Systematic screening of type B human natriuretic peptide receptor gene polymorphisms and association with essential hypertension.

C-type natriuretic peptide (CNP) dilates arteries, lowers blood pressure and inhibits proliferation of vascular smooth muscle cells via the type B natriuretic peptide receptor (NPRB). The CNP-NPRB system may play a crucial role in the development of cardiovascular disease. We recently determined the structure of the human NPRB gene. In the present study, our objectives are to identify the polymorphisms of the NPRB gene and investigate the association of this gene with essential hypertension (EH). We used the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique to study the NPRB gene polymorphism, and conducted an association study using a novel polymorphic marker. PCR-SSCP analysis of all 22 exons was done in 90 subjects, and abnormally-migrating bands were observed in the analyses of exon 11 and intron 18. Direct sequencing of these DNA fragments revealed the following sequence alterations: a C to T transition at nucleotide (nt) 2077 in exon 11 and a 9-bp insertion/deletion (I/D) in intron 18. PCR-restriction fragment length polymorphism analysis (PCR-RFLP) was developed to detect the C2077T transition. PCR-RFLP analyses of healthy subjects revealed that the C2077T polymorphism had complete linkage to GT repeats in intron 2 reported previously. The I/D polymorphism was identified by polyacrylamide gel electrophoresis, and it was not linked to any known polymorphic alleles of this gene. Therefore, the possible association between the I/D polymorphism and EH was investigated. A total of 123 individuals with EH and 123 age-matched normotensive control subjects were studied. Overall distributions of allele frequencies in the two groups were not significantly different. Although the I/D polymorphism in intron 18 of the NPRB gene was not associated with EH, the results of this study, which identified two novel polymorphisms in the human NPRB gene, will facilitate further genetic analysis of this gene and cardiovascular disease.     

心钠素基因T2238C多态性和C型受体基因A-55C多态性与老年高血压病的关系

目的探讨心钠素（ANP）基因T2238C多态性及其C型受体（NPRC）基因A-55C多态性与老年高血压病的关系。方法采用基因芯片技术测定高血压病患者（238例）和健康对照者（184例）的ANP基因T2238C、NPRC基因A-55C多态性,并对两组检测结果进行基因型和等位基因频率的对照观察,应用logistic回归分析基因多态性对血压的影响。结果ANP基因T2238C基因型及等位基因频率在高血压病组与对照组比较差异均有统计学意义（χ^2=4．240～4．728,P均〈0．05）;两组间NPRC基因A-55C基因型和等位基因频率比较差异也有统计学意义（χ^2=5．517～5．950,P均〈0．05）。logistic回归分析显示ANP基因T2238C、NPRC基因A-55C是高血压病发病的危险因素（P〈0．05）。结论ANP基因T2238C和NPRC基因A-55C可能是高血压病的遗传易感基因。     

Relationship between plasma atrial natriuretic peptide and left atrial and left ventricular involvement in essential hypertension

In order to investigate the role of cardiac hypertrophy in atrial natriuretic peptide (ANP) secretion in patients with essential hypertension, plasma levels of ANP were measured after overnight rest in 36 patients with untreated hypertension and in 31 normotensive controls. In the hypertensive subjects, plasma levels were correlated with left ventricular (LV) and left atrial abnormalities detected by chest X-ray, electrocardiogram (ECG) and M-mode echocardiography. Plasma ANP levels in patients with hypertension averaged 146 +/- 27 pg/ml compared to 46 +/- 7 pg/ml in the normotensive subjects (P less than 0.001). In patients with hypertension a significant correlation was found between ANP and supine systolic blood pressure (r = 0.54, P less than 0.001) and between ANP and diastolic blood pressure (r = 0.38, P less than 0.05). Furthermore, plasma ANP levels were correlated with total heart volume (r = 0.68, P less than 0.01), LV mass (r = 0.525, P less than 0.001), LV posterior wall thickness (r = 0.39, P less than 0.05), Sokolow-Lyon index (r = 0.721, P less than 0.001) and end-diastolic diameter of the left atrium (r = 0.334, P less than 0.05). The results suggest a contribution of LV and left atrial abnormalities to ANP secretion in essential hypertension.     

