaber, Herbert Schuster, Rainer Dietz, and Friedrich C. Luft, Angiotensin-Converting Enzyme and Angiotensinogen Gene Polymorphisms and Heart Rate Variability in Twins Am J Cardiol 1998;81:755-760
91 Julian F. Thayer, Marcellus M. Merritt, John J. Sollers Ⅲ, Alan B. Zonderman, Michele K. Evans, Sue Yie, and Darrell R. Abernethy Effect of Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism DD Genotype on High-Frequency Heart Rate Variability in African Americans Am J Cardiol 2003;92:1487-1490
92 Reid IA. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol. 1992;262:E763-E778
93 Wei-Zhong Wang, Lie Gao, Yan-Xia Pan, Irving H. Zucker, and Wei Wang AT1 receptors in the nucleus tractus solitarii mediate the interaction between the baroreflex and the cardiac sympathetic afferent reflex in anesthetized rats Am J Physiol Regul Integr Comp Physiol 292:R1137-R1145,2007
94 Campagnole-Santos MJ, Diz DI, Ferrario CM. Baroreceptor reflex modulation by angiotensin II at the nucleus tractus solitarii. Hypertension 11:1167-1171,1988.
95 Matsumura K, Averill DB, Ferrario CM. Angiotensin II acts at AT1 receptors in the nucleus of the solitary tract to attenuate the baroreceptor reflex. Am J Physiol Regul Integr Comp Physiol 275:R1611-R1619,1998.
96 Saqib CHOWDHARY, G Andre N G, Sarah L NUTTALL, John H COOTE. Hamish F ROSS, Jonathan N TOW NEND. Nitric oxide and cardiac parasympathetic control in human heart failure Clinical Science,2002,102:397-402
97 Yun He Liu, Jiang Xu, Xiao-Ping Yang, Fang Yang, Edward Shesely, Oscar A Carretero. Effect of ACE inhibitors and angiotensin II Type 1receptor antagonists on endothelial NO synthase knockout mice with heart failure. Hypertension,2002,39: 375-381
98 Fujiwara N, Osanai T, Kamada T, et al. Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension:modulation of nitric oxide synthesis by salt intake[J]. Circulation,2000,101:856-861.
99 Tanus-Santos JE, Desai M, Flockhart DA Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics.2001 Nov;11(8):719-25
100王从菊 赵景波 许加亮 向泽林 梁长威 李杰 中国人内皮型一氧化氮合酶基因G894T多态性与原发性高血压关系的Meta分析中华流行病学杂志2009年第30卷第8期845-849页
101 Node K, Kitakaze M, Yoshikawa H, Kosaka H, Hori M. Reduced plasma concentrations of nitrogen oxide in individuals with essential hypertension. Hypertension 1997; 30:405-408.
102 Mason RP, Kubant R, Jacob RF, Walter MF, Boychuk B, Malinski T. Effect of nebivolol on endothelial nitric oxide and peroxynitrite release in hypertensive animals: Role of antioxidant activity. J Cardiovasc Pharmacol 2006; 48:862-869.
103 Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T:Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88:14-22,2001 104 Forstermann U, Munzel T: Endothelial nitric oxide synthase in vascular disease:from marvel to menace. Circulation 113:1708-1714,2006
105 Sharma, V., Dhillon, P.,Wambolt, R., Parsons, H., Brownsey, R., Allard, M.F., McNeill, J.H.,2008. Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin (STZ) diabetic rat. Am. J. Physiol. Heart Circ. Physiol.294, H1609-H1620.
106 Vijay Sharma, Hannah Parsons, Michael F. Allard, John H. McNeill Metoprolol increases the expression of β3-adrenoceptors in the diabetic heart:Effects on nitric oxide signaling and forkhead transcription factor-3. European Journal of Pharmacology 595 (2008) 44-51. Gauthier, C., Leblais, V., Kobzik, L., Trochu, J.N., Khandoudi, N., Bril, A., Balligand, J.L., Le Marec, H.,1998.
107 The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J. Clin: Invest.102, 1377-1384.
108 Gauthier, C., Tavernier, G, Charpentier, F., Langin D., Le Marec, H.,1996 Functional beta3-adrenoceptor in the human heart. J. Clin. Invest.98,556-562.
109 Dincer UD, Bidasee KR. Gfiner A. et al. The effect of diabetes on expression of β1 β2 β3 adrenoreceptors in rat hearts. Diabetes 2001 50:455-461.
111 Tansey, C. Sztalryd, J. Gruia-Gray, et al., Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity, Proc. Natl. Acad. Sci. USA 98 (11) (2001) 6494-6499.
110 R. Preston Mason Ruslan Kubant, Robert F. Jacob, Peter Malinski, Xiaoyan Huang, Febee R. Louka, Jan Borowiec, Yoshiko Mizuno and Tadeusz Malinski. Loss of Arterial and Renal Nitric Oxide Bioavailability in Hypertensive Rats With Diabetes:Effect of β-Blockers. Am J Hypertens 2009;22:1160-1166
112 Martinez-Botas, J.B. Anderson, D. Tessier, et al., Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice, Nat. Genet.26 (4) (2000) 474-479.
113 Mottagui-Tabar S, Ryden M, Lofgren P, Faulds G, Hoffstedt J, Brookes AJ et al. Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis. Diabetologia 2003; 46:789-797.
114 Haemmerle G, Zimmermann R, Strauss JG, et al. Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissuespecific expression pattern of lipoprotein lipase in adipose tissue and muscle. J Biol Chem 2002; 277:12946-12952.
115 Tansey, J. T, A. M. Huml, R. Vogt, K. E. Davis, J. M. Jones, K.2003. Functional studies on native and mutated forms of perilipins a role in protein kinase A-mediated lipolysis of triacylglycerols. Biol. Chem.278:8401-8406.
116 Deram S, Nicolau CY, Perez-Martinez P, Guazzelli I, Halpern A, Wajchenberg BL, Ordovas JM, Villares SM Effects of perilipin (PLIN) gene variation on metabolic syndrome risk and weight loss in obese children and adolescents. J Clin Endocrinol Metab.2008 Dec; 93 (12):4933-40
117 LABBE L, SIROIS C, PILOTE S, et al. Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metab olic ratios of marker substrates. Pharmacogenetics 2000 10(5):425-38.
118 Rau T, Heide R, Bergmann K, Wuttke H, Werner U, Feifel N, Eschenhagen T. Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment. Pharmacogenetics 2002,12,465-472.
119 Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance:Part Ⅰ. Clin Pharmacokinet.2009; 48 (11):689-723
120 Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. Drug Metab Dispos.1999 Mar;27(3):385-8.
121 Nozawa T, Taguchi M, Tahara K, Hashimoto Y, Igarashi N, Nonomura M, Kato B, Igawa A, Inoue H. Influence of CYP2D6 Genotype on Metoprolol Plasma Concentration and b-Adrenergic Inhibition During Long-Term Treatment. J Cardiovasc Pharmacol 2005; 46:713-720
122 Taguchi M, Nozawa T, Kameyama T, Inoue H, Takesono C, Mizukami A, Hashimoto Y.. Effect of CYP2D6*10 on pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients. Eur J Clin Pharmacol.2003 Sep;59(5-6):385-8.
123 Zateyshchikov DA, Minushkina LO, Brovkin AN, Savel'eva EG, Zateyshchikova AA, Manchaeva BB, Nikitin AG, Sidorenko BA, Nosikov VV. Association of CYP2D6 and ADRB1 genes with hypotensive and antichronotropic action of betaxolol in patients with arterial hypertension Fundam Clin Pharmacol.2007 Aug; 21(4):437-43.
124 Bijl MJ, Visser LE, van Schaik RH, Kors JA, Witteman JC, Hofman A, Vulto AG, van Gelder T, Stricker BH. Genetic Variation in the CYP2D6 Gene Is Associated With a Lower Heart Rate and Blood Pressure in β-Blocker Users. Clin Pharmacol Ther.2009 Jan;85(1):45-50.
1 Johnson JA, Terra SG (2002) β-Adrenergic receptor polymorphisms:cardiovascular disease associations and pharmacogenetics. Pharm Res 19:1779-1787
2 Johnson JA, Terra SG (2002) β-Adrenergic receptor polymorphisms:cardiovascular disease associations and pharmacogenetics. Pharm Res 19:1779-1787
3 Levin MC, Marullo S, Muntaner O, Andersson B, Magnusson Y (2002) The myocardium-protective Gly-49 variant of the β1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation. J Biol Chem 277:30429-30435
4 Rathz DA, Brown KM, Kramer LA, Liggett SB (2002) Amino acid 49 polymorphism of the human β1-adrenergic receptor affect agonist-promoted trafficking. J Cardiovasc Pharmacol 39:155-160
5 Mason DA, Moore JD, Green SA, Liggett SB (1999) A gain-of function polymorphism in a G-protein coupling domain of the human β1-adrenergic receptor. J Biol Chem 274:12670-12674
6 Joseph SS, Lynham JA, Grace AA, Colledge WH, Kaumann AJ (2004) Markedly reduced effects of (-)-isoprenaline but not of (-)-CGP12177 and unchanged affinity of beta-blockers at Gly389-betal-adrenoceptors compared to Arg389-betal-adrenoceptors.Br J Pharmacol 142:51-56
7 Molenaar P, Rabnott G, Yang I, Fong KM, Savarimuthu SM, Li L, West MJ, Russell FD (2002) Conservation of the cardiostimulant effects of (-)-norepinephrine across Ser49Gly and Gly389Arg betal-adrenergic receptor polymorphisms in human right atrium in vitro. J Am Coll Cardiol 40:1275-1282.
8 Sandilands AJ, O'Shaughnessy KM, Brown MJ (2003) Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 β1-adrenoceptors versus Gly389 β1-adrenoceptors in isolated human atrial myocardium. Br J Pharmacol 138:386-392
9 Ranade K, Jorgenson E, Sheu WHH, Pei D, Hsiung CA, Chiang F-T, Chen YI, Pratt R, Olshen RA, Curb D, Cox DR, Botstein D, Risch N (2002) A polymorphism in the β1 adrenergic receptor is associated with resting heart rate. Am J Hum Genet 70:935 -942
10 Bengtsson K, Melander O, Orho-Melander M, Lindblad U, Ranstam J, Rastam L, Groop L (2001) Polymorphisms in the β1-adrenergic receptor gene and hypertension. Circulation 104:187-190
11 Humma LM, Puckett BJ, Richardson HE, Terra SG, Andrisin TE, Lejeune BL, Wallace MR, Lewis JF, McNamara M, Picoult-Newberg L, Pepine CJ, Johnson JA. Effects of β-1 AR genetic polymorphisms on resting haemodynamics in patients undergoing diagnostic testing fir ischaemia. Am J Cardiol 2001; 88:1034-7.
12 Tesson F, Charron P, Peuchmaurd M, Nicaud V, Cambien F, Tiret L, Poirier O, Desnos M, Jullieres Y, Amouyel P, Roizes G, Dorent R, Schwartz K, Komajda M, Cardigene Group. A characterization of a unique gene variant in the β-1 AR gene and evaluation of its role in IDCM. J Mol Cell Cardiol 1999; 31:1025-32.
13 Borjesson M, Magnusson Y, Hjalmarson A, Andersson B. A novel polymorphism in the gene coding for the β1-adrenergic receptor associated with survival in patients with heart failure. Eur Heart J 2000; 21:1853-8.
14 White HL, Maqbool A, McMahon AD, Yates L, Ball SG, Hall AS, Balmforth AJ. An evaluation of the β-1 AR Arg389Gly polymorphism in individuals at risk of coronary events. Eur Heart J 2002; 23:1087-92.
15 Tesson, F. et al. (1999) Characterization of a unique genetic variant in the β1-adrenoceptor gene and evaluation of its role in idiopathic dilated cardiomyopathy. CARDIGENE Group. J. Mol. Cell. Cardiol.31,1025-1032.
16 Iwai, C. et al. (2003) Arg389Gly polymorphism of the human β1-adrenergic receptor in patients with nonfatal acute myocardial infarction. Am. Heart J.146, 106-109.
