Article

Controlled analysis of blood pressure sensitivity to sodium intake

Article

Controlled analysis of blood pressure sensitivity to sodium intake

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Abstract

Objective: The contribution of salt intake to the pathogenesis of hypertension holds longstanding interest. Recent studies employed the sensitivity of blood pressure (BP) to salt intake as an intermediate phenotype. The validity of this approach relative to the homogeneity of sodium-sensitive hypertension was investigated while simultaneously controlling multiple putative factors. Methods: Blood pressure responses to shifts in salt intake were measured in 274 individuals with essential hypertension in steady-state sodium balance on high (200 mEq) and low (10 mEq) sodium intakes. Univariate and multivariate analyses predicted systolic and diastolic sodium sensitivity based on interactions among demographic factors (age, gender, race, body mass index) and hypertensive type [low-renin (LR), modulator (M), non-modulator (NM)]. Results: The influence of hypertension type on systolic salt sensitivity (SSS) depended on gender (P = 0.03). In females, highest SSS was in LR (21, 14, 13 mmHg for LR, M, NM, P = 0.02), while in males highest SSS was in NM (11, 10, 16 mmHg for LR, M, NM, P = 0.07). Age predicted SSS without interacting with other factors, producing a 2.4 mmHg increase per decade (P = 0.02). Hypertension type affected diastolic salt sensitivity (DSS) (P = 0.002) without interacting with other factors. M had less DSS (6 mmHg) than LR (9 mmHg) and NM (11 mmHg) (P < 0.01). Conclusions: For subjects in sodium balance, the distributions of SSS and DSS were unimodal and the mechanisms mediating SSS and DSS were different. Controlling for multiple demographic factors, at least two hypertensive types have largest BP responses to sodium intake, reducing the usefulness of blood pressure sensitivity to salt intake as an intermediate phenotype.

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... We assume that, in contrast to normotensive subjects, a larger variety of unknown genetic and environmental confounding factors are likely to contribute to higher blood pressure values in hypertensive patients, masking the potential effect of a single gene or SNP. As a large variety of uncontrollable factors, such as demographic factors, are likely to confound blood pressure, in particular SBP, there is an ongoing debate about the usefulness of salt sensitivity of blood pressure per se as an intermediate phenotype (Hurwitz et al. 2003 ). On the other hand, all study subjects underwent a paired intervention design with rigorous control for sodium intake, race, gender, BMI, and blood pressure phenotype, which are all potential confounders of the LSD1 genotype salt sensitivity relationship, representing a major strength of our study. ...
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Salt sensitivity, the heterogeneity in the response of blood pressure (BP) to alterations in sodium intake, has been studied extensively, whereas weight sensitivity, the heterogeneity in BP response to weight change, has received scant attention. We examined the relationship of 21 gene polymorphisms previously found to be associated with hypertension, diabetes mellitus, or obesity, with weight sensitivity in the Trial of Nonpharmacologic Interventions in the Elderly, where participants with hypertension were randomized to receive intensive dietary intervention of sodium reduction, weight loss, both, or attention control, whereas pharmacological therapy was kept constant. After correcting for multiplicity, we identified significant associations of 3 polymorphisms with weight sensitivity of systolic BP (rs4646994, rs2820037, and rs1800629) and 3 polymorphisms for diastolic BP (rs4646994, rs2820037, and rs5744292). A recursive partitioning algorithm selected the combination of rs4646994, rs1800629, rs1982073, and rs1800896 as the set associated with the highest weight sensitivity. Polymorphisms related to hypertension, obesity, and diabetes mellitus are associated with weight sensitivity of BP.
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See related article, p 499–505 Almost 110 years ago, Ambard and Beaujard1 were the first to systematically explore the association between salt intake and blood pressure. They start their article with the following statement (translated from French): “It seems to us that one can say that each individual who is able to retain chloride is, by that very fact, apt to develop arterial hypertension.” They go on by describing several patients in whom an increase in salt intake was associated with retention of sodium (or rather chloride) and a rise in pressure. Interestingly, they also observed that in a few patients blood pressure did not increase despite massive salt loading, and they wondered whether there would be an internal mechanism that would serve to keep arterial pressure constant. It is clear that these investigators are to be credited for their discovery of the phenomenon of salt-sensitivity. Nevertheless, it took another 75 years before the terms salt-sensitive and salt-resistant became familiar in the literature.2 An important question is whether salt-sensitivity is a fortuitous phenomenon that may or may not be found on a certain occasion or that it is a trait that will be repeatedly demonstrable in the same person. To answer this question, we first need to address how we should define salt-sensitivity. Unfortunately, there is no consensus in the literature, and one can find almost every possible definition that one can think of. Both the amount of salt administered and the magnitude of the response above which pressure is considered to …
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Aim The present study investigated the association of dietary sodium intake and blood pressure (BP) based on existing data from the German National Health Interview and Examination Survey (GNHIES) and the associated German Nutrition Survey (GeNuS). Subject and methods After exclusion of participants with known hypertension and/or anti-hypertensive medication use, complete data of the GeNuS subsample of the 1998 GNHIES were analysed for 1,539 men and 1,553 women aged 18–79 years. The survey included a health and lifestyle questionnaire, a medical examination and a comprehensive diet history interview. Sodium density (g/1,000 kcal) was examined in quartiles of systolic and diastolic BP (SBP and DBP). Multiple linear regression models were used to investigate associations of sodium density and SBP or DBP. Adjustments were made for sex, age and socio- and health-behavioral risk factors previously found to be related to BP in univariate analysis. Results Participants with a high SBP and DBP (fourth quartile of SBP: ≥ 142 mmHg in men; ≥ 139 mmHg in women) had a significantly higher dietary sodium intake than individuals with a lower BP. In the multiple models, both SBP and DBP were significantly associated with sodium density when adjusted for other factors such as sex, age, body mass index and alcohol consumption. Conclusion An association of dietary sodium intake and BP in the German population could be found. Further research using sodium data collected via 24-h urine samples is urgently needed for evidence-based public health policy reducing risk of BP associated morbidities and mortalities in Germany.
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Striatin is a novel protein that interacts with steroid receptors and modifies rapid, nongenomic activity in vitro. We tested the hypothesis that striatin would in turn affect mineralocorticoid receptor function and consequently sodium, water, and blood pressure homeostasis in an animal model. We evaluated salt sensitivity of blood pressure in novel striatin heterozygote knockout mice. Compared with wild type, striatin heterozygote exhibited a significant increase in blood pressure when sodium intake was increased from restricted (0.03%) to liberal (1.6%) sodium. Furthermore, renal expression of mineralocorticoid receptor and its genomic downstream targets serum/glucocorticoid-regulated kinase 1, and epithelial sodium channel was increased in striatin heterozygote versus wild-type mice on liberal sodium intake while the pAkt/Akt ratio, readout of mineralocorticoid receptor's rapid, nongenomic pathway, was reduced. To determine the potential clinical relevance of these findings, we tested the association between single nucleotide polymorphic variants of striatin gene and salt sensitivity of blood pressure in 366 white hypertensive subjects. HapMap-derived tagging single nucleotide polymorphisms identified an association of rs2540923 with salt sensitivity of blood pressure (odds ratio, 6.25; 95% confidence interval, 1.7-20; P=0.01). These data provide the first in vivo evidence in humans and rodents that associates striatin with markers of mineralocorticoid receptor activity. The data also support the hypothesis that the rapid, nongenomic mineralocorticoid receptor pathway (mediated via striatin) has a role in modulating the interaction between salt intake and blood pressure.