心钠素基因多态性与原发性高血压患者左心室肥厚的关系

目的 探讨人类心钠素（ANP）基因多态性与原发性高血压患者左心室肥厚的关系.方法 选择原发性高血压患者106例,根据心脏超声检查结果分为单纯高血压组（对照组）75例和高血压合并左心室肥厚组（观察组）31例,采用PCR技术检测人类ANP基因C664G、G1837A和T2238C位点的多态性,比较两组基因型及等位基因分布差异.结果 观察组患者人类ANP基因C664G位点GG基因型频率为54.8％,高于对照组的33.3％（P＜0.05）.两组患者人类ANP基因G1837A位点和T2238C位点基因型和各等位基因频率差异无统计学意义.结论 人类ANP基因C664G位点的基因变异可能与原发性高血压患者左心室肥厚有关.     

原发性高血压患者动态血压节律异常对利钠肽及左室质量的影响

目的:评价原发性高血压(EH)患者动态血压节律异常对利钠肽及左室质量的影响.方法:根据24 h动态血压结果将65例EH患者分为杓形高血压组与非杓形高血压组,分别进行了血心房利钠肽(ANP)、脑钠肽(BNP)及超声心动图测定.结果:杓形高血压组与非杓形高血压组的ANP、BNP及左室质量指数(LVMI)均显著高于对照组(P<0 01);其中非杓形高血压组显著高于杓形高血压组(P<0 01);且ANP、BNP浓度与LVMI呈正相关(R=0 45,0 67;P< 0 01).结论:EH患者血压昼夜节律异常者,心脏ANP分泌增加,与LVMI呈正相关性.     

瘦素受体基因Gln223Arg多态性与原发性高血压相关性研究

目的:研究高血压候选基因瘦素受体基因(LEPR)在中国北方汉族人群的分布,探讨LEPR基因Gln223Arg多态性与原发性高血压(EH)的关系。方法:采集健康体检人群临床资料,分析体质量指数、血脂、血糖等临床指标,同时调查受检者吸烟和饮酒等生活习惯;Taq Man-MGB法分析LEPR基因Gln223Arg多态性在中国北方汉族人群(样本总数1 273例,其中原发性高血压病患者774例,血压正常的健康体检者499例)的分布及其与临床指标的相关性。结果:LEPR基因Gln223Arg基因型在两组总体的差异具有统计学意义(P=0.036)。按照血尿酸水平进行亚组分析,高尿酸亚组基因型(P=0.039)和等位基因频率(P=0.037)的差异具有统计学意义;调整相关因素的影响后,多因素Logistic回归模型分析显示:LEPR基因Gln223Arg多态性与EH相关[(GG+AG)vs.AA模型,OR=3.23,95%CI:1.01~10.34,P=0.008;GG vs.AA模型,OR=3.43,95%CI:1.35~8.75,P=0.010];高尿酸亚组也显示该多态性与EH发病密切相关[G vs.A模型,OR=1.89,95%CI:1.09~3.28,P=0.023;(GG+AG)vs.AA模型,OR=7.76,95%CI:1.18~49.80,P=0.033;GG vs.AA模型,OR=8.50,95%CI:1.29~56.12,P=0.026;GG vs.AG vs.AA模型,OR=1.94,95%CI:1.10~3.43,P=0.023]。结论:在中国北方汉族人群中,LEPR基因Gln223Arg多态性与原发性高血压相关。     

Association of estrogen receptor beta gene polymorphisms with left ventricular mass and wall thickness in women