17 Covolo, L. et al. (2004) Role of β1-and β2-adrenoceptor polymorphisms in heart failure:a case-control study. Eur. Heart J.25,1534-1541
18 Small, K.M. et al. (2002) Synergistic polymorphisms of β1-and a2Cadrenergic receptors and the risk of congestive heart failure. N. Engl. J. Med.347,1135-1142.
19 de Groote, P. et al. (2005) The impact of P-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure. Eur. J. Heart Fail.7,966-973
20 Sofowora GG, Dishy V, Muszkat M, Xie G, Kim RB, Harris PA, Prasad HC, Byrne DW, Nair UB, Wood AJ, Stein CM. A common β-1 adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to β-blockade. Clin Pharmacol Ther 2003; 73:366-71.
21 Liu J, Liu ZQ, Tan ZR, Chen XP, Wang LS, Zhou G, Zhou HH. Gly389Arg polymorphism of betal-adrenergic receptor is associated with the cardiovascular response to metoprolol. Clin Pharmacol Ther 2003; 74:372-9.
22 B. J. Puckett, D. F. Pauly, I. Zineh, and J. A. Johnson. Beta adrenergic receptor polymorphisms and antihypertensive response to beta-blocker therapy. Clin. Pharmacol. Ther.71:2 (2002).
23 Liu, J. et al. Betal-Adrenergic receptor polymorphisms influence the response to metoprolol monotherapy in patients with essential hypertension. Clin. Pharmacol. Ther.80,23-32 (2006).
24 O'Shaughnessy KM, Fu B, Dickerson C, Thurston D, Brown MJ. The gain of function variant (R389G) of the β-1 AR does not influence blood pressure or response to b-blockade in hypertensive subjects. Clin Sci (Lond) 2000; 99:233-8.
25 Johnson, J.A., Zineh, I., Puckett, B.J., McGorray, S.P., Yarandi, H.N.& Pauly, D.F. Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin. Pharmacol. Ther.74,44-52 (2003).
26 Pacanowski MA, Gong Y, Cooper-Dehoff RM, Schork NJ, Shriver MD, Langaee TY, Pepine CJ, Johnson JA.β-Adrenergic Receptor Gene Polymorphisms and β-Blocker Treatment Outcomes in Hypertension. Clin Pharmacol Ther.2008 Dec;84(6):715-21
27 Borjesson M, Magnusson Y, Hjalmarson A, Andersson B (2000) A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure. Eur Heart J 21:1853-1858
28 Terra SG, Hamilton KK, Pauly DF, Lee CR, Patterson JH,Adams KF, Schofield RS, Belgado BS, Hill JA, Aranda JM, Yarandi HN, Johnson JA (2005) Betal-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy. Pharmacogenet Genomics 15:227-234
29 Magnusson Y, Levin MC, Eggertsen R, Nystrom E, Mobini R,Schaufelberger M, Andersson B (2005) Ser49Gly of betal-adrenergic receptor is associated with effective beta-blocker dose in dilated cardiomyopathy. Clin Pharmacol Ther 78:221-231
30 Liggett, S.B. et al. A polymorphism within a conserved beta (1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc. Natl. Acad. Sci. USA 103,11288-11293 (2006).
31 Mialet Perez JM, Rathz DA, Petrashevskaya NN, Hahn HS, Wagoner LE, Scwartz A, Dorn ⅡGW, Liggett SB. (3-1 AR polymorphisms confer differential function and predisposition to heart failure. Nature Med 2003; 9:1300-5.
32 Chen L, Meyers D, Javorsky G, Burstow D, Lolekha P, Lucas M, Semmler AB, Savarimuthu SM, Fong KM, Yang IA, Atherton J, Galbraith AJ, Parsonage WA, Molenaar P (2007) Arg389Gly betal-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol. Pharmacogenet Genomics 17:941-949
33 White HL, de Boer RA, Maqbool A, Greenwood D, van Veldhuisen DJ, Cuthbert R, Ball SG, Hall AS, Balmforth AJ. An evaluation of the β-1 AR Arg389Gly polymorphism in individuals with heart failure:a MERIT-HF sub study. Eur J Heart Fail 2003; 5:463-8.
34 Postava L, Mahlab D, Holubkov R, Janosko K, Palmer A, MacGowan G, Murali S, London B, McNamara DM. P-1 AR and β-2 AR polymorphisms and heart failure survival:interaction with β-blockade. Circulation 2002; 105:Abstract 3019.
35 Green SA, Turki J, Innis M, Liggett SB (1994) Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 33:9414-9419
36 Liggett SB. Molecular and genetic basis of beta2-adrenergic receptor function. J Allergy Clin Immunol 1999;104(Pt 2):S42-6.
37 L. K. Chong, J. Chowdry, P. Ghahramani, and P. T. Peachell. Influence of genetic polymorphisms in the beta2-adrenoceptor on desensitization in human lung mast cells. Pharmacogenetics 10:153-162 (2000).
38 Busjahn A, Li G-H, Faulhaber H-D, Rosenthal M, Becker A, Jeschke E, Schuster H, Timmermann B, Hoehe MR, Luft FC (2000) β2-Adrenergic receptor gene variations, blood pressure, and heart size in normal twins. Hypertension 35:555-560,
39 Bengtsson K, Melander O, Orho-Melander M, Lindblad U, Ranstam J, Rastam L, Groop L (2001) Polymorphisms in the β1-adrenergic receptor gene and hypertension. Circulation 104:187-190
40 R. Rosmond, O. Ukkola, M. Chagnon, C. Bouchard, and P.Bjorntorp. Polymorphisms of the beta2-adrenergic receptor gene (ADRB2) in relation to cardiovascular risk factors in men. J. Intern. Med.248:239-244 (2000).
41 P. Kotanko, A. Binder, J. Tasker, P. DeFreitas, S. Kamdar, A. J. Clark, F. Skrabal, and M. Caulfield. Essential hypertension in African Caribbeans associates with a variant of the beta2-adrenoceptor. Hypertension 30:773-776 (1997).
42 Hermann V, Buscher R, Go MM, Ring KM, Hofer JK, Kailasam MT,O'Conner DT, Parmer RJ, Insel PA (2000) β2-Adrenergic receptor polymorphisms at codon 16, cardiovascular phenotypes and essential hypertension in Whites and African Americans. Am J Hypertens 13:1021-1026,
43 Kato N, Sugiyama T, Morita H, Kurihara H, Sato T, Yamori Y, Yazaki Y (2001) Association analysis of β2-adrenergic receptor polymorphisms with hypertension in Japanese. Hypertension 37:286-292
44 M. S. Bray, J. Krushkal, L. Li, R. Ferrell, S. Kardia, C. F. Sing, S.T. Turner, and E. Boerwinkle. Positional genomic analysis identifies the beta(2)-adrenergic receptor gene as a susceptibility locus for human hypertension. Circulation 101:2877-2882 (2000).
45 Iaccarino G, Izzo R, Trimarco V, Cipolletta E, Lanni F, Sorriento D, Iovino GL, Rozza F, De Luca N, Priante O, Di Renzo G, Trimarco B.β2-Adrenergic receptor polymorphisms and treatment-induced regression of left ventricular hypertrophy in hypertension Clin Pharmacol Ther 2006;80:633-45.
46 Joseph J and Gilbert EM The sympathetic nervoos system in chronic heart failure. Prog Cardiovasc Dis.1998.41(Suppl 1):9-16.
47 S. B. Liggett, L. E. Wagoner, L. L. Craft, R. W. Hornung, B. D. Hoit, T. C. McIntosh, and R. A. Walsh. The Ilel64 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J. Clin. Invest. 102:1534-1539(1998).)
48 Covolo, L. et al. (2004) Role of (β1-and β2-adrenoceptor polymorphisms in heart failure:a case-control study. Eur. Heart J.25,1534-1541.
49 Sotoodehnia, N. et al. (2006) P2-adrenergic receptor genetic variants and risk of sudden cardiac death. Circulation 113,1842-1848.
50 Pacanowski MA, Gong Y, Cooper-Dehoff RM, Schork NJ, Shriver MD, Langaee TY, Pepine CJ, Johnson JA.β-Adrenergic Receptor Gene Polymorphisms and β-Blocker Treatment Outcomes in Hypertension. Clin Pharmacol Ther.2008 Dec;84(6):715-21
51 de Groote P, Helbecque N, Lamblin N, Hermant X, Mc Fadden E, Foucher-Hossein C, Amouyel P, Dallongeville J, Bauters C (2005) Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure. Pharmacogenet Genomics 15:137-142
52 Terra SG, Pauly DF, Lee CR, Patterson JH, Adams KF, Schofield RS, Belgado BS, Hamilton KK, Aranda JM, Hill JA, Yarandi HN, Walker JR, Phillips MS, Gelfand CA, Johnson JA. β-Adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure. Clin Pharmacol Ther 2005;77:127-37.
53 Kaye DM, Smirk B, Williams C, Jennings G, Esler M, Holst D (2003) Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics 13:379-382
54 Lelias JM, Kaghad M, Redriguez M et al. Molecular cloning of a human beta3-adrenegic receptor cDNA[J]. FEBS Lett,1993,32,1:127-30
55 Pietri Rouxel F, St John Manning B, Gros J et al, The biochemical effect of the naturally occurring Trp64-Arg mutation on human beta3-adrenoceptor activity [J]. Eur J Biochem,1997,247(3):1174-9
56 Widen, E., Lehto, M., Kanninen, T., Walston, J., Shuldiner, A. R.,& Groop, L. C. (1995). Association of a polymorphism in the beta 3-adrenergicreceptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med 333(6),348-351.
57 Clement, K., Vaisse, C., Manning, B. S., Basdevant, A., Guy-Grand, B., Ruiz, J., et al. (1995). Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med 333(6), 352-354.
58 Corella, D., Guillen, M., Portoles,O., Sorli, J. V., Alonso, V., Folch, J., et al.(2001). Gender specific associations of the Trp64Arg mutation in the beta3-adrenergic receptor gene with obesity-related phenotypes in a Mediterranean population:interaction with a common lipoprotein lipase gene variation. J Intern Med 250(4),348-360.
59 Clement, K., Vaisse, C., Manning, B. S., Basdevant, A., Guy-Grand, B., Ruiz, J., et al. (1995). Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med 333(6), 352-354.
60 Endo, K., Yanagi, H., Hirano, C., Hamaguchi, H., Tsuchiya, S.,& Tomura, S. (2000). Association of Trp64Arg polymorphism of the beta3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity. Int J Obes Relat Metab Disord 24(4),443-449.
61 Tonolo G, Melis MG, Secchi G, Atzeni MM, Angius MF, Carboni A, Ciccarese M, Malavasi A, Maioli M (1999) Association of Trp64Arg (33-adrenergic-receptor gene polymorphism with essential hypertension in the Sardinian population. J Hypertens 17:33-38
62 Baba T, Nakajima S, Yajima Y (1998) β3-adrenergic receptor gene polymorphism is not associated with hypertension in NIDDM patients without nephropathy. Horm Metab Res 30:629-632.
63 Fujisawa T, Ikegami H, Yamato E, Hamada Y, Kamide K, Rakugi H, Higaki J, Murakami H, Shimamoto K, Ogihara T (1997) Trp64Arg mutation of 03-adrenergic receptor in essential hypertension:insulin resistance and the adrenergic system. Am J Hypertens 10:101-105 。
64 Thomas GN, Tomlinson B, Chan JC, Young RP, Critchley JA (2000) The Trp64Arg polymorphism of the β3-adrenergic receptor gene and obesity in Chinese subjects with components of the metabolic syndrome. Int J Obes Relat Metab Disord 24:545-551
65 Strazzullo P, Iacone R, Siani A, Cappuccio FP, Russo O, Barba G, Barbato A, D' Elia L, Trevisan M, Farinaro E (2001) Relationship of the Trp64Arg polymorphism of the β3-adrenoceptor gene to central adiposity and high blood pressure:interaction with age. Cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study. J Hypertens 19:399-406)
66 Moniotte S, Kobzik L, Feron 0, et al. Upregulation of β3-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation,2001,103:1649-1655.
67 Rouget, C., Breuiller-Fouche, M., Mercier, F. J., Leroy, M. J., Loustalot, C.,Naline, E., et al. (2004). The human near-term myometrial beta 3-adrenoceptor but not the beta 2-adrenoceptor is resistant to desensitization after sustained agonist stimulation. Br J Pharmacol 141(5),831-841.