Article
The thiazide-sensitive Na(+)-Cl(-) cotransporter (TSC) is responsible for the major sodium chloride reabsorption pathway, which is located in the apical membrane of the epithelial cells of the distal convoluted tubule. TSC is involved in several physiological activities including transepithelial ion absorption and secretion, cell volume regulation, and setting intracellular Cl(-) concentration below or above its electrochemical potential equilibrium. In addition, TSC serves as the target of thiazide-type diuretics that are the first line of therapy for the treatment of hypertension in the clinic, and its mutants are also reported to be associated with the hereditary disease, Gitelman's syndrome. This review aims to summarize the publications with regard to the TSC by focusing on the association between TSC mutants and human hypertension as well as Gitelman's syndrome. © The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
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Obesity and 4 of the leading causes of death—heart disease, cancer, stroke, and type 2 diabetes mellitus—are related to lifestyle. The combination of a healthy weight, prudent diet, and daily physical activity clearly plays a role in primary, secondary, and tertiary prevention of these and other chronic diseases. Because nearly 65% of the adult population is overweight or obese, weight loss and maintenance are central to this review article. Improved lipid profiles, blood pressure, insulin sensitivity, and euglycemia are associated with weight loss or a normal body weight; thus, maintaining a healthy weight is a universal recommendation for health. The methods for improving lifestyle described in the section on obesity include assessing nutritional status and stages of change of the client, setting realistic goals, eating a diet high in fruits and vegetables with low-fat sources of dairy and protein, and achieving appropriate physical activity levels. The importance of physicians discussing weight with clients and vice versa is stressed. The common features of lifestyle-related diseases make them amenable to similar lifestyle interventions.
Article
The simplest definition of salt sensitivity of blood pressure (SSBP) states that it is a physiological trait present in rodents and other mammals, including humans, by which the blood pressure (BP) of some members of the population exhibits changes parallel to changes in salt intake. In animals, the trait has been inbred such that the salt-sensitive (SS) ones will sustain increases in BP with salt loading and decreases with salt depletion, whereas the salt resistant (SR) ones will not. In humans, the trait is normally distributed; therefore, the distinction between SS and SR members of the population has been made by choosing an arbitrary magnitude of the salt-induced change in BP to define the groups. Regardless of possible causation by abnormalities of sodium handling, the SS phenotype is not usually characterized by alterations in salt balance (eg, impaired natriuresis or expanded plasma volume) but rather by a hypertensive response to maintain it. In an unselected population, SSBP is a continuous, normally distributed quantitative trait.1 As with any other trait with these characteristics, there is the issue of whether population members with the largest and smallest quantities of the trait represent the randomness of its distribution or are qualitatively different from the population at large. An example of this controversy is the old analyses of the unimodality versus bimodality of BP incidence or prevalence in humans that tried to determine whether hypertension is a distinct entity or simply an extreme of the gaussian distribution of BP.2 The development of the spontaneously hypertensive rat by Japanese investigators3 showing that the trait could be selected by inbreeding made it clear that hypertension had a genetic component. The gaussian distribution of population BP is probably the result of a random mixture of prohypertensive and antihypertensive genes and genetic variants in a …
Article
Background: Understanding the interactions between genetics, sodium (Na+) intake, and blood pressure (BP) will help overcome the lack of individual specificity in our current treatment of hypertension. This study had 3 goals: expand on the relationship between striatin gene (STRN) status and salt-sensitivity of BP (SSBP); evaluate the status of Na+ and volume regulating systems by striatin risk allele status; evaluate potential SSBP mechanisms. Methods: We assessed the relationship between STRN status in humans (HyperPATH cohort) and SSBP and on volume regulated systems in humans and a striatin knockout mouse (STRN+/-). Results: The previously identified association between a striatin risk allele and systolic SSBP was demonstrated in a new cohort (P = 0.01). The STRN-SSBP association was significant for the combined cohort (P = 0.003; β = +5.35 mm Hg systolic BP/risk allele) and in the following subgroups: normotensives, hypertensives, men, and older subjects. Additionally, we observed a lower epinephrine level in risk allele carriers (P = 0.014) and decreased adrenal medulla phenylethanolamine N-methyltransferase (PNMT) in STRN+/- mice. No significant associations were observed with other volume regulated systems. Conclusions: These results support the association between a variant of striatin and SSBP and extend the findings to normotensive individuals and other subsets. In contrast to most salt-sensitive hypertensives, striatin-associated SSBP is associated with normal plasma renin activity and reduced epinephrine levels. These data provide clues to the underlying cause and a potential pathway to achieve, specific, personalized treatment, and prevention.
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Background We hypothesized that caloric restriction (CR) and salt restriction (ResS) would have similar effects on reducing cardiovascular risk markers and that combining CR and ResS would be synergistic in modulating these markers. Methods and Results To test our hypothesis, rats were randomized into 2 groups: ad libitum liberal salt diet (ad libitum/high‐sodium, 1.6% sodium) or ResS diet (ad libitum/ResS, 0.03% sodium). CR was initiated in half of the rats in each group by reducing caloric intake to 60% while maintaining sodium intake constant (CR/high‐sodium, 2.7% sodium or CR/ResS, 0.05% sodium) for 4 weeks. CR in rats on a high‐sodium diet improved metabolic parameters, renal transforming growth factor‐β and collagen‐1α1 and increased plasma adiponectin and renal visfatin and NAD⁺ protein levels. Although CR produced some beneficial cardiovascular effects (increased sodium excretion and reduced blood pressure), it also was associated with potentially adverse cardiovascular effects. Adrenal zona glomerulosa cell responsiveness and aldosterone levels and activation were inappropriately increased for the volume state of the rodent. Like CR on HS, CR on a ResS diet also produced relative increased zona glomerulosa responsiveness and an increased blood pressure with no improvement in metabolic parameters. Conclusions These results suggest that combining CR and ResS may decrease the beneficial effects of each alone. Furthermore, CR, regardless of dietary salt intake, inappropriately activates aldosterone production. Thus, caution should be used in combining ResS and CR because the combination may lead to increased cardiovascular risk.
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BACKGROUND: Sleep-disordered breathing has been implicated in hypertension, but whether daytime breathing is a factor in blood pressure regulation has not been investigated to date. The present study sought to determine the role of breathing pattern in salt sensitivity of blood pressure. METHODS AND RESULTS: Thirty-six women, ages 40-70, were placed on a six-day low sodium/low potassium diet followed by a six day high sodium/low potassium diet. Breathing pattern at rest and 24-hr ambulatory blood pressure were monitored at baseline and after each six-day diet period. Respiratory rate (but not tidal volume or minute ventilation) was an inverse predictor of systolic (r = -0.50 p <.001) and diastolic (r = = -0.59; p <.001) blood pressure sensitivity to high sodium intake. Respiratory rate was positively associated with hemoglobin (r = +0.38; p <.01), and the salt-induced change in hemoglobin was associated with salt-induced change in blood pressure (r= -0.35; p <.05). CONCLUSION: These findings indicate that a pattern of slow breathing not compensated by increased tidal volume is associated with salt sensitivity of blood pressure in women. Breathing patterns could play a role in the hypertensive response via sustained effects on blood gases and acid-base balance, and/or be a marker for other biological factors mediating the cardiovascular response to dietary salt intake.
