Role of oxidative stress in angiotensin-induced hypertension

Infusion of ANG II at a rate not sufficient to evoke an immediate vasoconstrictor response, produces a slow increase in blood pressure. Circulating levels of ANG II may be within ranges found in normotensive individuals, although inappropriately high with respect to sodium intake. When ANG II levels are dissociated from sodium levels, oxidative stress (OXST) occurs, which can increase blood pressure by several mechanisms. These include inadequate production or reduction of bioavailability of nitric oxide, alterations in metabolism of arachidonic acid, resulting in an increase in vasoconstrictors and decrease in vasodilators, and upregulation of endothelin. This cascade of events appears to be linked, because ANG II hypertension can be blocked by inhibition of any factor located distally, blockade of ANG II, OXST, or endothelin. Such characteristics are shared by other models of hypertension, such as essential hypertension, hypertension induced by reduction in renal mass, and renovascular hypertension. Thus these findings are clinically important because they reveal 1) uncoupling between ANG II and sodium, which can trigger pathological conditions; 2) the various OXST mechanisms that may be involved in hypertension; and 3) therapeutic interventions for hypertension developed with the knowledge of the cascade involving OXST.     

Inverse regulation of alpha-2 and beta-2 adrenoceptors in salt-sensitive hypertension: an hypothesis

A high salt diet leads to up-regulation of alpha-2 adrenoceptors and down-regulation of beta-2 adrenoceptors in normotensive subjects. Although the increase in blood pressure with a high salt diet is not related to the magnitude of the alpha-2 or beta-2 adrenoceptor changes alone, it is related to the increase in the ratio of the receptor changes (operative alpha/beta adrenoceptor ratio). An increase in the operative alpha/beta adrenoceptor ratio with a high salt intake results in vasoconstriction and reduced vasodilatation at resistance vessels, as well as increased renal proximal tubular sodium reabsorption. An influence of heredity on this relationship is supported by four lines of evidence: 1) salt-sensitivity of blood pressure occurs predominantly in subjects with a family history of hypertension; 2) studies in twin children document the influence of genetic variance on salt-sensitivity of blood pressure; 3) subjects with a family history of hypertension have a significantly lower salivary sodium concentration and an altered urinary sodium excretion after salt loading compared to subjects with no such history; 4) salt-sensitivity of blood pressure may be associated with specific genetic markers. On the basis of these observations, we propose the hypothesis that enhanced inverse alpha-beta-adrenoceptor regulation in response to a high salt intake may be responsible for salt sensitivity in the normal population, and may contribute to the development of essential hypertension in susceptible individuals. This alteration is likely to be genetically mediated.     

Atrial natriuretic peptides in essential hypertension: basal plasma levels and relationship to sodium balance.

The identification of the atrial natriuretic peptides (ANP) as a new hormonal system has provided a new perspective on the mechanisms controlling renal sodium excretion and abnormalities in sodium homeostasis. The present article focuses on the potential importance of ANP (ANF 99-126) in essential hypertension with particular reference to circulating ANP levels and the relationship between the ANP and the renin-angiotensin system in the control of sodium balance and blood pressure. There is now considerable evidence demonstrating that a substantial proportion of patients with essential hypertension have raised circulating ANP levels. Given the known biological actions of ANP, these raised levels point to important compensatory mechanisms. This is further supported by studies during alterations in dietary sodium intake, as sodium restriction high-lighted important relationships between ANP and the renin angiotensin system. The potential importance of ANP in essential hypertension is strengthened by recent demonstration of natriuretic and antihypertensive actions associated with small increases in circulating ANP as induced by administration of exogenous ANP. Furthermore, the recent development of orally active inhibitors of ANP metabolism now provides a basis to determine the therapeutic importance of specific manipulation of endogenous ANP levels in patients with essential hypertension.     

Sodium and potassium in essential hypertension.