68 Stangl, K., Cascorbi, I., Laule, M., Stangl, V., Meisel, C.,& Wernecke, K. D.(2001). The beta3-adrenergic receptor Trp64Arg mutation is not associated with coronary artery disease. Metabolism 50(2),184-188.
69 Morrison, A. C., Brancati, F. L., Folsom, A. R., Smith, L.,& Boerwinkle, E. (1999). Beta3-adrenergic receptor Trp64Arg polymorphism does not predict incident CHD or carotid intima-media thickness in a community-based sample of whites:the ARIC study. Atherosclerosis Risk in Communities. Hum Genet 105(4),314-319.
70 Tamaki, S., Iwai, N., Tsujita, Y., Nakamura, Y., Ohmichi, N.,& Kinoshita, M. (1999). Variant of the beta3-adrenergic receptor gene and coronary atherosclerosis in Japanese subjects. Int J Cardiol 69(3),309-311.
71 Thomas, G. N., Tomlinson, B., Chan, J. C., Young, R. P.,& Critchley, J. A. (2000). The Trp64Arg polymorphism of the beta3-adrenergic receptor gene and obesity in Chinese subjects with components of the metabolic syndrome. Int J Obes Relat Metab Disord 24(5),545-551.
71 Saino A, Pomidossi G, Perondi R, Valentini R, Rimini A, Di Francesco L, Mancia G. Intracoronary angiotensin II potentiates coronary sympathetic vasoconstrictions in humans. Circulation 1997; 96:148-153.
72 Saino A, Pomidossi G, Perondi R, Morganti A, Turolo L, Mancia G. Modulation of sympathetic coronary vasoconstriction by cardiac rennin angiotensin system in human coronary artery disease. Circulation 2000; 101:2277-2283。
73Karin Malmqvist, K. Peter Ohman, Lars Lind, Fredrik Nystrom, and Thomas Kahan Long-Term Effects of Irbesartan and Atenolol on the Renin-Angiotensin-Aldosterone System in Human Primary Hypertension J Cardiovasc PharmacolTM 2003;42:719-726
74 Blumenfeld JD, Sealey JE, Mann SJ, et al. Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensinaldosterone system in normotensive and hypertensive subjects. Am J Hypertens.1999;12:451-459.
75Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.
76 Zhu X, McKenzie CA, Forrester T, Nickerson DA, Broeckel U, Schunkert H, Doering A, Jacob HJ, Cooper RS, Rieder MJ. Localization of a small genomic region associated with elevated ACE. Am J Hum Genet 2000; 67:1144-1153.
77Timo Suonsyrj, Tuula Hannila-Handelberg, Heidi Fodstad, Kati Donner, Kimmo Kontula and Timo P. Hiltunenl Renin-Angiotensin System and a-Adducin Gene Polymorphisms and Their Relation to Responses to Antihypertensive Drugs:Results From the GENRES Study Am J Hypertens 2009;22:169-175
78Hedi Schelleman, Olaf H Klungel, Cornelia M van Duijn, Jacqueline CM Witteman, Albert Hofman, Anthonius de Boer, and Bruno HCh Stricker Drug-Gene Interaction Between the Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Antihypertensive Therapy Ann Pharmacother 2006;40:212-8.
79 H Schelleman, BHCh Stricker, WMM Verschuren, A de Boer, AA Kroon, PW de Leeuw, D Kromhout and OH Klungel Interactions between five candidate genes and antihypertensive drug therapy on blood pressure. The Pharmacogenomics Journal (2006)6,22-26
80 Dudley C, Keavney B, Casadei B, Conway J, Bird R, Ratcliffe P Prediction of patient responses to antihypertensive drugs using genetic polymorphisms: investigation of renin-angiotensin system genes. J Hypertens.1996 Feb;14(2):259-62
81 Kurland L, Melhus H, Karlsson J, Kahan T, Malmqvist K, Ohman KP, Nystrom F, Hagg A, Lind L Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients. J Hypertens.2001 Oct; 19(10):1783-7
82Bei Sun, Ekaterina Kintsurashvili, Deborah Ona, Ivana Ignjacev-Lazich, Irene Gavras, and Haralambos Gavras. Inhibition of the α 1D-Adrenergic Receptor Gene by RNA interference (RNAi) in Rat Vascular Smooth Muscle Cells and its effects on other adrenergic receptors. Vascul Pharmacol.2007 May; 46(5):367-372.
83张幼怡韩启德α1与β肾上腺素受体间的交互作用基础医学与临床1997,17：241-24584余细勇林曙光肾上腺素受体亚型的调节及其交互作用国外医学·生理、病理科学与临床手册1998.18(2)125-129
85 Skomedal T, et al. J Pharmacol Exp Ther,1988,247:1204
86 Tanoue A, Nasa Y, Koshimizu Shinoura H, Oshikawa S, KawaiT, et al. The alpha (1 D)(?) adrenergic receptor directly regulates arterial blood pressure via vasoconstriction. J Clin Invest 2002:109:765-75.
87 Duka I, Gavras I, Johns C, Handy DE, Gavras H. Role of the postsynaptic a 2-adrenergic receptor subtypes in catecholamine-induced vasoconstriction. Gen Pharmacol The Vascular System 2000; 34:101-106.
88 Bei Sun, Ekaterina Kintsurashvili, Deborah Ona, Ivana Ignjacev-Lazich, Irene Gavras, and Haralambos Gavras. Inhibition of the α 1D-Adrenergic Receptor Gene by RNA interference (RNAi) in Rat Vascular Smooth Muscle Cells and its effects on other adrenergic receptors. Vascul Pharmacol.2007 May; 46(5):367-372.
89 GISBERT, R., ZIANI, K., MIQUEL, R., NOGUERA, M.A., IVORRA,M.D., ANSELMI, E.& D'OCON, P. (2002). Pathological role of a constitutively active population of alD-adrenoceptors in arteries of spontaneously hypertensive rats. Br. J. Pharmaco.,135,206-216.
90 GARCI'A-SA'INZ, J.A.& VILLALOBOS-MOLINA, R. (2004). The elusive alD-adrenergic receptor:molecular and cellular characteristics and integrative roles. Eur. J. Pharmacol.,500,113-120.
91 Akito Tanoue, Masahiro Koba, Shigeki Miyawaki, Taka-aki Koshimizu, Chihiro Hosoda, Sayuri Oshikawa, Gozoh Tsujimoto Role of the αlD-Adrenegric Receptor in the Development of Salt-Induced Hypertension. Hypertension.2002;40:101-106.
92 Hu, Z.W., Shi, X.Y., Okazaki, M., and Hoffman, B.B. Angiotensin II induces transcription and expression of alpha-1 adrenergic receptors in vascular smooth muscle cells. Am. J. Physiol.268, H1006-H1014(1995).
93 Schiffrin, E.L., Thome, F.S., and Genest, J. Vascular angiotensin II receptors in SHR. Hypertension 6,682-688 (1984)
94 Gisbert, R., Ziani, K., Miquel, R., Noguera, M.A., Ivorra, M.D., Anselmi, E., and D'Ocon, P. Pathological role of a constitutively active population of alD-adrenoceptors in arteries of spontaneously hypertensive rats. Br. J. Pharmacol. 135,206-216(2002).
95 D. Godi'nez-Herna'ndez, I. A. Gallardo-Orti'z, P. Lo'pez-Sa'nchez & R. Villalobos-Molina Captopril therapy decreases both expression and function of a1D-adrenoceptors in prehypertensive rat aorta. Autonomic & Autacoid Pharmacology,2006,26,21-29
96李艳芳 张幼怡 吕志珍 韩启德 长期饮用普萘洛尔对大鼠心脏α1肾上腺素受体亚型数量的影响中国药理学与毒理学杂志1996年11月：11：281-284
97 Nonen, H Okamoto,Y Fujio, Y Takemoto, M Yoshiyama, T Hamaguchi, Y Matsui, J Yoshikawa, A Kitabatake and J Azuma Polymorphisms of norepinephrine transporter and adrenergic receptor alD are associated with the response to b-blockers in dilated cardiomyopathy The Pharmacogenomics Journal (2008) 8,78-84
98 Aggarwal A, Esler MD, Socratous F, Kaye DM. Evidence for functional presynaptic alpha-2 adrenoreceptors and their down-regulation in human heart failure. J Am Coll Cardiol 2001; 37:1246-1251.
99 Lahdesmaki J et al. Behavioral and neurochemical characterization of alpha(2A)-adrenergic receptor knockout mice Neuroseience,2002,1 13(2): 289-299
100 Brede M, Wiesmann F, Jahns R, et al. Feedback inhibition of catecholamine release by two different alpha 2-adrenoceptor subtypes prevents progression of heart failure. Circulation 2002; 106:2491-2496.
101 Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB (2000) A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem 275:23059-23064)
102 Hein L, Altman JD, Kobilka BK (1999) Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature 402:181-184
103 Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB. Synergistic polymorphisms of betal-and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 2002; 347:1135-1142.
104 Nonen S, Okamoto H, Akino M, Matsui Y, Fujio Y, Yoshiyama M, Takemoto Y, Yoshikawa J, Azuma J, Kitabatake A (2005) No positive association between adrenergic receptor variants of alpha2cDel322-325, betalSer49, betal Arg389 and the risk for heart failure in the Japanese population. Br J Clin Pharmacol 60:414-417
105 Metra M, Zani C, Covolo L, Nodari S, Pezzali N, Gelatti U, Donato F, Nardi G, Dei Cas L (2006) Role of betal-and alpha2c-adrenergic receptor polymorphisms and their combination in heart failure:a case-control study. Eur J Heart Fail 8:131-135
106 Lobmeyer MT, Gong Y, Terra SG, Beitelshees AL, Langaee TY, Pauly DF, Schofield RS, Hamilton KK, Herbert Patterson J, Adams KF, Hill JA, Aranda JM, Johnson JA (2007) Synergistic polymorphisms of betal and alpha2C-adrenergic receptors and the influence on left ventricular ejection fraction response to beta-blocker therapy in heart failure. Pharmacogenet Genomics 17:277-282
107 Kobayashi H, Adachi-Akahane S, Nagao T. Involvement of BKCa channels in the relaxation of detrusor muscle via beta-adrenoceptors. Eur J Pharmacol 404: 231-238,2000
108 Petkov GV and Nelson MT. Differential regulation of Ca2+-activated K+ channels by beta-adrenoceptors in guinea pig urinary bladder smooth muscle.Am J Physiol Cell Physiol 288:C1255-C1263,2005
109 Pelaia G, Gallelli L, Vatrella A, Grembiale RD, Maselli R, De Sarro GB, Marsico SA (2002) Potential role of potassium channel openers in the treatment of asthma and chronic obstructive pulmonary disease. Life Sci 70:977-990
110 Liu G, Shi J, Yang L, Cao L, Park SM, Cui J, Marx SO Assemble of pendent BK channelgnaling complex by binding to β2 adrenergic receptor. EMBO J.2004 Jun 2;23(11):2196-205.
111 Brown SM, Bentcheva-Petkova LM, Liu L, Hristov KL, Chen M, Kellett WF, Meredith AL, Aldrich RW, Nelson MT, Petkov GV.β-Adrenergic relaxation of mouse urinary bladder smooth muscle in the absence of large-conductance Ca2+-activated K+channel. Am J Physiol Renal Physiol.2008 Oct;295(4):F1149-57
112 Fernandez-Fernandez JM, Tomas M, Vazquez E, Orio P, Latorre R, Senti M, et al. Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. J Clin Invest 2004; 113:1032-1039.
113 Senti M, Fernandez-Fernandez JM, Tomas M, Vazquez E, Elosua R, Marrugat J, Valverde MA. Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk. Circ Res 2005.
114 Zhao Q, Wang L, Yang W, Chen S, Huang J, Fan Z, Li H, Lu X, Gu D. Interactions among genetic variants from contractile pathway of vascular smooth muscle cell in essential hypertension susceptibility of Chinese Han population. Pharmacogenet Genomics.2008 Jun;18(6):459-66.