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The "gold standard" for the assessment of salt sensitivity of hypertension is the blood pressure response to dietary NaCl restriction; nevertheless, for practical purposes, a more rapid test that would not depend on the patient's compliance to the dietary prescription would be very useful in clinical research and medical practice. The aim of this study was thus to evaluate the effectiveness and reliability of a rapid, easy-to-standardize protocol for the assessment of salt sensitivity against the blood pressure response to dietary salt restriction. A total of 108 hypertensive patients were screened for salt sensitivity by the modified protocol of Grim et al. Thereafter, nine patients identified by the test as salt sensitive and nine identified as salt resistant followed, for two consecutive periods of 1 week, a diet with normal (200 mmol/day) or low (50 mmol/day) NaCl content. Compliance to the diet was checked by repeated 24-h urine collections. The group as a whole experienced a significant fall in blood pressure during the low Na diet (mean pressure = 123 +/- 3 v 118 +/- 3 mm Hg; P < .05). However, whereas patients identified as salt sensitive by the Grim protocol had a marked and significant blood pressure decrease (systolic -12 mm Hg, diastolic -7 mm Hg), no change was observed in those classified as salt resistant (systolic -2 mm Hg, diastolic -2 mm Hg). A significant correlation between changes in urinary Na excretion and changes in blood pressure was found only in salt-sensitive hypertensive patients. In conclusion, the modified Grim protocol tested in this study was able to correctly predict a significant blood pressure response to dietary salt restriction in the majority of cases. A validation of this test in a larger patient population may be advisable.
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Insulin resistance is a feature common to patients with diabetes and to some with hypertension. It is assumed that this feature confers the increased metabolic risk in hypertension. However, the state of the renin-angiotensin system might contribute to cardiovascular risk, although there is no clear mechanistic explanation. Our recent observation that insulin levels are increased in a specific subset of patients with normal/high-renin hypertension, the nonmodulators, provided the background for the current hypothesis: to ascertain whether abnormalities in lipid and carbohydrate metabolism are observed in the same patients in whom alterations in sodium transport, sodium homeostasis, and the renin-aniotensin system response have been identified. Exploration of a family history of cardiovascular risk was a secondary goal. Insulin sensitivity (assessed by a 75-g oral glucose load), lipid levels, and two defects in the renin-angiotensin system were assessed in 62 hypertensive and 14 normotensive subjects placed on a high (210 mmol/l) and a low (10 mmol/l) sodium intake for 2 weeks, to classify them as low-renin, nonmodulator, or modulating hypertensive subjects. Only in nonmodulators were the following cardiovascular risk factors significantly increased: fasting insulin (P < 0.01); increment in post-glucose load insulin (P < 0.01); total, LDL, and VLDL cholesterol and triglyceride levels (P < 0.05); and erythrocyte Na+/Li+ countertransport activity (P < 0.001). Both nonmodulators and low-renin hypertensive subjects had a significantly (P < 0.01) increased frequency of a family history of hypertension by questionnaire compared with subjects with intact modulation. However, only nonmodulators had a significantly (P < 0.02) higher frequency of a family history of myocardial infarction. Thus, there is a clustering of metabolic abnormalities in a discrete subset of the essential hypertensive population with a specific dysregulation of the renin-angiotensin system--nonmodulation. The absence of this cluster in low-renin hypertensive subjects may explain their relatively diminished cardiovascular risk. Its presence in nonmodulators likely contributes to the increased cardiovascular risk observed in normal/high-renin hypertension.
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Objective. - To assess the ability of antihypertensive drug treatment to reduce the risk of nonfatal and fatal (total) stroke in isolated systolic hypertension. Design. - Multicenter, randomized, double-blind, placebo-controlled. . Setting. - Community-based ambulatory population in tertiary care centers. Participants. - 4736 persons (1.06%) from 447 921 screenees aged 60 years and above were randomized (2365 to active treatment, 2371 to placebo). Systolic blood pressure ranged from 160 to 219 mm Hg and diastolic blood pressure was less than 90 mm Hg. Of the participants, 3161 were not receiving antihypertensive medication at initial contact, and 1575 were. The average systolic blood pressure was 170 mm Hg; average diastolic blood pressure, 77 mm Hg. The mean age was 72 years, 57% were women, and 14% were black. Interventions. - Participants were stratified by clinical center and by antihypertensive medication status at initial contact. For step 1 of the trial, dose 1 was chlorthalidone, 12.5 mg/d, or matching placebo; dose 2 was 25 mg/d. For step 2, dose 1 was atenolol, 25 mg/d, or matching placebo; dose 2 was 50 mg/d. Main Outcome Measures. - Primary. - Nonfatal and fatal (total) stroke. Secondary. - Cardiovascular and coronary morbidity and mortality, all-cause mortality, and quality of life measures. Results. - Average follow-up was 4.5 years. The 5-year average systolic blood pressure was 155 mm Hg for the placebo group and 143 mm Hg for the active treatment group, and the 5-year average diastolic blood pressure was 72 and 68 mm Hg, respectively. The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo. The relative risk by proportional hazards regression analysis was 0.64 (P = .0003). For the secondary end point of clinical nonfatal myocardial infarction plus coronary death, the relative risk was 0.73. Major cardiovascular events were reduced (relative risk, 0.68). For deaths from all causes, the relative risk was 0.87. Conclusion. - In persons aged 60 years and over with isolated systolic hypertension, antihypertensive stepped-care drug treatment with low-dose chlorthalidone as step 1 medication reduced the incidence of total stroke by 36%, with 5-year absolute benefit of 30 events per 1 000 participants. Major cardiovascular events were reduced, with 5-year absolute benefit of 55 events per 1000.
Article
The Intersalt Cooperative Research Group, together with Laaser U Intersalt: An International Study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion.
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Background Isolated systolic hypertension occurs in about 15% of people aged 60 years or older. In 1989, the European Working Party on High Blood Pressure in the Elderly investigated whether active treatment could reduce cardiovascular complications of isolated systolic hypertension. Fatal and non-fatal stroke combined was the primary endpoint. Methods All patients (≥60 years) were initially started on masked placebo. At three run-in visits 1 month apart, their average sitting systolic blood pressure was 160–219 mm Hg with a diastolic blood pressure lower than 95 mm Hg. After stratification for centre, sex, and previous cardiovascular complications, 4695 patients were randomly assigned to nitrendipine 10–40 mg daily, with the possible addition of enalapril 5–20 mg daily and hydrochlorothiazide 12·5–25·0 mg daily, or matching placebos. Patients withdrawing from double-blind treatment were still followed up. We compared occurrence of major endpoints by intention to treat. Findings At a median of 2 years' follow-up, sitting systolic and diastolic blood pressures had fallen by 13 mm Hg and 2 mm Hg in the placebo group (n=2297) and by 23 mm Hg and 7 mm Hg in the active treatment group (n=2398). The between-group differences were systolic 10·1 mm Hg (95% CI 8·8–11·4) and diastolic, 4·5 mm Hg (3·9–5·1). Active treatment reduced the total rate of stroke from 13·7 to 7·9 endpoints per 1000 patient-years (42% reduction; p=0·003). Non-fatal stroke decreased by 44% (p=0·007). In the active treatment group, all fatal and non-fatal cardiac endpoints, including sudden death, declined by 26% (p=0·03). Non-fatal cardiac endpoints decreased by 33% (p=0·03) and all fatal and non-fatal cardiovascular endpoints by 31% (p<0·001). Cardiovascular mortality was slightly lower on active treatment (27%, p=0·07), but all-cause mortality was not influenced (−14%; p=0·22). Interpretation Among elderly patients with isolated systolic hypertension, antihypertensive drug treatment starting with nitrendipine reduces the rate of cardiovascular complications. Treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major cardiovascular endpoints.