BACKGROUND: Left ventricular (LV) hypertrophy is a significant risk factor for cardiovascular disease. Given sex-based differences in cardiac structure and remodeling, we hypothesized that variation in estrogen pathway genes might be associated with alteration of LV structure. METHODS: We studied 1249 unrelated individuals, 547 men and 702 women (mean age 59 years) from the Framingham Heart Study. Eight single nucleotide polymorphisms in the genes for estrogen receptor alpha and estrogen receptor beta (ESR2) were tested for association with 5 LV measures: LV mass (LVM), LV wall thickness (LVWT), LV internal diameter at end-diastole and end-systole, and fractional shortening. Sex-specific multiple regression analyses were performed adjusting for age, weight, height, systolic and diastolic blood pressure, hypertension treatment, diabetes, and in women, menopausal status. RESULTS: In men, there was no evidence of association between the estrogen pathway polymorphisms tested and LV structure or function. In women, however, two polymorphisms, ESR2 rs1256031 and ESR2 rs1256059, in linkage disequilibrium with one another, were associated with LVM and LVWT (P = .0007 to .03); the association was most pronounced in those women with hypertension (P = .0006 to .01). The association did not appear to be explained by variation in blood pressure, plasma lipoprotein levels, or hyperglycemia. CONCLUSIONS: The ESR2 polymorphisms are associated with LV structural differences in women with hypertension in a community-based population. These data are consistent with the hypothesis that genetic factors may mediate part of the observed sex-based differences in LV structure and remodeling.     

Effect of beta-adrenergic receptor blockade on atrial natriuretic peptide in essential hypertension

Plasma levels of atrial natriuretic peptide (ANP) were measured in 32 untreated subjects with essential hypertension and in 31 patients undergoing long-term treatment with beta-blockers. Patients receiving beta-blockers had significantly higher mean plasma ANP levels (72.0 +/- 36.0 [SD] pg/ml) than did untreated hypertensive subjects (39.8 +/- 15.8 pg/ml; p less than 0.01) and healthy normotensive controls (33.9 +/- 16.6 pg/ml; n = 61, p less than 0.01), while the mean plasma ANP concentration in untreated hypertensive subjects was not statistically different from that in control subjects. Administration of atenolol, 50 mg/day, for 4 weeks to 10 untreated subjects resulted in a significant (p less than 0.001) rise in plasma ANP levels (from 38.8 +/- 9.5 to 68.7 +/- 20.6 pg/ml). In 31 patients undergoing long-term treatment with beta-blockers, multivariate regression analysis revealed that age, pretreatment mean blood pressure, and plasma concentration of cyclic 3',5'-guanosine monophosphate (cGMP) were significant predictors of plasma ANP levels. These results suggest that beta-adrenergic receptor blockade in patients with essential hypertension elevates plasma ANP levels with a concomitant rise in cGMP concentrations, and that increased ANP in plasma may play a role in the compensatory mechanism that operates in response to beta-adrenergic receptor blockade.     

应用多普勒组织成像技术评价原发性高血压左室舒张功能及其相关因素

目的:应用多普勒组织成像技术(DTI)探讨原发性高血压(EH)左室舒张功能的特点,同时检测血中心钠素(ANP)、脑钠素(BNP)的变化,分析两者与左室舒张功能的关系。方法:对照组20例,EH患者(EH组)61例,均行常规超声及DTI检查,EH患者根据左室质量指数(LVMI)分为左室心肌肥厚(LVH)亚组和无 LVH(NLVH )亚组。DTI测量二尖瓣侧环心肌舒张早期峰值运动速度(e)、晚期峰值运动速度(a)及其比值(e/a),测量二尖瓣瓣尖水平舒张早期的最大流速(E0)、舒张晚期的最大流速(A)及 E0 与A流速的比值E0/A。入选病例均测定血浆ANP、BNP浓度。结果:与对照组相比,EH患者E0/A、e/a减小,LVH亚组减小更明显;与对照组相比,EH血浆 ANP、BNP浓度升高, LVH升高更明显; E0/A、e/a比值与 ANP 呈负相关( r = - 0.56和 r = -0.60, 均P<0.01),与BNP呈负相关( r=-0.62和 r=-0.65,均 P<0.01)。结论:血浆 ANP、BNP与应用DTI技术评价的EH左室舒张功能均有较好相关性。     