115 Kelley-Hedgepeth A, Peter I, Kip K, Montefusco M, Kogan S, Cox D, Ordovas J, Levy D, Reis S, Mendelsohn M, Housman D, Huggins G The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with beta-blockade. Journal of Human Hypertension (2008) 22,512-515;
116 Kobayashi N, Mori Y, Nakano S。 et al. Cellprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in deoxyeortieesterone acetate-salt hypertensive rats. J Hypertens,2001 。 19(4): 795.801
117 Yosimura M, Yasue H, Nakayama M, et al. A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese [J]. Hum Genet,1998,103:65-69.
118 Hingorani AD. Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep,2003,5:19-25.
119 Wang X L, Mahaney M C, Sim A S, Wang J, Wang J, BlangeroJ, Almasy L, Badenhop R B, W ilcken D E Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels. Arterioscler Thromb Vobc Biol.1997,17(11):3147-3153.
120 Y Miyamoto Y, Saito Y, Kajiyama N, Yoshimura M, Shimasaki Y, Nakayama M, Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertens,1998,32(1):3-8.
121李东宝,华琦.皮林.内皮型一氧化氮合酶基因G894T多态性与原发性高血压的相关关系。高血压杂志,2004,12(4)：326—330.
122 Iturry Yamamoto GR, Moriguchi EH, Zago AC, et al. Association of the 894G>T polymorphism of the endothelial constitutive nitric oxide synthase gene with unstable angina. Braz J Med Biol Res.2007。 40(4):475-483.
123 Pacanowski MA, Zineh I, Cooper-Dehoff RM, Pepine CJ, Johnson JA. Genetic and pharmacogenetic associations between NOS3 polymorphisms, blood pressure, and cardiovascular events in hypertension. Am J Hypertens.2009 Jul;22(7):748-53.
124 Lennard, M.S., Silas, J.H., Freestone, S., Ramsay, L.E., Tucker, GT.& Woods, H.F. Oxidation phenotype-a major determinant of metoprolol metabolism and response. N. Engl. J. Med(1982).307,1558-1560
125 Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance:Part Ⅰ. Clin Pharmacokinet.2009;48(11):689-723
126 Bijl MJ, Visser LE, van Schaik RH, Kors JA, Witteman JC, Hofman A, Vulto AG, van Gelder T, Stricker BH. Genetic Variation in the CYP2D6 Gene Is Associated With a Lower Heart Rate and Blood Pressure in β-Blocker Users. Clin Pharmacol Ther.2009 Jan;85(1):45-50.
127 Zateyshchikov DA, Minushkina LO, Brovkin AN, Savel'eva EG, Zateyshchikova AA, Manchaeva BB, Nikitin AG, Sidorenko BA, Nosikov VV. Association of CYP2D6 and ADRB1 genes with hypotensive and antichronotropic action of betaxolol in patients with arterial hypertension Fundam Clin Pharmacol.2007 Aug;21(4):437-43.
2李娜等β肾上腺素受体和G蛋白的基因多态性与美托洛尔药效学和血脂升高的相关性研究
3 Saino A, Pomidossi G, Perondi R, Valentini R, Rimini A, Di Francesco L, Mancia G. Intracoronary angiotensin Ⅱ potentiates coronary sympathetic vasoconstrictions in humans. Circulation 1997; 96:148-153.
4 Saino A, Pomidossi G, Perondi R, Morganti A, Turolo L, Mancia G Modulation of sympathetic coronary vasoconstriction by cardiac rennin angiotensin system in human coronary artery disease. Circulation 2000; 101:2277-2283
5 Karin Malmqvist, K. Peter Ohman, Lars Lind, Fredrik Nystrom, and Thomas Kahan Long-Term Effects of Irbesartan and Atenolol on the Renin-Angiotensin-Aldosterone System in Human Primary Hypertension J Cardiovasc PharmacolTM 2003;42:719-726
6 Blumenfeld JD, Sealey JE, Mann SJ, et al. Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensinaldosterone system in normotensive and hypertensive subjects. Am J Hypertens.1999;12:451-459.
7 Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.
8 Zhu X, McKenzie CA, Forrester T, Nickerson DA, Broeckel U, Schunkert H, Doering A, Jacob HJ, Cooper RS, Rieder MJ. Localization of a small genomic region associated with elevated ACE. Am J Hum Genet 2000; 67:1144-1153.
9 Bei Sun, Ekaterina Kintsurashvili, Deborah Ona, Ivana Ignjacev-Lazich, Irene Gavras, and Haralambos Gavras. Inhibition of the α 1D-Adrenergic Receptor Gene by RNA interference (RNAi) in Rat Vascular Smooth Muscle Cells and its effects on other adrenergic receptors. Vascul Pharmacol.2007 May; 46(5):367-372.
10张幼怡韩启德(α1与β肾上腺素受体间的交互作用基础医学与临床1997,17：241-245
11余细勇林曙光肾上腺素受体亚型的调节及其交互作用国外医学·生理、病理科学与临床手册1998.18(2)125-129
12 Skomedal T, et al. Both alpha and beta adrenoceptor-mediated components contribute to final inotropic response to norepinephrine in rat heart J Pharmacol Exp Ther,1988,247:1204
13 Tanoue A, Nasa Y, Koshimizu Shinoura H, Oshikawa S, KawaiT, et al. The alpha (1 D)- adrenergic receptor directly regulates arterial blood pressure via vasoconstriction. J Clin Invest 2002:109:765-75.
14 Akito Tanoue, Masahiro Koba, Shigeki Miyawaki, Taka-aki Koshimizu, Chihiro Hosoda, Sayuri Oshikawa, Gozoh Tsujimoto Role of the α1D-Adrenegric Receptor in the Development of Salt-Induced Hypertension. Hypertension.2002;40:101-106.
15李艳芳 张幼怡 吕志珍 韩启德长期饮用普萘洛尔对大鼠心脏α1肾上腺素受体亚型数量的影响中国药理学与毒理学杂志1996年11月：11：281-284
16 S Nonen, H Okamoto,Y Fujio, Y Takemoto, M Yoshiyama, T Hamaguchi, Y Matsui, J Yoshikawa, A Kitabatake and J Azuma. Polymorphisms of norepinephrine transporter and adrenergic receptor alD are associated with the response to β-blockers in dilated cardiomyopathy. The Pharmacogenomics Journal (2008) 8,78-84
17 Wellman GC, Cartin L, Eckman DM, Stevenson AS, Saundry CM, Lederer WJ, Nelson MT. Membrane depolarization, elevated Ca(2+) entry, and gene expression in cerebral arteries of hypertensive rats. Am J Physiol Heart Circ Physiol 2001; 281:H2559-H2567.
18 Davare MA, Avdonin V, Hall DD, Peden EM, Burette A,Weinberg RJ,Horne MC, Hoshi T, Hell JW (2001) A beta2 adrenergic receptor signaling complex assembled with the Ca2+ channel Cav1.2. Science 293:98-101
19 Brown SM, Bentcheva-Petkova LM, Liu L, Hristov KL, Chen M, Kellett WF, Meredith AL, Aldrich RW, Nelson MT, Petkov GV.β-Adrenergic relaxation of mouse urinary bladder smooth muscle in the absence of large-conductance Ca2+-activated K+channel. Am J Physiol Renal Physiol.2008 Oct;295(4):F1149-57
20 Pluger S, Faulhaber J, Furstenau M, Lohn M, Waldschutz R, Gollasch M, et al. Mice with disrupted BK channel betal subunit gene feature abnormal Ca(2+) spark/STOC coupling and elevated blood pressure. Circ Res 2000; 87:E53-E60.
21 Brenner R, Perez GJ, Bonev AD, Eckman DM, Kosek JC, Wiler SW, et al. Vasoregulation by the betal subunit of the calcium-activated potassium channel. Nature 2000; 407:870-876.
22 Fernandez-Fernandez JM, Tomas M, Vazquez E, Orio P, Latorre R, Senti M, et al. Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. J Clin Invest 2004; 113:1032-1039.
23 Senti M, Fernandez-Fernandez JM, Tomas M, Vazquez E, Elosua R, Marrugat J, Valverde MA. Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk. Circ Res 2005.
24 Kelley-Hedgepeth A, Peter I, Kip K, Montefusco M, Kogan S, Cox D, Ordovas J, Levy D, Reis S, Mendelsohn M, Housman D, Huggins G. The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with beta-blockade. Journal of Human Hypertension (2008) 22,512-515
25Yosimura M, Yasue H, Nakayama M, et al. Amissense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese [J]. Hum Genet,1998,103:65-69.
26 Hingorani AD. Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep,2003,5:19-25.
27 Wang X L, Mahaney M C, Sim A S, Wang J, Wang J, BlangeroJ, Almasy L, Badenhop R B, W ilcken D E Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels. Arterioscler Thromb Vobc Biol.1997,17(11):3147-3153.
28 Y Miyamoto Y, Saito Y, Kajiyama N, Yoshimura M, Shimasaki Y, Nakayama M, Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertens,1998,32(1):3-8.
29 asujima M, Tsutaya S, Shoji M Endothelial nitric oxide synthase gene polymorphism and hypertension Rinsho Byori,1998,46(12):1199- 1204.
30李东宝,华琦.皮林.内皮型一氧化氮合酶基因G894T多态性与原发性高血 压的相关关系。高血压杂志,2004,12(4)：326—330.
31 Jachymova M, Horky K, Bultas J, et al. Association of the Glu298Asp polymorphism in the endothelial nitric oxide synthase gene with essential hypertension resistant to conventional therapy[J]. Biochem Biophys Res Commun, 2001,284:426-430.
32 Tuomo R, Treva R, Louis P, etal. NOS3 Glu298Asp genotype and blood pressure response to endurance training. The HERITAGE family study[J]. Hypertension, 2000,36:885-889.
33 Kim JS Endothelial nitric oxide synthase Glu298Asp gene polymorphism is associated with hypertensive response to exercise in well-controlled hypertensive patients. Yonsei Med J.2007 Jun 30;48(3):389-95
34 Greenberg, A. S., J. J. Egan, S. A. Wek, N. B. Garty, E. J. Blanchette-Mackie, and C. Londos.1991. Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets. J. Biol. Chem. 266:11341-11346.
35 Brasaemle, D. L., Rubin, B., Harten, I. A., Gruia-Gray, J., Kimmell, A. R. and Londos, C. (2000) Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J. Biol. Chem.275,38486-38493
36 Martinez-Botas, J., Anderson, J. B., Tessier, D., Lapiilonne, A., Chang, B. H.-J., Quast, M. J., Gorenstein, D., Chen, K..-H. and Chan, L. (2000) Absence of perilipin results in leanness and reverses obesity in Leprdb/db mice. Nat. Genet.26,474-479
37Tansey, J. T., Sztalryd, C., Gruia-Gray, J., Roush, D. L., Zee, J. V., Gavrilova, O., Reitman, M. L., Deng, C.-X., Li, C., Kimmel, A. R. and Londos, C. (2001) Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc. Natl. Acad. Sci. U.S.A.98, 6494-6499
38 Clifford, G. M., Londos, C., Kraemer, F. B., Vernon, R. G. and Yeaman, S. J. (2000) Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation of rat adipocytes. J. Biol. Chem.275,5011-5015
39 Martinez-Botas, J., Anderson, J.B., Tessier, D., Lapillonne, A., Chang, B.H., Quast, M.J., Gorenstein, D., Chen, K.H. and Chan, L. (2000) Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. Nat. Genet. 26,474-479
40 Tansey, J.T., Sztalryd, C., Gruia-Gray, J., Roush, D.L., Zee, J.V., Gavrilova, O., Reitman,. (2001) Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity.Proc. Natl. Acad. Sci. U.S.A.98,6494-6499
41 Mottagui-Tabar S, Ryden M, Lofgren P, Faulds G, Hoffstedt J, Brookes AJ et al. Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis. Diabetologia 2003; 46:789-797.
42 Qi L, Corella D, Sorli JV, Portoles O, Shen H, Coltell O et al. Genetic variation at the perilipin (PLIN) locus is associated with obesity-related phenotypes in White women. Clin Genet 2004; 66:299-310.