Article
Objective Recently, we reported evidence for genetic linkage between human essential hypertension and the angiotensinogen gene (AGT) and an association with a common molecular variant of this gene (methionine 235->threonine or T235). Other studies had led us to hypothesize that blunted renal plasma flow responses to infused angiotensin II (Ang II) when in high salt balance may reflect increased intrarenal formation of Ang II, a condition that might promote hypertension. Here we examine the relationship between AGT genotype and renal vascular response to infused Ang II. Methods Hypertensive (n=34, all off medication) and normotensive (n=57) members of families with a history of hypertension (age 18-60 years) as well as 29 normotensive volunteers without a family history of hypertension were studied after controlled diets with 200 mequiv./day sodium. Ang II was infused at a mildly pressor dose (3ng/kg/min) and renal plasma flow was determined by steady-state plasma para-aminohippurate concentration. Results After correction for covariates in multivariate analyses, participants homozygous for the T235 variant had significantly diminished renal plasma flow responses to the Ang II infusion (P=0.005). Changes in renal arterial resistance were also blunted in the T235 homozygotes. Similar results were found when analysis was restricted to normotensive participants or subdivided based on family history of hypertension. No confounding factors associated with AGT genotype that could explain these differences were found. Furthermore, obesity, which also suppressed renovascular response to Ang II, was found to interact significantly (P=0.017) with genotype such that, among T235 homozygotes, obesity had a greater blunting effect on renal vascular response. Conclusions Expected renovascular response to infused Ang II was blunted in persons with the AGT TT genotype. This is the first report of an association between a specific gene variant and altered renal physiology in humans with particular relevance to essential hypertension. (C) Lippincott-Raven Publishers.
Article
To investigate the effect of dietary sodium restriction on blood pressure in healthy, normotensive adults, 82 individuals (36 men, 46 women) participated in a study of restricted sodium intake (⩽ 75 mEq/day) for a period of 12 weeks. For the entire population there was a small but significant (p < 0.01) decrease in mean arterial pressure during sodium restriction. The change in blood pressure was significantly correlated with age (r = 0.23, p < 0.05). Division of the population at age 40, showed that the older individuals were more likely to have a decreased blood pressure during sodium restriction, while as a group younger adults showed no change. The individual blood pressure responses were heterogeneous with increases in pressure observed in some subjects. These results suggest that “sodium sensitivity” of blood pressure may be more evident with increasing age. Further, sodium restriction in all normotensive adults may not be innocuous.
Article
Blood pressure responses to 1 week of low (20 mmol sodium/day) and high (300 mmol sodium/day) salt intake were investigated in a double-blind, randomized study in 46 white, nonobese subjects with essential hypertension (13 women, 33 men; mean age 45.3 ± 2.2 years, age range 25 to 80 years). The individuals were classified as salt-sensitive when mean arterial blood pressure rose by at least 5 mm Hg during high salt intake, as salt-resistant when mean arterial blood pressure changed by less than 5 mm Hg, and as “counter-regulators” when mean arterial blood pressure fell by at least 5 mm Hg during the high salt diet. Mean arterial blood pressure of all subjects taken together increased from 101.9 ± 1.4 mm Hg during salt restriction to 103.7 ± 1.5 mm Hg (P < .05) during salt loading. Eleven subjects (23.9%) were classified as salt-sensitive, 27 (58.7%) as salt-resistant, and 8 (17.4%) as counter-regulators. Multiple regression analysis revealed that age, but not baseline blood pressure, sex, body mass index, or family history of hypertension contributed significantly to the change in blood pressure following the diets. Ten of the 11 salt-sensitive subjects were older than the median age of 45 years. In salt-sensitive, as compared to salt-resistant, hypertensive subjects, creatinine clearance was lower and plasma renin activity was suppressed at baseline as well as during low and high salt intake. In contrast, plasma concentrations of norepinephrine and atrial natriuretic peptide were elevated in salt-sensitive subjects. These differences between the groups appeared, at least partially, to be age-related. We concluded that age is a major determinant of the blood pressure response to varying salt intake in essential hypertension and that salt-sensitivity is linked to age-related changes in renal and endocrine function. Am J Hypertens 1995;8:829–836
Article
To compare the independent and additive effects of sodium restriction and a low-fat, high polyunsaturated: saturated fatty acids (P:S) ratio, high-fibre diet upon blood pressure. A randomized, parallet, double-blind, placebo-controlled (for sodium) 2 x 2 factorial trial. Clinical. Ninety-five hypertensive subjects (mean blood pressure, 137/83 mmHg), mean age 53.5 years, consuming less than 30 ml ethanol/day were selected from community volunteers. Seventy-nine treated and twelve untreated hypertensives completed the trial. Subjects followed either a low-sodium, low-fat/high-fibre diet (less than 60 mmol sodium/day; 30% fat energy; P:S ratio = 1; 30-50 g fibre/day) or a low-sodium, normal-fat/normal-fibre diet (less than 60 mmol sodium/day; 40% fat energy; P:S ratio = 0.3; 15 g fibre/day) for 8 weeks. Half of each group received 100 mmol/day NaCl and the remainder received placebo. Blood pressure and blood lipids. Sodium restriction significantly reduced standing and supine systolic blood pressure, with no effect upon diastolic blood pressure. The low-fat/high-fibre diet had no effect upon blood pressure, but significantly reduced total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Sodium restriction reduced blood pressure and did not raise low-density lipoprotein cholesterol. A low-fat/high-fibre diet did not reduce blood pressure but lowered cholesterol levels. A combination of the two regimes has the greater potential for reducing cardiovascular risk in hypertensives.