Effects of alpha-human atrial natriuretic peptide in essential hypertension

Because there is little published information on the effects of atrial peptides in hypertensive humans, 100 micrograms of alpha-human atrial natriuretic peptide was injected intravenously into six patients with essential hypertension in a double-blind, placebo-controlled study under standardized conditions of body posture and dietary sodium and potassium intake. The peptide increased urine sodium excretion sixfold in the first 30 minutes. Smaller increments occurred in urine volume and in calcium, magnesium, and phosphorus excretion; the rise in urine potassium concentration was not statistically significant. Most of these indices returned to time-matched placebo values within 1 hour, but urine sodium excretion remained high for 2 1/2 hours. Arterial pressure fell within 2 minutes of alpha-human atrial natriuretic peptide injection, then returned to matching placebo levels by 10 minutes. Conversely, heart rate increased rapidly and remained elevated for 3 hours. The peptide induced a prompt, brief rise in plasma norepinephrine concentration and a more sustained fall in epinephrine and aldosterone levels, but it did not affect plasma renin activity or cortisol concentration. Compared with normotensive volunteers studied previously under the same conditions, the hypertensive subjects had a greater response in urine volume and sodium, calcium, and magnesium excretion but a less sustained fall in arterial pressure.     

脑钠肽与高血压左室重塑、左室功能的关系

目的:探讨原发性高血压(EH)患者脑钠肽(BNP)水平与左室几何构型、左室功能的关系。方法:应用荧光免疫法快速测定EH组(106例)和对照组(46例)的血浆BNP浓度,根据心脏彩色超声检测结果,依照左室重量指数(LVMI)、相对室壁厚度(RWT)将106例EH患者分为:正常构型亚组(12例)、向心性重构亚组(9例)、离心性肥厚亚组(64例)、向心性肥厚亚组(21例)。应用相关性分析了解EH组LVMI、RWT、年龄、血压、体质指数(BMI)、左室射血分数(LVEF)等因素与BNP关系。结果:在EH各构型亚组中LVMI以离心性肥厚亚组最高,向心性肥厚亚组、离心性肥厚亚组BNP水平较对照组升高明显。EH组LVMI与BNP具有明显的正相关性(r=0.605,P<0.01),RWT与BNP具有明显的负相关(r=-0.266,P<0.01),LVEF与BNP呈负相关(r=-0.552,P<0.01),LVMI、RWT与血压、BMI之间无明显相关性。结论:EH组中不同的左室几何构型对BNP水平产生不同影响,具有更高的LVMI值和更低的LVEF、RWT值患者,BNP水平更高,而年龄、血压、BMI与BNP、LVMI、RWT无明显相关性。     

Atrial natriuretic peptide, left ventricular mass and renin-angiotensin-aldosterone system in essential arterial hypertension of a mild or moderate degree]

OBJECTIVE. The relationship between plasma atrial natriuretic peptide (ANP), renin-angiotensin-aldosterone system and left ventricular mass in essential hypertension was assessed. PATIENTS AND METHODS. Immunoreactive ANP in 10 normal subjects and 20 untreated patients with mild to moderate essential hypertension was compared with echocardiographic measurement of cardiac size, function and blood pressure. Venous plasma concentrations of ANP were also studied in relation to urinary sodium and potassium excretion, as well as the renin-angiotensin-aldosterone system. RESULTS. Plasma ANP was higher in hypertensive patients (25.3 +/- 13.3 pg/ml; p = 0.003) than normotensive subjects (11.1 +/- 2.7 pg/ml). In hypertensive patients, plasma ANP was inversely related to plasma renin activity (PRA) (r = -0.6; p = 0.009). No relationship was found between ANP and blood pressure, nor between the indices of left ventricular mass and function or urinary electrolytes. CONCLUSIONS. This study showed that circulating ANP is, in average, significantly increased in hypertensive patients, consistent with previous reports. Our data do not support a direct link between left ventricular mass and increased plasma ANP levels in hypertensive patients. Whether the inverse relationship between ANP and PRA in this pathologic state is a direct one or merely a secondary association has not been clearly established.     