43 Weili Yan, Shufeng Chen, Jianfeng Huang, Yan Shen, Boqin Qiang, and Dongfeng Gu Polymorphisms in PLIN and Hypertension Combined with Obesity and Lipid Profiles in Han Chinese Obes Res.2004; 12:1733-1737.
44 van der Vliet H N, Sammels M G, Leegwater A C, Levels J H, Reitsma P H, Boers W, Chamuleau R A. Apolipoprotein AV a novel apolipoprotein associated with an early phase of liver regeneration. J Bio Chem,2001,276:44512-44520
45刘琼,赵水平.APOA5单克隆抗体的制备及其临床初步应用[J].医学临床研究,2006；23(2)：153-6.
46 Remen Apolipoprotein AV:low concentration, high impact. Arterioscler Thromb Vasc Biol 2005,25(12) 2445-2447
47 Pennacchio LA. Rubin EM. Apolipoprotein A5. a newly identified gene that affects plasma triglyceride levels in human s an d mice. Arterioseler Thromb Vasc Biol,2003.23:529-534.
48 Olofeson SO. ApoA-V:the regulation of a regulator of plasma triglyceride. Arterioscler Thromb Vasc Biol 2005,25(6) 1097-99
49李国平,陈保生载脂蛋白家族新成员：载脂蛋白A5基因研究进展.中国动脉硬化杂志2004,112(2)：229-232
50 Nowak M. Helleboid-Chapman A, Jakel H, et al. Insulin-mediated down regulation of apolipoprotein A5 gene expression through the phosphatidylinositol 3-kinase pathway:rule of upstream stimulatory factor [J). Mol Cell Biol,2005; 25(4): 1537-43
51 Seda O, Sedova L New apolipoprotein AV:comparative genomics meets metabolism Physiol Res,2003,52:141- 146.
52 Baum L. Tomlinson B. Thomas GN. ApoA5-1131T> C polymorphism is associated with triglyceride levels in Chinese men. Clin Genet.2oo3.63:377-379.
53 Lai CQ, Tai ES, Tan CE, et al. The APOA5 locus is a strong determinant of plasma triglyceride concentrations across ethnic groups in Singapore. J Lipid Res, 2003,44:2365-2373.
54 Nabika T, Nasre n S, Kobayashi S, Masuda J The genetic effect of the apoprotein AV gene on the serum triglyceride level in Japanese. Atherosclerosis 2002,165: 201-204.)
55 Pasalic D, Sertic J, Kunovic B, et al. Lipoprotein lipase gene polymorphism and lipid profile in patients with hypertriglycerdemia. Clinical Sciences.2001; 42: 517.22
56 Tu X, Tu J, W en X, Wang J, Zhang D. A study of lipoprotein lipase gene intron 8 polymorphisms in Chinese Han race essential hypertension patients. Int J Cardiol, 2005,99(2):263-267.
57Hendemon HE, Kastelein JJ, Zwinderman AH, et al. Lipoprotein lipase activity is decreased in a large cohort of patients with coronary artery disease and is associated with changes in lipids and lipoproteins. J Lipid Res,1999.40:735-743.
58Wittrnp HH, Nordestgaard BG Stefensen R, Jensen G Tybjaerg-Hansen A. Effect of gender on phenotypic expression of the S447X mutation in LPL:the Copenhagen city heart study. Atherosclerosis,2002,165(1):119 - 126.
59官国东 徐恩 王小娟 许寅宏 邱少东 脂蛋白脂酶Ser447Ter基因多态性与动脉硬化性脑梗死的相关研究中华医学遗传学杂志2006年10月第23卷第5期519-523页
60 Regardh, C.G.& Johnsson, G. Clinical pharmacokinetics of metoprolol. Clin. Pharmacokinet (1980).5,557-569.
61 Lennard, M.S., Silas, J.H., Freestone, S., Ramsay, L.E., Tucker, G.T.& Woods, H.F. Oxidation phenotype-a major determinant of metoprolol metabolism and response. N. Engl. J. Med(1982).307,1558-1560.)
62 Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity Of CYP2D6 in Chinese. Drug Metab Dispos 1999; 27(3):385-80
63 Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus:characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol.1994 Sep;46(3):452-9.
64Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. Drug Metab Dispos.1999 27(3):385-8.
65 Garcia-Barcelo M, Chow LY, Chiu HF, Wing YK, Lee DT, Lam KL, Waye MM. Genetic analysis of the CYP2D6 locus in a Hong Kong Chinese population. Clin Chem 2000,46(1):18-23.
66 Ji L, Pan S, Wu J, Marti-Jaun J, Hersberger M.. Genetic polymorphisms of CYP2D6 in Chinese mainland. Chin Med J (Engl).2002 Dec; 115(12):1780-4.
67Gao Y, Zhang Q. Polymorphisms of the GSTM1 and CYP2D6 genes associated with susceptibility to lung cancer in Chinese. Mutat Res,1999,444(2):441-449
68Taguchi M, Nozawa T, Kameyama T, Inoue H, Takesono C, Mizukami A, Hashimoto Y.. Effect of CYP2D6*10 on pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients. Eur J Clin Pharmacol.2003 Sep;59(5-6):385-8.
69 Huang J., Chuang S.K., Cheng C.L., Lai M.L. Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes. Clin. Pharmacol. Ther. (1999)65 402-407.
70 Huang J., Chuang S.K., Cheng C.L., Lai M.L. Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes. Clin. Pharmacol. Ther. (1999)65 402-407.
71 Agema WR, Jukema JW, Zwinderman AH, Wall EE van der:A metaanalysis of the angiotensin-converting enzyme gene polymorphism and restenosis after percutaneous transluminal coronary revascularization:evidence for publication bias. Am Heart J 2002,144:760-768.
72 Danser AH, Schalekamp MA, Bax WA, Brink AM van den, Saxena PR, Riegger GA, Schunkert H:Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation 1995,92:1387-1388.
73 Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.
74 Zhu X, McKenzie CA, Forrester T, Nickerson DA, Broeckel U, Schunkert H, Doering A, Jacob HJ, Cooper RS, Rieder MJ. Localization of a small genomic region associated with elevated ACE. Am J Hum Genet 2000; 67:1144-1153.
75 Kurland L, Melhus H, Karlsson J, Kahan T, Malmqvist K, Ohman KP, et al. Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin Ⅱ receptor type 1 antagonist treatment in hypertensive patients. J Hypertens 2001; 19:1783-4787.
76 Schelleman H, Klungel OH, van Duijn CM, Witteman JC, Hofman A, de Boer A, et al. Drug-Gene Interaction Between the Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Antihypertensive Therapy. Ann Pharmacother 2006; 40:212-218.
77 Schelleman H, Stricker BH, Verschuren WM, de Boer A, Kroon AA, de Leeuw PW, et al. Interactions between five candidate genes and antihypertensive drug therapy on blood pressure. Pharmacogenomics J 2006; 6:22-26.
78 Suonsyrja T, Hannila-Handelberg T, Fodstad H, Donner K, Kontula K, Hiltunen TP. Renin-Angiotensin System and α-Adducin Gene Polymorphisms and Their Relation to Responses to Antihypertensive Drugs:Results From the GENRES Study. Am J Hypertens 2009; 22:169-175
79 Kolloch R, Legler UF, Champion A, Cooper-Dehoff RM, Handberg E, Zhou Q, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease:findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J 2008; 29:1327-1334.
80 Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol 2008; 101:865-869.
81 Shepherd JT, Mancia G. Reflex control of the human cardiovascular system. Rev Physiol Biochem Pharmacol 1986; 105:1-99.
82 Parati G, Saul JP, Di Rienzo M, Mancia G. Spectral analysis of blood pressure and heart failure variability in evaluating cardiovascular regulation. Hypertension 1995; 25:1276-1286.
83 Mancia G, Daffonchio A, Di Rienzo M, Ferrari AU, Grassi G. Methods to quantify sympathetic cardiovascular influences. Eur Heart J 1998; 19:F7-F13.
84 Montgomery HE, Marshall R, Hemingway H, et al. Human gene for physical performance. Nature 1998;393:221-2
85 Heled Yuval, Daniel S. Moran, Liran Mendel, Arie Laor, Elon Pras, and Yair Shapiro. Human ACE I/D polymorphism is associated with individual differences in exercise heat tolerance. J Appl Physiol 97:72-76,2004
86 Euan A. Ashley, Attila Kardos, Ewan S. Jack, Walter Habenbacher, Mathew Wheeler, Young M. Kim, Jeffrey Froning, Jonathan Myers, Gregory Whyte, PHD, Victor Froelicher, Pamela Douglas Angiotensin-Converting Enzyme Genotype Predicts Cardiac and Autonomic Responses to Prolonged Exercise J Am Coll Cardiol 2006;48:523-31
87 1996 Heart rate variability:standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 93:1043-1065
88 Kupper NH, Willemsen G, van den Berg M, de Boer D, Posthuma D, Boomsma DI, de Geus EJ. Heritability of ambulatory heart rate variability. Circulation 2004; 110:2792-2796.
89 Singh JP, Larson MG, O'Donnell CJ, Tsuji H, Evans JC, Levy D. Heritability of heart rate variability:the Framingham Heart Study. Circulation 1999;99:2251-2254.
90 Andreas Busjahn, Andreas Voss, Hans Knoblauch, Margit Knoblauch, Eva Jeschke, Niels Wessel, Ju'rgen Bohlender, Jesse McCarron, BS, Hans-Dieter Faulhaber, Herbert Schuster, Rainer Dietz, and Friedrich C. Luft, Angiotensin-Converting Enzyme and Angiotensinogen Gene Polymorphisms and Heart Rate Variability in Twins Am J Cardiol 1998;81:755-760
91 Julian F. Thayer, Marcellus M. Merritt, John J. Sollers Ⅲ, Alan B. Zonderman, Michele K. Evans, Sue Yie, and Darrell R. Abernethy Effect of Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism DD Genotype on High-Frequency Heart Rate Variability in African Americans Am J Cardiol 2003;92:1487-1490
92 Reid IA. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol. 1992;262:E763-E778
93 Wei-Zhong Wang, Lie Gao, Yan-Xia Pan, Irving H. Zucker, and Wei Wang AT1 receptors in the nucleus tractus solitarii mediate the interaction between the baroreflex and the cardiac sympathetic afferent reflex in anesthetized rats Am J Physiol Regul Integr Comp Physiol 292:R1137-R1145,2007
94 Campagnole-Santos MJ, Diz DI, Ferrario CM. Baroreceptor reflex modulation by angiotensin II at the nucleus tractus solitarii. Hypertension 11:1167-1171,1988.
95 Matsumura K, Averill DB, Ferrario CM. Angiotensin II acts at AT1 receptors in the nucleus of the solitary tract to attenuate the baroreceptor reflex. Am J Physiol Regul Integr Comp Physiol 275:R1611-R1619,1998.
96 Saqib CHOWDHARY, G Andre N G, Sarah L NUTTALL, John H COOTE. Hamish F ROSS, Jonathan N TOW NEND. Nitric oxide and cardiac parasympathetic control in human heart failure Clinical Science,2002,102:397-402
97 Yun He Liu, Jiang Xu, Xiao-Ping Yang, Fang Yang, Edward Shesely, Oscar A Carretero. Effect of ACE inhibitors and angiotensin II Type 1receptor antagonists on endothelial NO synthase knockout mice with heart failure. Hypertension,2002,39: 375-381
98 Fujiwara N, Osanai T, Kamada T, et al. Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension:modulation of nitric oxide synthesis by salt intake[J]. Circulation,2000,101:856-861.
99 Tanus-Santos JE, Desai M, Flockhart DA Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics.2001 Nov;11(8):719-25
100王从菊 赵景波 许加亮 向泽林 梁长威 李杰 中国人内皮型一氧化氮合酶基因G894T多态性与原发性高血压关系的Meta分析中华流行病学杂志2009年第30卷第8期845-849页
101 Node K, Kitakaze M, Yoshikawa H, Kosaka H, Hori M. Reduced plasma concentrations of nitrogen oxide in individuals with essential hypertension. Hypertension 1997; 30:405-408.
102 Mason RP, Kubant R, Jacob RF, Walter MF, Boychuk B, Malinski T. Effect of nebivolol on endothelial nitric oxide and peroxynitrite release in hypertensive animals: Role of antioxidant activity. J Cardiovasc Pharmacol 2006; 48:862-869.