Article
Non-modulation is a trait characterized by abnormal angiotensin-mediated control of aldosterone release and the renal blood supply. To determine whether non-modulation defines a specific subgroup of the hypertensive population and its utility as an intermediate phenotype, we have studied the distribution of this quantitative trait, whether its features are reproducible on repeated testing, and whether there is concordance of its multiple features. Essential hypertensive patients (224) and normotensive subjects (119) received an infusion of angiotensin II (Ang II) at 3 ng.kg-1.min-1 for 30-45 minutes. p-Aminohippurate (PAH) clearance was assessed as an index of renal plasma flow while the subjects were on a 200 meq sodium diet; plasma aldosterone levels were measured while the subjects were on a 10 meq sodium diet. In 54 subjects, diuretic-induced volume depletion superimposed on a low salt diet was substituted for the Ang II infusion. The results of each study were submitted to maximum likelihood analysis to assess bimodality. In response to both diuretic-induced volume depletion (p < 0.000023) and Ang II infusion (p < 0.0009), aldosterone responses were bimodally distributed in the essential hypertensive but not in the normotensive subjects, suggesting that this trait identifies a discrete subgroup. In the 59 subjects who had both an adrenal and renal study, 50 (85%) were concordant. Finally, in 27 subjects studied two to six times over a span of 1-60 months, the intraclass correlations of the adrenal, PAH, or both responses were highly significant (p values between 0.001 and 0.00007), indicating high reproducibility of results on repeated testing.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Salt sensitivity of blood pressure can be identified in half of the hypertensive population and one-fourth of normotensive subjects. Salt sensitivity of blood pressure is especially frequent in normotensives from subpopulations known to have a higher frequency of hypertension, such as blacks, older subjects, and first-degree relatives of hypertensives, suggesting a link between salt and the subsequent development of hypertension. A variety of associated markers of salt sensitivity has been described. Recent studies also link calcium and salt sensitivity of blood pressure.
Article
To identify characteristics that may contribute to salt sensitivity, we conducted studies of normal subjects who are at risk for hypertension, namely blacks, subjects older than 40 years of age, and first-degree relatives of subjects with essential hypertension. We also formulated definitions for salt sensitivity and resistance with a short-term volume expansion and contraction protocol and additionally from data derived from studies of long-term reduced dietary salt intake. We examined the effects of augmented potassium and calcium intake and also those of sodium as the chloride or the bicarbonate salt. Finally, we sought genetic markers that are associated with salt sensitivity. We found that salt sensitivity is a function of age and is more common in blacks than whites. These groups also have relatively delayed acute salt excretion compared with controls. We were unable to identify effects of gender. Haptoglobin phenotypes (HP 1-1) may facilitate identification of salt-sensitive individuals. A high potassium intake may make individuals less salt sensitive. Sodium chloride and sodium bicarbonate differ in their effects on blood pressure. Sodium chloride augments urinary calcium excretion, but sodium bicarbonate does not. Differences between susceptible and nonsusceptible groups, together with improved knowledge of electrolyte interactions, may facilitate our understanding of salt-sensitive hypertension.
Article
Data from six surveys of systolic blood pressure conducted in Belgium between 1967 and 1986 were analyzed. The mean ages of the six groups of 3,328 subjects ranged from 70 to 81 years. The prevalence of systolic blood pressure levels above 159 mm Hg decreased between 1967 and 1986 from 51% to 21% in men and 66% to 22% in women; severe hypertension (systolic blood pressure greater than 220 mm Hg) nearly disappeared. During the same period, body mass index increased 1.1 kg/m2 in men and was unchanged in women; mean systolic blood pressure decreased from 159 to 142 mm Hg in men and from 171 to 147 mm Hg in women; the proportion of subjects receiving treatment for hypertension increased from 10% to 36% in men and from 18% to 41% in women; and the mean standardized 24-hour sodium excretion decreased from 265 to 188 mmol in men and from 208 to 160 mmol in women. Systolic blood pressure levels were significantly and independently related to sodium excretion in the 1967 and 1972 studies. The decrease in systolic blood pressure in Belgium was influenced by the combined effects of more and better treatment for hypertension and a decrease in sodium intake.
Article
Dietary salt reduction is an important nonpharmacologic remedy for mild hypertension as well as a useful adjunct to drug treatment. However, a reduced salt intake diet is not effective in reducing the blood pressure of all hypertensive patients. Several lines of evidence indicate that some patients are salt-sensitive whereas others are salt-resistant. A series of investigations have been conducted showing that the blood pressure responses to either acute salt and volume loading or to a reduced dietary salt intake are normally distributed. Blood pressure, humoral regulators of blood pressure and renal sodium handling are each found to be influenced by genetic variance. The change in blood pressure from dietary salt reduction is influenced by genetic variance as well. Definitions of salt sensitivity and resistance were formulated, and salt sensitivity of blood pressure was found to occur significantly more often in black than in white Americans. Furthermore, preliminary data suggest that measurement of phenotypes of haptoglobin in blood may assist in identifying salt-sensitive and salt-resistant subjects. Trials of a reduced salt intake diet in pharmacologically treated hypertensive patients are currently being conducted. The data suggest that at least half of the patients are salt-sensitive and that their medications may be reduced in response to the intervention. Results of this study may be of relevance to many of the 60 million Americans with hypertension, particularly to those who are black and elderly.
Article
Sensitivity and resistance to the effects of sodium were evaluated in normotensive and hypertensive humans by two approaches. Blood pressure was measured after an intravenous infusion of 2 L of normal (0.9%) saline and after sodium and volume depletion induced by a low sodium diet and furosemide administration in 378 normal volunteers and 198 subjects with essential hypertension. Those in whom mean arterial blood pressure decreased by at least 10 mm Hg after sodium and volume depletion were considered sodium-sensitive, and those with a decrease of 5 mm Hg or less (including an increase in pressure) were considered sodium-resistant. The second study utilized the blood pressure response to modest dietary sodium restriction in 74 normotensive subjects to identify sodium sensitivity and resistance. In both studies the responses were heterogeneous. In the first study significantly more hypertensive subjects were sodium-sensitive, as compared with those in the normotensive group (p less than 0.001). Plasma renin activity (low, normal, or high) did not predict sodium responses. In both groups sodium-sensitive individuals were significantly older (p less than 0.001) and had lower baseline renin values than sodium-resistant subjects. Factors related to the change in mean arterial blood pressure after sodium and volume depletion included baseline pressure (r = -0.54, p less than 0.001) and age (r = -0.16, p = 0.002 in the normotensive group; r = -0.28, p less than 0.001 in the hypertensive group). The response to dietary sodium restriction was also correlated with baseline pressure (r = 0.61, p less than 0.001) and the initial urinary sodium excretion (r = 0.27, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Familial resemblance in the blood pressure response to sodium restriction in normotensive persons was investigated. Forty-four families of identical twin children participated in a sodium restriction (less than or equal to 75 meq/day) protocol for a period of 12 weeks. Subjects were residents of central Indiana, and the study was conducted over a three-year period. Parent-offspring and sibling-sibling resemblances for actual blood pressure were not different under conditions of ad lib sodium intake versus sodium restriction. Mother-offspring resemblance in blood pressure change with sodium restriction was significant for systolic (p less than 0.001), diastolic (p less than 0.05), and mean arterial (p less than 0.05) pressures. Sibling-sibling and twin-twin resemblances were also highly significant for the change in all three blood pressures. Father-offspring resemblances were marginal (p less than 0.10). This study is, to the author's knowledge, the first to demonstrate significant familial resemblances in blood pressure change with sodium restriction in normotensive persons.