A study was carried out of arterial pressure and body content of electrolytes in 91 patients with essential hypertension and 121 normal controls. Exchangeable sodium was found to be positively correlated with arterial pressure in the patients, the correlation being closest in older patients; values of exchangeable sodium were subnormal in young patients; and plasma, exchangeable, and total body potassium correlated inversely with arterial pressure in the patients, the correlations being closest in young patients. Three hypotheses were proposed to explain the mechanisms relating electrolytes and arterial pressure in essential hypertension--namely, a cell-salt hypothesis, a dietary salt hypothesis, and a kidney-salt hypothesis. It was concluded that two mechanisms probably operate in essential hypertension. In the early stages of the disease blood pressure is raised by an abnormal process related more closely to potassium than to sodium. A renal lesion develops later, possibly as a consequence of the hypertension. This lesion is characterised by resetting of pressure natriuresis and is manifest by an abnormal relation between body sodium and arterial pressure and by susceptibility to increased dietary sodium intake.     

慢性动脉血压调节与原发性高血压病——Ⅱ.原发性高血压病

原发性高血压病的发生原因和发病机理十分复杂,很多问题目前并不十分清楚。通过近几十年的研究,大家比较一致的看法是,原发性高血压病的内因是肾脏功能的损伤,其发生条件（外因）是摄取的食盐（钠）过多。人类饮食中添加食盐已有几千年的历史,它是人类文明发展的一种表现。然而各种研究的结果表明,食盐的过量摄取的确是高血压的元凶。此外,原发性高血压多见于老年人。由于有这些特点,因此原发性高血压病常常被看成是一种“文明”病,一种肾脏的疾病,一种老年人常见的病。本文将对这些特点作进一步的分析和讨论。     

Kidney ion handling genes and their interaction in blood pressure control

Hypertension affects 30% of adults and is the leading risk factor for cardiovascular disease. Kidney sodium reabsorption plays a vital role in the initial stage and development of essential hypertension. It has been extensively reported that the variants of kidney ion handling genes are associated to blood pressure, and clinical features of hypertension. However, the underlying mechanisms by which these variants alter protein function are rarely summarized. In addition, the variation of one single gene is often limited to induce a significant effect on blood pressure. In the past few decades, the influence by genes × genes (G × G) and/or genotype × environment (G × E) interactions on a given trait, for example, blood pressure, have been widely considered, especially in studies on polygenic genetic traits. In the present review, we discuss the progress in genetics studies on kidney ion handling genes, encoding Na⁺ channels (Na⁺-Cl⁻ cotransporter [NCC], Na-K-2Cl cotransporter [NKCC2], epithelial Na⁺ channels [ENaCs]), K⁺ channel (renal outer medullary potassium channel [ROMK]), and Cl⁻ channels (Pendrin, chloride voltage-gated channel Kb [CLC-Kb]), respectively, and their upstream kinases, WNKs and SGK1. We seek to clarify how these genes are involved in kidney sodium absorption and influence blood pressure, especially emphasizing the underlying mechanisms by which genetic variants alter protein functions and interaction in blood pressure regulation. The present review aims to enhance our understanding of the important role of kidney ion handling genes/channels in blood pressure control.     

Dopamine and G protein-coupled receptor kinase 4 in the kidney: Role in blood pressure regulation