103 Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T:Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88:14-22,2001 104 Forstermann U, Munzel T: Endothelial nitric oxide synthase in vascular disease:from marvel to menace. Circulation 113:1708-1714,2006
105 Sharma, V., Dhillon, P.,Wambolt, R., Parsons, H., Brownsey, R., Allard, M.F., McNeill, J.H.,2008. Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin (STZ) diabetic rat. Am. J. Physiol. Heart Circ. Physiol.294, H1609-H1620.
106 Vijay Sharma, Hannah Parsons, Michael F. Allard, John H. McNeill Metoprolol increases the expression of β3-adrenoceptors in the diabetic heart:Effects on nitric oxide signaling and forkhead transcription factor-3. European Journal of Pharmacology 595 (2008) 44-51. Gauthier, C., Leblais, V., Kobzik, L., Trochu, J.N., Khandoudi, N., Bril, A., Balligand, J.L., Le Marec, H.,1998.
107 The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J. Clin: Invest.102, 1377-1384.
108 Gauthier, C., Tavernier, G, Charpentier, F., Langin D., Le Marec, H.,1996 Functional beta3-adrenoceptor in the human heart. J. Clin. Invest.98,556-562.
109 Dincer UD, Bidasee KR. Gfiner A. et al. The effect of diabetes on expression of β1 β2 β3 adrenoreceptors in rat hearts. Diabetes 2001 50:455-461.
111 Tansey, C. Sztalryd, J. Gruia-Gray, et al., Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity, Proc. Natl. Acad. Sci. USA 98 (11) (2001) 6494-6499.
110 R. Preston Mason Ruslan Kubant, Robert F. Jacob, Peter Malinski, Xiaoyan Huang, Febee R. Louka, Jan Borowiec, Yoshiko Mizuno and Tadeusz Malinski. Loss of Arterial and Renal Nitric Oxide Bioavailability in Hypertensive Rats With Diabetes:Effect of β-Blockers. Am J Hypertens 2009;22:1160-1166
112 Martinez-Botas, J.B. Anderson, D. Tessier, et al., Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice, Nat. Genet.26 (4) (2000) 474-479.
113 Mottagui-Tabar S, Ryden M, Lofgren P, Faulds G, Hoffstedt J, Brookes AJ et al. Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis. Diabetologia 2003; 46:789-797.
114 Haemmerle G, Zimmermann R, Strauss JG, et al. Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissuespecific expression pattern of lipoprotein lipase in adipose tissue and muscle. J Biol Chem 2002; 277:12946-12952.
115 Tansey, J. T, A. M. Huml, R. Vogt, K. E. Davis, J. M. Jones, K.2003. Functional studies on native and mutated forms of perilipins a role in protein kinase A-mediated lipolysis of triacylglycerols. Biol. Chem.278:8401-8406.
116 Deram S, Nicolau CY, Perez-Martinez P, Guazzelli I, Halpern A, Wajchenberg BL, Ordovas JM, Villares SM Effects of perilipin (PLIN) gene variation on metabolic syndrome risk and weight loss in obese children and adolescents. J Clin Endocrinol Metab.2008 Dec; 93 (12):4933-40
117 LABBE L, SIROIS C, PILOTE S, et al. Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metab olic ratios of marker substrates. Pharmacogenetics 2000 10(5):425-38.
118 Rau T, Heide R, Bergmann K, Wuttke H, Werner U, Feifel N, Eschenhagen T. Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment. Pharmacogenetics 2002,12,465-472.
119 Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance:Part Ⅰ. Clin Pharmacokinet.2009; 48 (11):689-723
120 Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. Drug Metab Dispos.1999 Mar;27(3):385-8.
121 Nozawa T, Taguchi M, Tahara K, Hashimoto Y, Igarashi N, Nonomura M, Kato B, Igawa A, Inoue H. Influence of CYP2D6 Genotype on Metoprolol Plasma Concentration and b-Adrenergic Inhibition During Long-Term Treatment. J Cardiovasc Pharmacol 2005; 46:713-720
122 Taguchi M, Nozawa T, Kameyama T, Inoue H, Takesono C, Mizukami A, Hashimoto Y.. Effect of CYP2D6*10 on pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients. Eur J Clin Pharmacol.2003 Sep;59(5-6):385-8.
123 Zateyshchikov DA, Minushkina LO, Brovkin AN, Savel'eva EG, Zateyshchikova AA, Manchaeva BB, Nikitin AG, Sidorenko BA, Nosikov VV. Association of CYP2D6 and ADRB1 genes with hypotensive and antichronotropic action of betaxolol in patients with arterial hypertension Fundam Clin Pharmacol.2007 Aug; 21(4):437-43.
124 Bijl MJ, Visser LE, van Schaik RH, Kors JA, Witteman JC, Hofman A, Vulto AG, van Gelder T, Stricker BH. Genetic Variation in the CYP2D6 Gene Is Associated With a Lower Heart Rate and Blood Pressure in β-Blocker Users. Clin Pharmacol Ther.2009 Jan;85(1):45-50.
1 Johnson JA, Terra SG (2002) β-Adrenergic receptor polymorphisms:cardiovascular disease associations and pharmacogenetics. Pharm Res 19:1779-1787
2 Johnson JA, Terra SG (2002) β-Adrenergic receptor polymorphisms:cardiovascular disease associations and pharmacogenetics. Pharm Res 19:1779-1787
3 Levin MC, Marullo S, Muntaner O, Andersson B, Magnusson Y (2002) The myocardium-protective Gly-49 variant of the β1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation. J Biol Chem 277:30429-30435
4 Rathz DA, Brown KM, Kramer LA, Liggett SB (2002) Amino acid 49 polymorphism of the human β1-adrenergic receptor affect agonist-promoted trafficking. J Cardiovasc Pharmacol 39:155-160
5 Mason DA, Moore JD, Green SA, Liggett SB (1999) A gain-of function polymorphism in a G-protein coupling domain of the human β1-adrenergic receptor. J Biol Chem 274:12670-12674
6 Joseph SS, Lynham JA, Grace AA, Colledge WH, Kaumann AJ (2004) Markedly reduced effects of (-)-isoprenaline but not of (-)-CGP12177 and unchanged affinity of beta-blockers at Gly389-betal-adrenoceptors compared to Arg389-betal-adrenoceptors.Br J Pharmacol 142:51-56
7 Molenaar P, Rabnott G, Yang I, Fong KM, Savarimuthu SM, Li L, West MJ, Russell FD (2002) Conservation of the cardiostimulant effects of (-)-norepinephrine across Ser49Gly and Gly389Arg betal-adrenergic receptor polymorphisms in human right atrium in vitro. J Am Coll Cardiol 40:1275-1282.
8 Sandilands AJ, O'Shaughnessy KM, Brown MJ (2003) Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 β1-adrenoceptors versus Gly389 β1-adrenoceptors in isolated human atrial myocardium. Br J Pharmacol 138:386-392
9 Ranade K, Jorgenson E, Sheu WHH, Pei D, Hsiung CA, Chiang F-T, Chen YI, Pratt R, Olshen RA, Curb D, Cox DR, Botstein D, Risch N (2002) A polymorphism in the β1 adrenergic receptor is associated with resting heart rate. Am J Hum Genet 70:935 -942
10 Bengtsson K, Melander O, Orho-Melander M, Lindblad U, Ranstam J, Rastam L, Groop L (2001) Polymorphisms in the β1-adrenergic receptor gene and hypertension. Circulation 104:187-190
11 Humma LM, Puckett BJ, Richardson HE, Terra SG, Andrisin TE, Lejeune BL, Wallace MR, Lewis JF, McNamara M, Picoult-Newberg L, Pepine CJ, Johnson JA. Effects of β-1 AR genetic polymorphisms on resting haemodynamics in patients undergoing diagnostic testing fir ischaemia. Am J Cardiol 2001; 88:1034-7.
12 Tesson F, Charron P, Peuchmaurd M, Nicaud V, Cambien F, Tiret L, Poirier O, Desnos M, Jullieres Y, Amouyel P, Roizes G, Dorent R, Schwartz K, Komajda M, Cardigene Group. A characterization of a unique gene variant in the β-1 AR gene and evaluation of its role in IDCM. J Mol Cell Cardiol 1999; 31:1025-32.
13 Borjesson M, Magnusson Y, Hjalmarson A, Andersson B. A novel polymorphism in the gene coding for the β1-adrenergic receptor associated with survival in patients with heart failure. Eur Heart J 2000; 21:1853-8.
14 White HL, Maqbool A, McMahon AD, Yates L, Ball SG, Hall AS, Balmforth AJ. An evaluation of the β-1 AR Arg389Gly polymorphism in individuals at risk of coronary events. Eur Heart J 2002; 23:1087-92.
15 Tesson, F. et al. (1999) Characterization of a unique genetic variant in the β1-adrenoceptor gene and evaluation of its role in idiopathic dilated cardiomyopathy. CARDIGENE Group. J. Mol. Cell. Cardiol.31,1025-1032.
16 Iwai, C. et al. (2003) Arg389Gly polymorphism of the human β1-adrenergic receptor in patients with nonfatal acute myocardial infarction. Am. Heart J.146, 106-109.
17 Covolo, L. et al. (2004) Role of β1-and β2-adrenoceptor polymorphisms in heart failure:a case-control study. Eur. Heart J.25,1534-1541
18 Small, K.M. et al. (2002) Synergistic polymorphisms of β1-and a2Cadrenergic receptors and the risk of congestive heart failure. N. Engl. J. Med.347,1135-1142.
19 de Groote, P. et al. (2005) The impact of P-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure. Eur. J. Heart Fail.7,966-973
20 Sofowora GG, Dishy V, Muszkat M, Xie G, Kim RB, Harris PA, Prasad HC, Byrne DW, Nair UB, Wood AJ, Stein CM. A common β-1 adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to β-blockade. Clin Pharmacol Ther 2003; 73:366-71.
21 Liu J, Liu ZQ, Tan ZR, Chen XP, Wang LS, Zhou G, Zhou HH. Gly389Arg polymorphism of betal-adrenergic receptor is associated with the cardiovascular response to metoprolol. Clin Pharmacol Ther 2003; 74:372-9.
22 B. J. Puckett, D. F. Pauly, I. Zineh, and J. A. Johnson. Beta adrenergic receptor polymorphisms and antihypertensive response to beta-blocker therapy. Clin. Pharmacol. Ther.71:2 (2002).
23 Liu, J. et al. Betal-Adrenergic receptor polymorphisms influence the response to metoprolol monotherapy in patients with essential hypertension. Clin. Pharmacol. Ther.80,23-32 (2006).
24 O'Shaughnessy KM, Fu B, Dickerson C, Thurston D, Brown MJ. The gain of function variant (R389G) of the β-1 AR does not influence blood pressure or response to b-blockade in hypertensive subjects. Clin Sci (Lond) 2000; 99:233-8.
25 Johnson, J.A., Zineh, I., Puckett, B.J., McGorray, S.P., Yarandi, H.N.& Pauly, D.F. Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin. Pharmacol. Ther.74,44-52 (2003).
26 Pacanowski MA, Gong Y, Cooper-Dehoff RM, Schork NJ, Shriver MD, Langaee TY, Pepine CJ, Johnson JA.β-Adrenergic Receptor Gene Polymorphisms and β-Blocker Treatment Outcomes in Hypertension. Clin Pharmacol Ther.2008 Dec;84(6):715-21
27 Borjesson M, Magnusson Y, Hjalmarson A, Andersson B (2000) A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure. Eur Heart J 21:1853-1858
28 Terra SG, Hamilton KK, Pauly DF, Lee CR, Patterson JH,Adams KF, Schofield RS, Belgado BS, Hill JA, Aranda JM, Yarandi HN, Johnson JA (2005) Betal-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy. Pharmacogenet Genomics 15:227-234
29 Magnusson Y, Levin MC, Eggertsen R, Nystrom E, Mobini R,Schaufelberger M, Andersson B (2005) Ser49Gly of betal-adrenergic receptor is associated with effective beta-blocker dose in dilated cardiomyopathy. Clin Pharmacol Ther 78:221-231
30 Liggett, S.B. et al. A polymorphism within a conserved beta (1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc. Natl. Acad. Sci. USA 103,11288-11293 (2006).