Article
This study assessed renal sodium handling in a group of patients with essential hypertension in whom control of the renal blood supply and aldosterone release by angiotensin II is abnormal ("non-modulating") because of recent evidence that these patients have sodium-sensitive hypertension. Sixty-one patients were studied, 25 as balance was achieved with a daily sodium intake of 10 meq and 36 after a shift from a 10 meq to 200 meq sodium intake for five days. Renal and adrenal responsiveness to angiotensin II was assessed by measurement of para-aminohippurate clearance and plasma aldosterone prior to and during the infusion of 3 ng/kg per minute of angiotensin II, to identify the non-modulator group (n = 32). The half-time of the exponential function relating sodium excretion to time during the three to five days when external balance was being achieved with a 10 meq sodium intake was 23.9 +/- 0.3 hours in 60 normal subjects, 24.5 +/- 1.8 hours in the patients with essential hypertension in whom renal responsiveness to angiotensin II was normal, and prolonged (p less than 0.001) to 36.6 +/- 2.1 hours in the non-modulating patients. A prolonged half-time suggests that, with a shift to a high sodium intake, more time will be required to achieve external sodium balance and at the expense of more retained sodium. During the shift from a 10 to 200 meq sodium intake, the non-modulator group showed a delayed rate at which external sodium balance was achieved, greater cumulative positive sodium balance, more weight gain, and a greater frequency of blood pressure rise. The abnormality in the rate at which external sodium balance is achieved in non-modulation results in a difference in total body sodium that varies with sodium intake and that may well contribute to, or cause, sodium-sensitive hypertension.
Article
Plasma renin activity and aldosterone secretion rates were measured in 100 patients with essential hypertension in response to a low sodium diet and upright posture. Plasma renin activity showed a subnormal response in 22 percent of patients, and a greater than normal response in 4 percent. In contrast to findings in 50 normal subjects, there was a significant positive correlation between the incidence of subnormal renin response and patient age and level of diastolic blood pressure. There was no correlation between renin response and known duration of hypertension. Comparison of several clinical and biochemical variables among the renin study subgroups revealed no differences except that the group with a low level of renin activity excreted a greater amount of sodium. These data support the hypothesis that a low renin activity level may evolve with time in patients with essential hypertension.
Article
The purpose of this study was to compare the blood pressure response to two commonly used protocols for the assessment of salt sensitivity in normotensive men, involving either the rapid intravenous administration of a saline load followed by diuretic-induced salt depletion, or the more physiologic but time-consuming approach involving dietary salt depletion and repletion. Twenty-two healthy male volunteers (22-35 years old) were given a saline load (2 L of 0.9% NaCl over 4 h, i.v.), and on the following day, a low-salt diet (20 mmol NaCl) and furosemide (3 x 40 mg, po). Resting mean arterial blood pressure (MABP) was assessed after the saline load and on the morning following salt depletion. After a 2-week wash-out period, subjects were given a low-salt diet (20 mmol/day NaCl) for 2 weeks, supplemented by either 220 mmol/day NaCl or placebo for 1 week each. At the end of each week, resting MABP was assessed in the supine subjects. Although MABP changes were quite variable (iv, mean -2.1 mm Hg; range, -9.1 to +5.6; diet, mean -2.0 mm Hg; range, -14.3 to +7.2), there was a significant correlation between the salt-induced changes in MABP (r = 0.56, P < .01) and diastolic blood pressure (r = 0.56, P < .01) between the two protocols. However, in individual subjects, blood pressure response to the intravenous protocol did not uniformly predict the blood pressure response to the dietary protocol.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
We examined the interactions between sodium and calcium responsiveness of blood pressure by studying the effects of calcium supplementation in 46 normotensive and hypertensive subjects who had been previously characterized as salt sensitive or salt resistant on the basis of their blood pressure responses to rapid sodium and extracellular volume expansion and contraction. The calcium supplementation study utilized a placebo-controlled, double- blind, randomized crossover design. Subjects received calcium carbonate supplementation (1.5 g/day) for 8 weeks or matching placebo, with 2- week placebo lead-in and crossover periods. For the entire group, no significant blood pressure changes were seen with calcium supplementation. When the subjects were separated on the basis of race or prior salt sensitivity, significant differences were seen. Blacks and salt sensitive subjects exhibited a significant (P < .05) blood pressure decrease when compared to their counterparts. Calcium sensitive subjects had significantly (P < .02) lower levels of plasma renin activity than those not demonstrating a decrease in blood pressure with added calcium. When urinary calcium excretion of subjects previously defined as salt sensitive or salt resistant were compared, the former had significantly (P < .001) higher calcium excretion values at baseline as well as during the placebo and calcium supplementation periods than did the latter. There were no known differences in dietary calcium intake to account for the striking urinary findings. These observations confirm the heterogeneity of blood pressure response to calcium supplementation and demonstrate congruity between sodium and calcium responsiveness of blood pressure in normal and hypertensive humans. These observations provide further evidence for a urinary calcium leak in sodium sensitive subjects independent of hypertension. Am J Hypertens 1993;6:799-805
Article
Blood pressure responses to 1 week of low-salt (20 mmol sodium/d) and high-salt (300 mmol sodium/d) intake were investigated in a single-blind randomized study in 163 white, nonobese normotensive subjects (65 women and 98 men; mean age, 38 +/- 1.2 years). The individuals were classified as salt sensitive when mean arterial blood pressure rose by at least 5 mm Hg during high-salt intake, as salt resistant when mean arterial blood pressure changed by less than 5 mm Hg, and as "counterregulator" when mean arterial blood pressure fell by at least 5 mm Hg during the high-salt diet. Reexamination of 31 subjects showed that this approach to the testing of salt sensitivity was reliable and reproducible. Thirty subjects (18.4%) were classified as salt sensitive, 108 (66.3%) as salt resistant, and 25 (15.3%) as counterregulators. Multiple regression analysis revealed that age, body weight, and family history of hypertension contributed significantly to the change in blood pressure after the diets. Salt sensitivity was more frequent in older subjects and in those with a positive family history of hypertension. An increase in blood pressure after salt restriction was more likely in younger individuals and in those with a negative family history of hypertension. Plasma renin activity and plasma aldosterone concentrations were lower in salt-sensitive compared with salt-resistant and counterregulating subjects. The rise in plasma renin activity during salt restriction was most pronounced in counterregulating subjects. Plasma norepinephrine concentrations were not different among the groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
A variety of different techniques have been used for the assessment of the blood pressure response to changes in salt and water balance in humans. These have generally been found to be reproducible and to yield congruent results. This review surveys the characteristics of subjects identified as salt sensitive and salt resistant by different investigators from demographic and physiological perspectives.
Article
The angiotensinogen gene is one of the very few related by linkage analysis to human hypertension, but the linkage has been consistently shown only among males. Moreover, polymorphisms in this gene predict an abnormal renal responsiveness to angiotensin II, a feature of non-modulation, but again, only among males. To pursue these related bridges between genetics and physiology, we evaluated the effects of sex on a second feature of non-modulation, the aldosterone response to infused angiotensin II during low sodium balance. We tested the resultant hypothesis-that non-modulation would be less frequent in women-by conducting identical protocols on 225 hypertensive inpatients (70 women, 155 men). Non-modulation was strikingly less frequent among women (26%; 95% confidence interval, 16% to 37%) than men (49%; 95% confidence interval, 40% to 57% (P = .001). We tested the hypothesis that sex steroids play a role by comparing young, premenopausal women (< 35 years) with women who were perimenopausal (45 to 55 years) and postmenopausal (> 55 years). Among the youngest women, the frequency of non-modulation was only 7%, significantly less than in young men (41%, P = .02). A steady increase in non-modulation frequency accompanied advancing age in women, reaching 47% in those older than 55 years, equal to the fraction of men affected. Age influenced non-modulation frequency in men far less. We conclude that a striking sex difference underlies the non-modulation phenotype and that female sex hormones may confer protection against a genotypic predisposition in women. This "override" of genotype, manifest by a very low frequency of non-modulation in young women, may participate in their known protection against cardiovascular disease.