Complex interactions between genes and environment result in a sodium-induced elevation in blood pressure (salt sensitivity) and/or hypertension that lead to significant morbidity and mortality affecting up to 25% of the middle-aged adult population worldwide. Determining the etiology of genetic and/or environmentally-induced high blood pressure has been difficult because of the many interacting systems involved. Two main pathways have been implicated as principal determinants of blood pressure since they are located in the kidney (the key organ responsible for blood pressure regulation), and have profound effects on sodium balance: the dopaminergic and renin–angiotensin systems. These systems counteract or modulate each other, in concert with a host of intracellular second messenger pathways to regulate sodium and water balance. In particular, the G protein-coupled receptor kinase type 4 (GRK4) appears to play a key role in regulating dopaminergic-mediated natriuresis. Constitutively activated GRK4 gene variants (R65L, A142V, and A486V), by themselves or by their interaction with other genes involved in blood pressure regulation, are associated with essential hypertension and/or salt-sensitive hypertension in several ethnic groups. GRK4γ ?142V?transgenic mice are hypertensive on normal salt intake while GRK4γ? 486V? transgenic mice develop hypertension only with an increase in salt intake. GRK4 gene variants have been shown to hyperphosphorylate, desensitize, and internalize two members of the dopamine receptor family, the D₁ (D₁R) and D₃ (D₃R) dopamine receptors, but also increase the expression of a key receptor of the renin–angiotensin system, the angiotensin type 1 receptor (AT₁R). Knowledge of the numerous blood pressure regulatory pathways involving angiotensin and dopamine may provide new therapeutic approaches to the pharmacological regulation of sodium excretion and ultimately blood pressure control.     

The population mean predicts the number of deviant individuals.

OBJECTIVE--To examine the relation between the prevalence of deviation and the mean for the whole population in characteristics such as blood pressure and consumption of alcohol. DESIGN--Re-examination of standardised data from the Intersalt study, an international, multicentre study on the determinants of blood pressure. SETTING AND SUBJECTS--Samples of adults representing 52 populations in 32 countries. MAIN OUTCOME MEASURES--The relations, expressed as correlation coefficients, between the mean population values for blood pressure, body mass index, alcohol consumption, and sodium intake and the prevalence of, respectively, hypertension (greater than or equal to 140 mm Hg), obesity (body mass index greater than or equal to 30 kg/m2), high alcohol intake (greater than or equal to 300 ml/week), and high sodium intake (greater than or equal to 250 mmol/day). RESULTS--There were close and independent associations between the population mean and the prevalence of deviance for each of the variables examined: correlation coefficients were 0.85 for blood pressure, 0.94 for body mass index, 0.97 for alcohol intake, and 0.78 for sodium intake. CONCLUSIONS--These findings imply that distributions of health related characteristics move up and down as a whole: the frequency of "cases" can be understood only in the context of a population''s characteristics. The population thus carries a collective responsibility for its own health and well being, including that of its deviants.     

Endothelin-1 gene and endothelial nitric oxide synthase gene polymorphisms in adolescents with juvenile and obesity-associated hypertension

Hypertension is an increasing public health problem all over the world. Essential hypertension accounts for more than 90% of cases of hypertension. It is a complex genetic, environmental and demographic trait. New method in molecular biology has been proposed a number of candidate genes, but the linkage or association with hypertension has been problematic (lack of gene-gene and gene-environment interaction). It is well known that genetic influences are more important in younger hypertensives, because children are relatively free from the common environmental factors contributing to essential hypertension. The association studies compare genotype ferquencies of the candidate gene between patient groups and the controls, in pathways known to be involved in blood pressure regulation. This study examined three polymorphisms of these factors encoding genes (ET-1 G+5665T (Lys198Asn), endothelial nitric oxide synthase (eNOS) T-786C promoter polymorphism and 27-bp repeat polymorphism in intron 4) in adolescents with juvenile essential and obesity-associated hypertension. Significant differences were found in the G/T genotype of the ET-1 polymorphism in the hypertensive and obese+hypertensive patients (body mass index (BMI) > 30). A strong association was detected between the BMI and the polymorphism of the ET-1 gene. It seems that ET-1 gene polymorphism plays a role in the development of juvenile hypertension associated with obesity. Although no significant differences were seen in the case of the eNOS promoter polymorphism and the eNOS 4th intron 27-bp repeat polymorphism. It seems that eNOS may play a role, but this is not the main factor in the control of blood pressure; it is rather a fine regulator in this process. This study with adolescents facilitates an understanding of the genetic factors promoting juvenile hypertension and obesity.     

Abnormalities of sodium pump function in hypertension and the role of endogenous cardiotonic steroids.