31 Mialet Perez JM, Rathz DA, Petrashevskaya NN, Hahn HS, Wagoner LE, Scwartz A, Dorn ⅡGW, Liggett SB. (3-1 AR polymorphisms confer differential function and predisposition to heart failure. Nature Med 2003; 9:1300-5.
32 Chen L, Meyers D, Javorsky G, Burstow D, Lolekha P, Lucas M, Semmler AB, Savarimuthu SM, Fong KM, Yang IA, Atherton J, Galbraith AJ, Parsonage WA, Molenaar P (2007) Arg389Gly betal-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol. Pharmacogenet Genomics 17:941-949
33 White HL, de Boer RA, Maqbool A, Greenwood D, van Veldhuisen DJ, Cuthbert R, Ball SG, Hall AS, Balmforth AJ. An evaluation of the β-1 AR Arg389Gly polymorphism in individuals with heart failure:a MERIT-HF sub study. Eur J Heart Fail 2003; 5:463-8.
34 Postava L, Mahlab D, Holubkov R, Janosko K, Palmer A, MacGowan G, Murali S, London B, McNamara DM. P-1 AR and β-2 AR polymorphisms and heart failure survival:interaction with β-blockade. Circulation 2002; 105:Abstract 3019.
35 Green SA, Turki J, Innis M, Liggett SB (1994) Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 33:9414-9419
36 Liggett SB. Molecular and genetic basis of beta2-adrenergic receptor function. J Allergy Clin Immunol 1999;104(Pt 2):S42-6.
37 L. K. Chong, J. Chowdry, P. Ghahramani, and P. T. Peachell. Influence of genetic polymorphisms in the beta2-adrenoceptor on desensitization in human lung mast cells. Pharmacogenetics 10:153-162 (2000).
38 Busjahn A, Li G-H, Faulhaber H-D, Rosenthal M, Becker A, Jeschke E, Schuster H, Timmermann B, Hoehe MR, Luft FC (2000) β2-Adrenergic receptor gene variations, blood pressure, and heart size in normal twins. Hypertension 35:555-560,
39 Bengtsson K, Melander O, Orho-Melander M, Lindblad U, Ranstam J, Rastam L, Groop L (2001) Polymorphisms in the β1-adrenergic receptor gene and hypertension. Circulation 104:187-190
40 R. Rosmond, O. Ukkola, M. Chagnon, C. Bouchard, and P.Bjorntorp. Polymorphisms of the beta2-adrenergic receptor gene (ADRB2) in relation to cardiovascular risk factors in men. J. Intern. Med.248:239-244 (2000).
41 P. Kotanko, A. Binder, J. Tasker, P. DeFreitas, S. Kamdar, A. J. Clark, F. Skrabal, and M. Caulfield. Essential hypertension in African Caribbeans associates with a variant of the beta2-adrenoceptor. Hypertension 30:773-776 (1997).
42 Hermann V, Buscher R, Go MM, Ring KM, Hofer JK, Kailasam MT,O'Conner DT, Parmer RJ, Insel PA (2000) β2-Adrenergic receptor polymorphisms at codon 16, cardiovascular phenotypes and essential hypertension in Whites and African Americans. Am J Hypertens 13:1021-1026,
43 Kato N, Sugiyama T, Morita H, Kurihara H, Sato T, Yamori Y, Yazaki Y (2001) Association analysis of β2-adrenergic receptor polymorphisms with hypertension in Japanese. Hypertension 37:286-292
44 M. S. Bray, J. Krushkal, L. Li, R. Ferrell, S. Kardia, C. F. Sing, S.T. Turner, and E. Boerwinkle. Positional genomic analysis identifies the beta(2)-adrenergic receptor gene as a susceptibility locus for human hypertension. Circulation 101:2877-2882 (2000).
45 Iaccarino G, Izzo R, Trimarco V, Cipolletta E, Lanni F, Sorriento D, Iovino GL, Rozza F, De Luca N, Priante O, Di Renzo G, Trimarco B.β2-Adrenergic receptor polymorphisms and treatment-induced regression of left ventricular hypertrophy in hypertension Clin Pharmacol Ther 2006;80:633-45.
46 Joseph J and Gilbert EM The sympathetic nervoos system in chronic heart failure. Prog Cardiovasc Dis.1998.41(Suppl 1):9-16.
47 S. B. Liggett, L. E. Wagoner, L. L. Craft, R. W. Hornung, B. D. Hoit, T. C. McIntosh, and R. A. Walsh. The Ilel64 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J. Clin. Invest. 102:1534-1539(1998).)
48 Covolo, L. et al. (2004) Role of (β1-and β2-adrenoceptor polymorphisms in heart failure:a case-control study. Eur. Heart J.25,1534-1541.
49 Sotoodehnia, N. et al. (2006) P2-adrenergic receptor genetic variants and risk of sudden cardiac death. Circulation 113,1842-1848.
50 Pacanowski MA, Gong Y, Cooper-Dehoff RM, Schork NJ, Shriver MD, Langaee TY, Pepine CJ, Johnson JA.β-Adrenergic Receptor Gene Polymorphisms and β-Blocker Treatment Outcomes in Hypertension. Clin Pharmacol Ther.2008 Dec;84(6):715-21
51 de Groote P, Helbecque N, Lamblin N, Hermant X, Mc Fadden E, Foucher-Hossein C, Amouyel P, Dallongeville J, Bauters C (2005) Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure. Pharmacogenet Genomics 15:137-142
52 Terra SG, Pauly DF, Lee CR, Patterson JH, Adams KF, Schofield RS, Belgado BS, Hamilton KK, Aranda JM, Hill JA, Yarandi HN, Walker JR, Phillips MS, Gelfand CA, Johnson JA. β-Adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure. Clin Pharmacol Ther 2005;77:127-37.
53 Kaye DM, Smirk B, Williams C, Jennings G, Esler M, Holst D (2003) Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics 13:379-382
54 Lelias JM, Kaghad M, Redriguez M et al. Molecular cloning of a human beta3-adrenegic receptor cDNA[J]. FEBS Lett,1993,32,1:127-30
55 Pietri Rouxel F, St John Manning B, Gros J et al, The biochemical effect of the naturally occurring Trp64-Arg mutation on human beta3-adrenoceptor activity [J]. Eur J Biochem,1997,247(3):1174-9
56 Widen, E., Lehto, M., Kanninen, T., Walston, J., Shuldiner, A. R.,& Groop, L. C. (1995). Association of a polymorphism in the beta 3-adrenergicreceptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med 333(6),348-351.
57 Clement, K., Vaisse, C., Manning, B. S., Basdevant, A., Guy-Grand, B., Ruiz, J., et al. (1995). Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med 333(6), 352-354.
58 Corella, D., Guillen, M., Portoles,O., Sorli, J. V., Alonso, V., Folch, J., et al.(2001). Gender specific associations of the Trp64Arg mutation in the beta3-adrenergic receptor gene with obesity-related phenotypes in a Mediterranean population:interaction with a common lipoprotein lipase gene variation. J Intern Med 250(4),348-360.
59 Clement, K., Vaisse, C., Manning, B. S., Basdevant, A., Guy-Grand, B., Ruiz, J., et al. (1995). Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. N Engl J Med 333(6), 352-354.
60 Endo, K., Yanagi, H., Hirano, C., Hamaguchi, H., Tsuchiya, S.,& Tomura, S. (2000). Association of Trp64Arg polymorphism of the beta3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity. Int J Obes Relat Metab Disord 24(4),443-449.
61 Tonolo G, Melis MG, Secchi G, Atzeni MM, Angius MF, Carboni A, Ciccarese M, Malavasi A, Maioli M (1999) Association of Trp64Arg (33-adrenergic-receptor gene polymorphism with essential hypertension in the Sardinian population. J Hypertens 17:33-38
62 Baba T, Nakajima S, Yajima Y (1998) β3-adrenergic receptor gene polymorphism is not associated with hypertension in NIDDM patients without nephropathy. Horm Metab Res 30:629-632.
63 Fujisawa T, Ikegami H, Yamato E, Hamada Y, Kamide K, Rakugi H, Higaki J, Murakami H, Shimamoto K, Ogihara T (1997) Trp64Arg mutation of 03-adrenergic receptor in essential hypertension:insulin resistance and the adrenergic system. Am J Hypertens 10:101-105 。
64 Thomas GN, Tomlinson B, Chan JC, Young RP, Critchley JA (2000) The Trp64Arg polymorphism of the β3-adrenergic receptor gene and obesity in Chinese subjects with components of the metabolic syndrome. Int J Obes Relat Metab Disord 24:545-551
65 Strazzullo P, Iacone R, Siani A, Cappuccio FP, Russo O, Barba G, Barbato A, D' Elia L, Trevisan M, Farinaro E (2001) Relationship of the Trp64Arg polymorphism of the β3-adrenoceptor gene to central adiposity and high blood pressure:interaction with age. Cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study. J Hypertens 19:399-406)
66 Moniotte S, Kobzik L, Feron 0, et al. Upregulation of β3-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation,2001,103:1649-1655.
67 Rouget, C., Breuiller-Fouche, M., Mercier, F. J., Leroy, M. J., Loustalot, C.,Naline, E., et al. (2004). The human near-term myometrial beta 3-adrenoceptor but not the beta 2-adrenoceptor is resistant to desensitization after sustained agonist stimulation. Br J Pharmacol 141(5),831-841.
68 Stangl, K., Cascorbi, I., Laule, M., Stangl, V., Meisel, C.,& Wernecke, K. D.(2001). The beta3-adrenergic receptor Trp64Arg mutation is not associated with coronary artery disease. Metabolism 50(2),184-188.
69 Morrison, A. C., Brancati, F. L., Folsom, A. R., Smith, L.,& Boerwinkle, E. (1999). Beta3-adrenergic receptor Trp64Arg polymorphism does not predict incident CHD or carotid intima-media thickness in a community-based sample of whites:the ARIC study. Atherosclerosis Risk in Communities. Hum Genet 105(4),314-319.
70 Tamaki, S., Iwai, N., Tsujita, Y., Nakamura, Y., Ohmichi, N.,& Kinoshita, M. (1999). Variant of the beta3-adrenergic receptor gene and coronary atherosclerosis in Japanese subjects. Int J Cardiol 69(3),309-311.
71 Thomas, G. N., Tomlinson, B., Chan, J. C., Young, R. P.,& Critchley, J. A. (2000). The Trp64Arg polymorphism of the beta3-adrenergic receptor gene and obesity in Chinese subjects with components of the metabolic syndrome. Int J Obes Relat Metab Disord 24(5),545-551.
71 Saino A, Pomidossi G, Perondi R, Valentini R, Rimini A, Di Francesco L, Mancia G. Intracoronary angiotensin II potentiates coronary sympathetic vasoconstrictions in humans. Circulation 1997; 96:148-153.
72 Saino A, Pomidossi G, Perondi R, Morganti A, Turolo L, Mancia G. Modulation of sympathetic coronary vasoconstriction by cardiac rennin angiotensin system in human coronary artery disease. Circulation 2000; 101:2277-2283。
73Karin Malmqvist, K. Peter Ohman, Lars Lind, Fredrik Nystrom, and Thomas Kahan Long-Term Effects of Irbesartan and Atenolol on the Renin-Angiotensin-Aldosterone System in Human Primary Hypertension J Cardiovasc PharmacolTM 2003;42:719-726
74 Blumenfeld JD, Sealey JE, Mann SJ, et al. Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensinaldosterone system in normotensive and hypertensive subjects. Am J Hypertens.1999;12:451-459.
75Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.
76 Zhu X, McKenzie CA, Forrester T, Nickerson DA, Broeckel U, Schunkert H, Doering A, Jacob HJ, Cooper RS, Rieder MJ. Localization of a small genomic region associated with elevated ACE. Am J Hum Genet 2000; 67:1144-1153.