Article
Seventy-one white and 33 black patients with essential hypertension were studied while on a high sodium intake of 350 mmol/d for 5 days and low sodium intake of 10 mmol/d for 5 days. The fall in blood pressure on changing from the high sodium to the low sodium diet was 17/6 mm Hg in whites and 22/10 mm Hg in blacks. Compared with whites, black patients had a 7-mm Hg greater fall (P<0.05) in systolic blood pressure and 4-mm Hg greater fall (P=0.068) in diastolic blood pressure (adjusted for age and blood pressure on the normal diet) with similar changes in urinary sodium excretion. With sodium restriction, plasma renin activity rose from 0.65 to 3.03 ng. mL-1. h-1 in whites, whereas in blacks it rose only from 0.3 to 1.28 ng. mL-1. h-1 (P<0.001 between blacks and whites). From the high to the low salt diet, plasma angiotensin II increased by 31 pmol/L in whites and by 12 pmol/L in blacks (P<0.05 compared with whites), and plasma aldosterone rose by 499 pmol/L in whites and by 256 pmol/L in blacks (P<0.01). Significant inverse correlations were obtained for all patients between the fall in systolic blood pressure from the high to low salt diet and the rise in plasma renin activity and angiotensin II, as well as the absolute level on the low salt diet. These results demonstrate that the larger fall in blood pressure with a reduction in salt intake in blacks is due at least in part to a less responsive renin-angiotensin-aldosterone system in blacks.
Article
The relationship of high salt intake to elevated blood pressure levels has been demonstrated in most populations by cross-sectional, longitudinal, physiological, and clinical intervention studies. Variation within the angiotensinogen gene has been implicated in the genetic control of blood pressure levels and has been suggested to contribute to increased salt sensitivity. A total of 86 hypertensive men and women who had never been treated and who had participated in a 6-month randomized, placebo-controlled, clinical trial of low-sodium mineral salt (19% reduction in urinary sodium versus 12% increase in placebo group) were genotyped at the angiotensinogen M235T locus to test the hypothesis that the 235T allele is associated with a significant blood pressure response to a sodium reduction intervention whereas the 235M allele is not. After adjustment for gender and baseline blood pressure, persons with the TT and MT genotypes showed significant systolic blood pressure reductions on mineral salt compared with control subjects (P = .02 and P = .001, respectively) but not persons with the MM genotype (P = .10). Net adjusted diastolic blood pressure reductions also showed greater significance for persons with the TT and MT genotypes than for persons with the MM genotype (P = .08, P = .01, and P = .83, respectively). The net adjusted systolic and diastolic blood pressure reduction was -8.6/-3.9 mm Hg for persons with the TT genotype, -9.0/-5.2 mm Hg for the MT genotype, and -5.3/-1.0 mm Hg for the MM genotype. We conclude that the 235T allele of the angiotensinogen gene is associated with greater blood pressure decreases than the 235M allele after a sodium reduction intervention. The angiotensinogen gene accounts for some of the interindividual variation of the blood pressure response to sodium reduction.
Article
A single-nucleotide variant of the angiotensinogen gene (AGT 235T) has been associated with essential hypertension and increased plasma levels of angiotensinogen. This variant may also serve as a genetic marker for the increased blood pressure response to dietary salt intake, but the relationship between AGT genotype and salt sensitivity has not been studied until now. We therefore examined the relationship between the AGT 235T genotype and the blood pressure response to short-term dietary salt restriction in young normotensive men. A total of 187 young normotensive men were characterized for family history of hypertension, salt sensitivity, plasma parameters of the renin-angiotensin system under high- and low-salt diets, and the AGT 235T genotype. While the T allele was significantly associated with a positive family history of hypertension (chi2 = 7.0; P< 0.03) and higher plasma angiotensinogen levels (P< 0.015) and renin activity (P < 0.037), blood pressure under both diets was not significantly affected by the AGT genotype. When the subjects were classified into salt-resistant and salt-sensitive groups, genotypic distribution was nearly identical between both groups (frequency of T allele: 0.45 versus 0.46). Our findings demonstrate that the AGT 235T allele is significantly associated with a positive family history of hypertension, but is not an important determinant of the blood pressure response to dietary salt intake in young normotensive subjects. It is therefore unlikely that the AGT 235T genotype can serve as an early genetic marker of salt sensitivity.
Article
Low-renin essential hypertension (LREH) describes a widely recognized classification validated by clinical features, including salt-sensitive blood pressure and diuretic responsiveness. Classic physiological teaching has cited normal plasma aldosterone concentration despite suppressed renin as evidence for adrenal supersensitivity to angiotensin II (Ang II). We studied 94 patients with LREH, 242 normal-renin hypertensives, and 135 normal subjects as controls. Low-renin hypertensives did not differ significantly from the other groups in either basal or Ang II-stimulated aldosterone concentrations on a high-sodium diet. Stimulated with a low-sodium diet, LREH patients demonstrated the smallest rise in basal aldosterone secretion. Ang II responsiveness was also subnormal: the rise in aldosterone after Ang II infusion in LREH (613+/-39 pmol/L), although greater than in nonmodulators (180+/-17 pmol/L; P=0.001), was less than either the patients with intact modulation (940+/-53 pmol/L; P=0.001) or normotensives (804+/-50 pmol/L; P<0.05). Blacks with LREH demonstrated an even lower response than low-renin whites ((388+/-50 versus 610+/-47 pmol/L; P=0.0001). In contrast, the rise in systolic blood pressure with Ang II infusion on a low-salt diet was greatest among LREH patients (P=0. 001). Patients with LREH and nonmodulators were equally salt-sensitive. These results indicate that the adrenal response in LREH is normal on a high-salt diet but becomes progressively more abnormal as sodium control mechanisms are stressed. The factors that mediate enhanced adrenal response to Ang II with sodium restriction may be defective, suggesting the existence of alternative physiological mechanisms for sodium homeostasis in the low-renin state.