Plasma brain natriuretic peptide and atrial natriuretic peptide concentrations correlate with left ventricular end-diastolic pressure

The present study was designed to investigate whether brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) plasma concentrations correlate with left ventricular end-diastolic pressure (LVEDP), pulmonary capillary wedge pressure (PCWP), diastolic pulmonary arterial pressure (DPAP), right atrial pressure (RAP), or ejection fraction (EF). Plasma BNP and ANP levels were determined by commercial radioimmunoassays (Peninsula) after Sep Pak C₁₈ extraction in blood samples withdrawn from the pulmonary artery and the left ventricle or from the left ventricle and the femoral vein in 85 patients undergoing diagnostic cardiac catheterization. Linear and nonlinear regression analysis and the paired sample f-test were applied to the data. Pulmonary arterial plasma BNP and ANP levels showed a close nonlinear correlation with LVEDP (BNP: r=0.94, p < 0.001; ANP: r=0.81, p < 0.001), a significant linear correlation with PCWP, DPAP, and RAP, and a significant negative correlation with EE ANP concentrations decreased significantly from the pulmonary artery to the left ventricle and from the left ventricle to the femoral vein (p < 0.001). BNP levels also decreased significantly between the left ventricle and the femoral vein (p < 0.001), but there was no significant difference between pulmonary arterial and left ventricular BNP concentrations. BNP and ANP concentrations correlated significantly between pulmonary arterial and left ventricular blood samples (BNP: r = 0.99, ANP: r = 0.93, p < 0.001) and between left ventricular and peripheral blood samples (BNP: r=0.99, ANP: r=0.94, p<0.001). The present data suggest that peripheral plasma BNP and ANP levels are useful noninvasive indices of cardiac performance.     

A novel missense mutation of exon 3 in the type A human natriuretic peptide receptor gene: possible association with essential hypertension.

The natriuretic peptide (NP) family is involved in regulation of blood pressure and fluid volume. We recently characterized the exon/intron organization of the human type A NP receptor (hNPRA) gene. The aim of this study was to isolate the genetic markers according to the organization of this gene, and to study the association between this gene and essential hypertension. Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, we identified a novel missense mutation, M3411, consisting of a methionine (ATG) to isoleucine (ATC) substitution at nucleotide 1023 in exon 3. Computer-aided three-dimensional structural analysis suggested that M341 exists in the loop between two alpha-helices, and that the mutation may influence receptor activities by altering the conformation of the alpha-helices. We performed an association study of the mutation in 210 essential hypertension (EH) patients and 210 normotensive controls. The overall distribution of alleles was not significantly different between the control and EH groups. However, the C/C homozygous genotype was found only in the EH group. The ratio of plasma brain natriuretic peptide (BNP)/mean blood pressure of the C/C genotype was significantly higher than that of the G/G genotype or the G/C genotype. We conclude that the significance of homozygous M3411 mutation in exon 3 is worth investigating for its possible association with EH.     

内皮型一氧化氮合成酶基因多态性与原发性高血压的相关性

高血压是最常见的慢性病,也是心脑血管病最主要的危险因素,目前其发病率呈上升趋势[1,2].原发性高血压（essential hypertension,EH）是受遗传因素与环境因素共同影响的慢性疾病.近年来研究表明,遗传因素在原发性高血压的发生、发展中起着更重要的作用.内皮型一氧化氮合酶（endothelium nitrogen monoxide synthase,eNOS）是高血压的易感因素,它的基因编码所产生的一氧化氮（nitrc oxide,NO）具有调节血管张力、血管重塑、维持血管内皮的完整性等作用.随着血管生物学与临床医学领域联合研究的不断深入,在心血管疾病中研究调查调控高血压基因已成为热点.国内外研究表明,eNOS基因在原发性高血压中发挥重要作用.本文对eNOS基因G894T、T786C和27bpVNTR的多态性影响EH的机制及与EH相关性最新研究进展作一综述.     

Plasma atrial natriuretic peptide in essential hypertension after treatment with irbesartan

The aim of this study was to evaluate the medium-term effects of the selective AT 1 -blocker irbesartan on atrial natriuretic peptide (ANP) levels in patients with moderate essential hypertension. The drug was given orally in a daily dose of 300 mg for 30 days. Plasma ANP levels increased by 15.7% despite the drop in blood pressure and the slight decrease of atrial and ventricular diameters. These findings indicate that AT 1 -blockers like irbesartan exert part of their antihypertensive action by increasing ANP plasma levels.