Elevated arterial blood pressure is a common heritable susceptibility in the human population. The high penetrance of this trait in industrialized societies may be influenced by the interactions of environmental factors and common genetic variants. This review examines the role of the renal sodium pump (sodium, potassium-ATPase, NKA) in hypertension and its integration into mechanisms of body sodium balance. In particular, renal NKA provides an appealing target by which inherited factors caninfluence renal sodium reabsorption. Recent work has indicated how some such genetic mechanisms may function. In this paper, the capacity of renal NKA to integrate environmental and heritable factors to increase blood pressure are examined.     

The influence of basal metabolic rate on blood pressure among indigenous Siberians

Hypertension is an important global health issue and is currently increasing at a rapid pace in most industrializing nations. Although a number of risk factors have been linked with the development of hypertension, including obesity, high dietary sodium, and chronic psychosocial stress, these factors cannot fully explain the variation in blood pressure and hypertension rates that occurs within and between populations. The present study uses data collected on adults from three indigenous Siberian populations (Evenki, Buryat, and Yakut [Sakha]) to test the hypothesis of Luke et al. (Hypertension 43 (2004) 555-560) that basal metabolic rate (BMR) and blood pressure are positively associated independent of body size. When adjusted for body size and composition, as well as potentially confounding variables such as age, smoking status, ethnicity, and degree of urbanization, BMR was positively correlated with systolic blood pressure (SBP; P < 0.01) and pulse pressure (PP; P < 0.01); BMR showed a trend with diastolic blood pressure (DBP; P = 0.08). Thus, higher BMR is associated with higher SBP and PP; this is opposite the well-documented inverse relationship between physical activity and blood pressure. If the influence of BMR on blood pressure is confirmed, the systematically elevated BMRs of indigenous Siberians may help explain the relatively high blood pressures and hypertension rates documented among native Siberians in the post-Soviet period. These findings underscore the importance of considering the influence of biological adaptation to regional environmental conditions in structuring health changes associated with economic development and lifestyle change.     

Relation between arterial pressure,dietary sodium intake,and renin system in essential hypertension.

Forty-one patients with mild essential hypertension, 36 patients with severe hypertension, and 28 normotensive subjects were studied on a high sodium intake of 350 mmol/day for five days and low sodium intake of 10 mmol/day for five days. The fall in mean arterial pressure on changing from the high-sodium to the low-sodium diet was 0.7 +/- 1.7 mm Hg in normotensive subjects, 8 +/- 1.4 mm Hg in patients with mild hypertension, and 14.5 +/- 1.4 mm Hg in patients with severe hypertension. The fall in blood pressure was not correlated with age. Highly significant correlations were obtained for all subjects between the ratio of the fall in mean arterial pressure to the fall in urinary sodium excretion on changing from a high- to a low-sodium diet and (a) the level of supine blood pressure on normal diet, (b) the rise in plasma renin activity, and (c) the rise in plasma aldosterone. In patients with essential hypertension the blood pressure is sensitive to alterations in sodium intake. This may be partly due to some change either produced by or associated directly with the hypertension. A decreased responsiveness of the renin-angiotensin-aldosterone system shown in the patients with essential hypertension could partly account for the results.     

eNOS基因第四内含子a／b多态与湖北汉族人原发性高血压而不是2型糖尿病相关联

目的：探讨内皮型一氧化氮合酶基因（eNOS）与湖北汉族人原发性高血压（EH）和2型糖尿病（T2DM）的关系。方法：采用病例-对照设计,分析了657例样本eNOS第四内含子重复序列多态性a／b,测量了身高、体重、腰围、臀围、收缩压、舒张压、空腹血糖,餐后2小时血糖等临床指标。结果：EH病例组eNOSab＋aa基因型和a等位基因频率显著高于EH对照组（基因型：25．3％vs18．9％,P=0．049;等位基因：13．3％vs9．8％,P=0．045）;而T2DM病例组与T2DM对照组的eNOSab＋aa基因型频率没有显著差异（20．2％vs24．1％,P=0．247）。单因素Logistic回归分析显示eNOSab＋aa基因型是EH的危险因子（OR=1．623,95％CI 1．053—2．506,P=0．029）。多因素回归分析显示,EH的独立风险因素是年龄、体重指数和eNOS基因a／b多态性,而体重指数和腰臀比是T2DM的独立风险因素。结论：eNOS基因a／b多态性是湖北汉族人群EH的一个易感标记,而与T2DM没有相关性。     