Article
We evaluated the association between salt-sensitive hypertension and 3 different genetic polymorphisms of the renin-angiotensin system. Fifty patients with essential hypertension were classified as salt sensitive or salt resistant, depending on the presence or absence of a significant increase (P<0.05) in 24-hour ambulatory mean blood pressure (BP) after high salt intake. The insertion/deletion (I/D) angiotensin-converting enzyme (ACE) gene, the M235T angiotensinogen (AGT) gene, and the A1166C angiotensin II type 1 (AT1) receptor gene polymorphisms were determined with the use of standard polymerase chain reaction methods. Twenty-four (48%) patients with significantly increased (P<0.05) 24-hour mean BP with high salt intake (from 107.3+/-9.4 to 114.8+/-10.6 mm Hg) were classified as salt sensitive. In the remaining 26 patients (52%), high salt intake did not significantly modify 24-hour mean BP (from 107.6+/-10 to 107. 8+/-9 mm Hg), and they were classified as having salt-resistant hypertension. We did not find any significant association between either M235T AGT or A1166C AT1 receptor genotypes and the BP response to high salt intake. However, patients with essential hypertension homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake (9. 8+/-8.1 mm Hg for systolic BP and 5.2+/-4.2 mm Hg for diastolic BP) than that observed in patients homozygous for the deletion allele (DD) (1.2+/-5.9 mm Hg for systolic BP; P=0.0118 and -0.2+/-4.2 mm Hg for diastolic BP; P=0.0274). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension also was significantly higher (P=0.012) in II (67%) and DI patients (62%) compared with DD hypertensives (19%). We conclude that a significant association exists between the I/D polymorphism of the ACE gene and salt-sensitive hypertension. Patients with II and DI genotypes have significantly higher prevalence of salt sensitivity than DD hypertensives.
Article
To evaluate salt sensitivity in elderly subjects with different forms of hypertension and controls and to investigate any modulation by genotype Randomized, double-blinded, placebo-controlled latin-square Tertiary referral hospital Community subjects (n = 46) aged > or = 60 years classified as isolated systolic hypertension [ISH; systolic blood pressure (SBP) > or = 160, diastolic blood pressure (DBP) < 90 mmHg, n = 19], diastolic +/- systolic hypertension (SDH; DBP > or = 90 mmHg, n = 10) and normotension (SBP < 160, DBP < 90 mmHg, n = 17). Four 14 day treatments, 50, 100, 200 and 300 mmol/day of sodium chloride supplementation interspersed with 14 day washout periods on a salt-restricted diet. The 24 h blood pressure, heart rate, weight, urinary sodium and creatinine clearance measured during baseline, treatment and washout periods and angiotensinogen (AGT) and angiotensin converting enzyme (ACE) genotypes. For the entire cohort, the mean +/- standard error (SE) of change from baseline in SBP for 50, 100, 200 and 300 mmol/day salt was 7.7+/-2.4, 12.1+/-2.4, 16.6+/-3.0, 18.5+/-2.6 mmHg, respectively. For DBP, the respective changes were: -0.1+/-1.5, 2.4+/-1.6, 3.0+/-1.5, 5.8+/-1.7 mmHg. The increase in SBP among ISH subjects was significantly higher than among subjects in the SDH and normotensive groups (P < 0.05). AGT genotype influenced the effect of salt dose on the change in DBP (P = 0.006) but not SBP (P = 0.7). In healthy, older subjects, a linear increase in BP occurred with increasing salt dose, it appeared most pronounced in ISH subjects and could be modulated by AGT genotype.
Article
Hypertensive (n=93) and normotensive (n=39) white individuals were given a high sodium intake of approximately 350 mmol/d for 5 days followed by a low sodium intake of 10 to 20 mmol/d for 5 days. With this acute and large reduction in salt intake, no significant change was seen in blood pressure in the normotensive individuals, but blood pressure decreased in the hypertensive individuals. Compared with normotensive subjects, hypertensive patients had a 7/7-mm Hg greater fall in blood pressure (P<0.05 for systolic and P<0.01 for diastolic, adjusted for age), with similar changes in urinary sodium excretion. From the high-salt to low-salt diet, plasma renin activity rose from 0.90 to 5.99 ng. mL(-1). h(-1) in normotensives, whereas in hypertensives it rose from 0.73 to only 3.14 ng. mL(-1). h(-1) (P<0.05 between hypertensives and normotensives). Plasma aldosterone rose by 1396 pmol/L in normotensive subjects and by 511 pmol/L in hypertensive patients (P<0.05). Significant inverse correlations were obtained for all subjects between the fall in blood pressure from the high-salt to low-salt diet and the rise in plasma renin activity and aldosterone that occurred in addition to the absolute level on the low-salt diet. These results demonstrate that the larger fall in blood pressure with an acute reduction in salt intake in hypertensives compared with normotensives is, at least in part, due to a less-responsive renin-angiotensin-aldosterone system in the hypertensive patients.
Article
We analyzed the association between salt sensitivity in essential hypertension and 8 genetic polymorphisms in 6 genes of the renin-angiotensin aldosterone system. Seventy-one patients with essential hypertension were classified as salt sensitive or salt resistant by means of the 24-hour ambulatory blood pressure (BP) change to high salt intake. The polymorphisms evaluated correspond to the following genes: ACE (I/D), angiotensinogen (M235T), angiotensin II type 1 receptor (A1166C), 11beta-Hydroxysteroid dehydrogenase type 2 (11betaHSD2) (G534A), aldosterone synthase (C-344T and Intron 2 conversion), and the mineralocorticoid receptor (G3514C and A4582C); all were determined using standard polymerase chain reaction methods. Thirty-five patients (49%) were classified as salt sensitive. We analyzed the BP response to high salt intake among genotypes and found a significant association for ACE I/D and 11betaHSD2 G534A polymorphisms. Patients homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake than did patients homozygous for the deletion allele (DD). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension was also significantly higher (P=0.003) in II (68%) and DI patients (59%) compared with DD hypertensives (19%). With respect to 11betaHSD2 G534A, patients with the GG genotype had a significantly higher systolic BP increase with high salt intake than did GA patients. In addition, plasma renin activity suppression in response to high salt was significantly greater in GA patients than in GG patients. The prevalence of salt-sensitive hypertension was 14.3% in GA patients and 50.8% in GG patients (P=0.067). In conclusion, the I allele of ACE I/D polymorphism is significantly associated to salt-sensitive hypertension. The BP response to high salt intake was different among genotypes of ACE I/D and 11betaHSD G534A, suggesting that these polymorphisms may be potentially useful genetic markers of salt sensitivity.
Article
Renovascular and adrenal responses to infused angiotensin II (Ang II) are intermediate phenotypes that may indirectly reflect tissue renin-angiotensin system activity. We examine herein angiotensinogen (AGT) as a candidate gene to help elucidate potential mechanisms for previously reported AGT linkage and association studies. Renal plasma flow and plasma aldosterone were measured before and after a 45-minute infusion of Ang II (3 ng x kg(-1) x min(-1)) in 190 hypertensive patients who were on carefully controlled high- and low-salt diets. Reduced renal vascular (P=0.0002) and adrenal (P=0.002) responses to infused exogenous Ang II were associated with the AGT -6A allele. In multiple logistic regression, greater body mass index, lower basal renal plasma flow, and higher diastolic blood pressure together with AGT -6A genotype were associated with lower renal vascular response. In contrast, only male sex and AGT -6A genotype were associated with lower adrenal response. When both the renal and adrenal responses to Ang II were in the lowest tertile, the AGT -6AA genotype was present in 55.6%; in contrast, when both responses were in the upper 2 tertiles, the -6AA genotype was present in only 17.8% (P=0.001). A clear association between AGT genotype and response to infused Ang II was demonstrated for both the renal vasculature and the adrenal, consistent with the hypothesis that the AGT -6A genotype results in increased tissue expression of angiotensinogen and Ang II.
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