77Timo Suonsyrj, Tuula Hannila-Handelberg, Heidi Fodstad, Kati Donner, Kimmo Kontula and Timo P. Hiltunenl Renin-Angiotensin System and a-Adducin Gene Polymorphisms and Their Relation to Responses to Antihypertensive Drugs:Results From the GENRES Study Am J Hypertens 2009;22:169-175
78Hedi Schelleman, Olaf H Klungel, Cornelia M van Duijn, Jacqueline CM Witteman, Albert Hofman, Anthonius de Boer, and Bruno HCh Stricker Drug-Gene Interaction Between the Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Antihypertensive Therapy Ann Pharmacother 2006;40:212-8.
79 H Schelleman, BHCh Stricker, WMM Verschuren, A de Boer, AA Kroon, PW de Leeuw, D Kromhout and OH Klungel Interactions between five candidate genes and antihypertensive drug therapy on blood pressure. The Pharmacogenomics Journal (2006)6,22-26
80 Dudley C, Keavney B, Casadei B, Conway J, Bird R, Ratcliffe P Prediction of patient responses to antihypertensive drugs using genetic polymorphisms: investigation of renin-angiotensin system genes. J Hypertens.1996 Feb;14(2):259-62
81 Kurland L, Melhus H, Karlsson J, Kahan T, Malmqvist K, Ohman KP, Nystrom F, Hagg A, Lind L Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients. J Hypertens.2001 Oct; 19(10):1783-7
82Bei Sun, Ekaterina Kintsurashvili, Deborah Ona, Ivana Ignjacev-Lazich, Irene Gavras, and Haralambos Gavras. Inhibition of the α 1D-Adrenergic Receptor Gene by RNA interference (RNAi) in Rat Vascular Smooth Muscle Cells and its effects on other adrenergic receptors. Vascul Pharmacol.2007 May; 46(5):367-372.
83张幼怡韩启德α1与β肾上腺素受体间的交互作用基础医学与临床1997,17：241-24584余细勇林曙光肾上腺素受体亚型的调节及其交互作用国外医学·生理、病理科学与临床手册1998.18(2)125-129
85 Skomedal T, et al. J Pharmacol Exp Ther,1988,247:1204
86 Tanoue A, Nasa Y, Koshimizu Shinoura H, Oshikawa S, KawaiT, et al. The alpha (1 D)(?) adrenergic receptor directly regulates arterial blood pressure via vasoconstriction. J Clin Invest 2002:109:765-75.
87 Duka I, Gavras I, Johns C, Handy DE, Gavras H. Role of the postsynaptic a 2-adrenergic receptor subtypes in catecholamine-induced vasoconstriction. Gen Pharmacol The Vascular System 2000; 34:101-106.
88 Bei Sun, Ekaterina Kintsurashvili, Deborah Ona, Ivana Ignjacev-Lazich, Irene Gavras, and Haralambos Gavras. Inhibition of the α 1D-Adrenergic Receptor Gene by RNA interference (RNAi) in Rat Vascular Smooth Muscle Cells and its effects on other adrenergic receptors. Vascul Pharmacol.2007 May; 46(5):367-372.
89 GISBERT, R., ZIANI, K., MIQUEL, R., NOGUERA, M.A., IVORRA,M.D., ANSELMI, E.& D'OCON, P. (2002). Pathological role of a constitutively active population of alD-adrenoceptors in arteries of spontaneously hypertensive rats. Br. J. Pharmaco.,135,206-216.
90 GARCI'A-SA'INZ, J.A.& VILLALOBOS-MOLINA, R. (2004). The elusive alD-adrenergic receptor:molecular and cellular characteristics and integrative roles. Eur. J. Pharmacol.,500,113-120.
91 Akito Tanoue, Masahiro Koba, Shigeki Miyawaki, Taka-aki Koshimizu, Chihiro Hosoda, Sayuri Oshikawa, Gozoh Tsujimoto Role of the αlD-Adrenegric Receptor in the Development of Salt-Induced Hypertension. Hypertension.2002;40:101-106.
92 Hu, Z.W., Shi, X.Y., Okazaki, M., and Hoffman, B.B. Angiotensin II induces transcription and expression of alpha-1 adrenergic receptors in vascular smooth muscle cells. Am. J. Physiol.268, H1006-H1014(1995).
93 Schiffrin, E.L., Thome, F.S., and Genest, J. Vascular angiotensin II receptors in SHR. Hypertension 6,682-688 (1984)
94 Gisbert, R., Ziani, K., Miquel, R., Noguera, M.A., Ivorra, M.D., Anselmi, E., and D'Ocon, P. Pathological role of a constitutively active population of alD-adrenoceptors in arteries of spontaneously hypertensive rats. Br. J. Pharmacol. 135,206-216(2002).
95 D. Godi'nez-Herna'ndez, I. A. Gallardo-Orti'z, P. Lo'pez-Sa'nchez & R. Villalobos-Molina Captopril therapy decreases both expression and function of a1D-adrenoceptors in prehypertensive rat aorta. Autonomic & Autacoid Pharmacology,2006,26,21-29
96李艳芳 张幼怡 吕志珍 韩启德 长期饮用普萘洛尔对大鼠心脏α1肾上腺素受体亚型数量的影响中国药理学与毒理学杂志1996年11月：11：281-284
97 Nonen, H Okamoto,Y Fujio, Y Takemoto, M Yoshiyama, T Hamaguchi, Y Matsui, J Yoshikawa, A Kitabatake and J Azuma Polymorphisms of norepinephrine transporter and adrenergic receptor alD are associated with the response to b-blockers in dilated cardiomyopathy The Pharmacogenomics Journal (2008) 8,78-84
98 Aggarwal A, Esler MD, Socratous F, Kaye DM. Evidence for functional presynaptic alpha-2 adrenoreceptors and their down-regulation in human heart failure. J Am Coll Cardiol 2001; 37:1246-1251.
99 Lahdesmaki J et al. Behavioral and neurochemical characterization of alpha(2A)-adrenergic receptor knockout mice Neuroseience,2002,1 13(2): 289-299
100 Brede M, Wiesmann F, Jahns R, et al. Feedback inhibition of catecholamine release by two different alpha 2-adrenoceptor subtypes prevents progression of heart failure. Circulation 2002; 106:2491-2496.
101 Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB (2000) A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem 275:23059-23064)
102 Hein L, Altman JD, Kobilka BK (1999) Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature 402:181-184
103 Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB. Synergistic polymorphisms of betal-and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med 2002; 347:1135-1142.
104 Nonen S, Okamoto H, Akino M, Matsui Y, Fujio Y, Yoshiyama M, Takemoto Y, Yoshikawa J, Azuma J, Kitabatake A (2005) No positive association between adrenergic receptor variants of alpha2cDel322-325, betalSer49, betal Arg389 and the risk for heart failure in the Japanese population. Br J Clin Pharmacol 60:414-417
105 Metra M, Zani C, Covolo L, Nodari S, Pezzali N, Gelatti U, Donato F, Nardi G, Dei Cas L (2006) Role of betal-and alpha2c-adrenergic receptor polymorphisms and their combination in heart failure:a case-control study. Eur J Heart Fail 8:131-135
106 Lobmeyer MT, Gong Y, Terra SG, Beitelshees AL, Langaee TY, Pauly DF, Schofield RS, Hamilton KK, Herbert Patterson J, Adams KF, Hill JA, Aranda JM, Johnson JA (2007) Synergistic polymorphisms of betal and alpha2C-adrenergic receptors and the influence on left ventricular ejection fraction response to beta-blocker therapy in heart failure. Pharmacogenet Genomics 17:277-282
107 Kobayashi H, Adachi-Akahane S, Nagao T. Involvement of BKCa channels in the relaxation of detrusor muscle via beta-adrenoceptors. Eur J Pharmacol 404: 231-238,2000
108 Petkov GV and Nelson MT. Differential regulation of Ca2+-activated K+ channels by beta-adrenoceptors in guinea pig urinary bladder smooth muscle.Am J Physiol Cell Physiol 288:C1255-C1263,2005
109 Pelaia G, Gallelli L, Vatrella A, Grembiale RD, Maselli R, De Sarro GB, Marsico SA (2002) Potential role of potassium channel openers in the treatment of asthma and chronic obstructive pulmonary disease. Life Sci 70:977-990
110 Liu G, Shi J, Yang L, Cao L, Park SM, Cui J, Marx SO Assemble of pendent BK channelgnaling complex by binding to β2 adrenergic receptor. EMBO J.2004 Jun 2;23(11):2196-205.
111 Brown SM, Bentcheva-Petkova LM, Liu L, Hristov KL, Chen M, Kellett WF, Meredith AL, Aldrich RW, Nelson MT, Petkov GV.β-Adrenergic relaxation of mouse urinary bladder smooth muscle in the absence of large-conductance Ca2+-activated K+channel. Am J Physiol Renal Physiol.2008 Oct;295(4):F1149-57
112 Fernandez-Fernandez JM, Tomas M, Vazquez E, Orio P, Latorre R, Senti M, et al. Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. J Clin Invest 2004; 113:1032-1039.
113 Senti M, Fernandez-Fernandez JM, Tomas M, Vazquez E, Elosua R, Marrugat J, Valverde MA. Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk. Circ Res 2005.
114 Zhao Q, Wang L, Yang W, Chen S, Huang J, Fan Z, Li H, Lu X, Gu D. Interactions among genetic variants from contractile pathway of vascular smooth muscle cell in essential hypertension susceptibility of Chinese Han population. Pharmacogenet Genomics.2008 Jun;18(6):459-66.
115 Kelley-Hedgepeth A, Peter I, Kip K, Montefusco M, Kogan S, Cox D, Ordovas J, Levy D, Reis S, Mendelsohn M, Housman D, Huggins G The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with beta-blockade. Journal of Human Hypertension (2008) 22,512-515;
116 Kobayashi N, Mori Y, Nakano S。 et al. Cellprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in deoxyeortieesterone acetate-salt hypertensive rats. J Hypertens,2001 。 19(4): 795.801
117 Yosimura M, Yasue H, Nakayama M, et al. A missense Glu298Asp variant in the endothelial nitric oxide synthase gene is associated with coronary spasm in the Japanese [J]. Hum Genet,1998,103:65-69.
118 Hingorani AD. Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep,2003,5:19-25.
119 Wang X L, Mahaney M C, Sim A S, Wang J, Wang J, BlangeroJ, Almasy L, Badenhop R B, W ilcken D E Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels. Arterioscler Thromb Vobc Biol.1997,17(11):3147-3153.
120 Y Miyamoto Y, Saito Y, Kajiyama N, Yoshimura M, Shimasaki Y, Nakayama M, Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertens,1998,32(1):3-8.
121李东宝,华琦.皮林.内皮型一氧化氮合酶基因G894T多态性与原发性高血压的相关关系。高血压杂志,2004,12(4)：326—330.
122 Iturry Yamamoto GR, Moriguchi EH, Zago AC, et al. Association of the 894G>T polymorphism of the endothelial constitutive nitric oxide synthase gene with unstable angina. Braz J Med Biol Res.2007。 40(4):475-483.
123 Pacanowski MA, Zineh I, Cooper-Dehoff RM, Pepine CJ, Johnson JA. Genetic and pharmacogenetic associations between NOS3 polymorphisms, blood pressure, and cardiovascular events in hypertension. Am J Hypertens.2009 Jul;22(7):748-53.
124 Lennard, M.S., Silas, J.H., Freestone, S., Ramsay, L.E., Tucker, GT.& Woods, H.F. Oxidation phenotype-a major determinant of metoprolol metabolism and response. N. Engl. J. Med(1982).307,1558-1560
125 Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance:Part Ⅰ. Clin Pharmacokinet.2009;48(11):689-723
126 Bijl MJ, Visser LE, van Schaik RH, Kors JA, Witteman JC, Hofman A, Vulto AG, van Gelder T, Stricker BH. Genetic Variation in the CYP2D6 Gene Is Associated With a Lower Heart Rate and Blood Pressure in β-Blocker Users. Clin Pharmacol Ther.2009 Jan;85(1):45-50.
127 Zateyshchikov DA, Minushkina LO, Brovkin AN, Savel'eva EG, Zateyshchikova AA, Manchaeva BB, Nikitin AG, Sidorenko BA, Nosikov VV. Association of CYP2D6 and ADRB1 genes with hypotensive and antichronotropic action of betaxolol in patients with arterial hypertension Fundam Clin Pharmacol.2007 Aug;21(4):437-43.