D5 dopamine receptor knockout mice and hypertension

Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. All of the five dopamine receptor genes (D1, D2, D3, D4, and D5) expressed in mammals and some of their regulators are in loci linked to hypertension in humans and in rodents. Under normal conditions, D1-like receptors (D1 and D5) inhibit sodium transport in the kidney and the intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats, and humans with essential hypertension, the D1-like receptor-mediated inhibition of sodium transport is impaired because of an uncoupling of the D1-like receptor from its G protein/effector complex. The uncoupling is genetic, and receptor-, organ-, and nephron segment-specific. In human essential hypertension, the uncoupling of the D1 receptor from its G protein/effector complex is caused by an agonist-independent serine phosphorylation/desensitization by constitutively active variants of the G protein-coupled receptor kinase type 4. The D5 receptor is also important in blood pressure regulation. Disruption of the D5 or the D1 receptor gene in mice increases blood pressure. However, unlike the D1 receptor, the hypertension in D5 receptor null mice is caused by increased activity of the sympathetic nervous system, apparently due to activation of oxytocin, V1 vasopressin, and non-N-methyl D-aspartate receptors in the central nervous system. The cause of the activation of these receptors remains to be determined.     

基因多态性与原发性高血压的相关性

高血压是一种遗传因素和环境因素相互作用所致的疾病,但高血压的病因尚不明确。已有的研究结果表明,高血压患者或潜在患者常有一种以上与血压调节相关的基因异常。目前,已有多个与高血压相关的基因位点被深入广泛研究。本文旨在就基因多态性与高血压相关性的研究进展进行综述。     

Pharmacologic agents for the in vivo detection of vascular sodium transport defects in hypertension

Anatagonists to angiotensin, catecholamines, aldosterone, and vasopressin have long been used to help determine agonist roles in hypertension. We here call attention to a possible extension of this approach to detect, evaluate, and treat vascular sodium transport defects in hypertension. Two basic types of transport defects have been identified in the blood vessels of hypertensive animals, increased sodium permeability and decreased sodium pump activity. Intravenous injection of 6-iodo-amiloride, a sodium channel blocker and vasodilator, produces an immediate and sustained decrease in blood pressure in two genetic models of hypertension characterized by increased permeability of the vascular smooth muscle cell membrane to sodium (Okamoto spontaneously hypertensive rat, Dahl salt sensitive rat), whereas it produces only a transient fall in arterial pressure in two renal models of hypertension having normal sodium permeability in vascular smooth muscle cells (reduced renal mass-saline rat, one-kidney, one clip rat). Canrenone, a metabolic product of spironolactone which can compete with oubain for binding to Na+,K+-ATPase at the digitalis receptor site, decreases blood pressure in a low renin, volume expanded model of hypertension which has been shown to have depressed sodium pump activity in arteries and increased sodium pump inhibitor in plasma (reduced renal mass-saline rat) but has no effect on blood pressure in a genetic model of hypertension which has been shown to have increased sodium pump activity secondary to increased sodium permeability (spontaneously hypertensive rat). Thus, a sodium channel blocker and a competitor to ouabain binding can detect and determine the functional significance of sodium transport defects in the blood vessels of intact hypertensive animals. Studies in red and white blood cells suggest that similar defects may exist in the blood vessels of hypertensive humans. Thus, this approach, probing for vascular transport defects in the intact animal, may ultimately also be useful in the clinical setting.     

Regression of cardiac hypertrophy with drug treatment in spontaneously hypertensive rats

Left ventricular hypertrophy is an important complication of essential hypertension. Some antihypertensive drugs have been shown to allow regression of cardiac hypertrophy, both in spontaneously hypertensive rats and in hypertensive patients. Recent results show that the agents which interfere with the functions of the sympathetic nervous system, converting enzyme inhibitors and calcium antagonists are effective in reducing arterial blood pressure and regression of left ventricular hypertrophy. The use of vasodilators and diuretics may under certain circumstances, however, even exacerbate cardiac hypertrophy. Regression of left ventricular hypertrophy in hypertension does not appear to depend solely on reduction of arterial blood pressure. Other factors seem to modulate the myocardial response to antihypertensive treatment. Included among these mechanisms are neural, humoral, haemodynamic and biochemical factors. The available experimental data further suggest that some functional derangements and biochemical changes associated with hypertrophy may be reversed by antihypertensive treatment. There is, however, insufficient experience with human subjects to determine whether a reduction in left ventricular mass is associated with lower incidences of heart failure or mortality than may be achieved by adequate blood pressure control alone.     

Obesity-induced Hypertension: Role of Sympathetic Nervous System,Leptin, and Melanocortins

Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors.     

A Genome-Wide Association Study of Hypertension and Blood Pressure in African Americans

The evidence for the existence of genetic susceptibility variants for the common form of hypertension (“essential hypertension”) remains weak and inconsistent. We sought genetic variants underlying blood pressure (BP) by conducting a genome-wide association study (GWAS) among African Americans, a population group in the United States that is disproportionately affected by hypertension and associated complications, including stroke and kidney diseases. Using a dense panel of over 800,000 SNPs in a discovery sample of 1,017 African Americans from the Washington, D.C., metropolitan region, we identified multiple SNPs reaching genome-wide significance for systolic BP in or near the genes: PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H. Two of these genes, SLC24A4 (a sodium/potassium/calcium exchanger) and CACNA1H (a voltage-dependent calcium channel), are potential candidate genes for BP regulation and the latter is a drug target for a class of calcium channel blockers. No variant reached genome wide significance for association with diastolic BP (top scoring SNP rs1867226, p = 5.8×10⁻⁷) or with hypertension as a binary trait (top scoring SNP rs9791170, p = 5.1×10⁻⁷). We replicated some of the significant SNPs in a sample of West Africans. Pathway analysis revealed that genes harboring top-scoring variants cluster in pathways and networks of biologic relevance to hypertension and BP regulation. This is the first GWAS for hypertension and BP in an African American population. The findings suggests that, in addition to or in lieu of relying solely on replicated variants of moderate-to-large effect reaching genome-wide significance, pathway and network approaches may be useful in identifying and prioritizing candidate genes/loci for further experiments.     

Molecular aspects of blood pressure regulation.

After 100 years of measurement, reasons for interindividual and populational variation in blood pressure have proven difficult to identify. Use of 24-hr blood pressure monitoring has revealed additional intra-individual variation. Variability in kidney function, extracellular sodium and potassium (Na:K) balance, and factors affecting water, sodium, and potassium resorption obviously affect blood pressure. Alterations in these and additional factors predict development of hypertension. In recent decades the molecular revolution has increased scrutiny of genetic factors contributing to interindividual and populational differences in blood pressure and hypertension. Most investigations across populations and environments have focused on components of the renin-angiotensin-aldosterone system. DNA polymorphisms within this system clearly are associated with blood pressure and hypertension; however, these associations tend to vary across race and ethnicity, ecological settings, and sex. There is clear evidence that polymorphisms at the renin, angiotensinogen, and angiotensin-converting enzyme loci influence both blood pressure and hypertension. In addition, evidence suggests gene-gene and gene-environment interactions along with sex-specific actions of these loci on blood pressure.