Association of gene polymorphisms in microRNA with blood pressure responses to salt and potassium intake / 西安交通大学学报(医学版)

【Objective】 To investigate the relationship of miRNA gene polymorphisms with blood pressure (BP) responses to the sodium and potassium diet intervention. 【Methods】 In 2004, we recruited 514 participants from 124 families in seven villages of Baoji, Shaanxi Province, China. All subjects were given a three-day normal diet, followed by a seven-day low-salt diet, a seven-day high-salt diet, and finally a seven-day high-salt and potassium supplementation. A total of 19 miRNA single nucleotide polymorphisms (SNPs) were selected for analysis. 【Results】 Throughout the sodium-potassium dietary intervention, the BP of the subjects fluctuated across all phases, showing a decrease during the low-salt period and an increase during the high-salt period, followed by a reduction in BP subsequent to potassium supplementation during the high-salt diet. MiR-210-3p SNP rs12364149 was significantly associated with systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) responses to low-salt diet. MiR-4638-3p SNP rs6601178 was significantly associated with SBP while miR-26b-3p SNP rs115254818 was significantly associated with MAP responses to low-salt intervention. In addition, miR-26b-3p SNP rs115254818 was significantly correlated with SBP, DBP and MAP responses to high-salt intervention. MiR-1307-5p SNPs rs11191676 and rs2292807 were associated with SBP and MAP responses to high-salt diet. MiR-4638-3p SNP rs6601178, miR-210-3p SNP rs12364149, miR-382-5p SNP rs4906032 and rs4143957 were significantly associated with SBP response to high-salt diet. In addition, miR-26b-3p SNP rs115254818 was significantly associated with SBP, DBP and MAP responses to potassium supplementation. MiR-1307-5p SNPs rs11191676, rs2292807, and miR-19a-3p SNP rs4284505 were significantly associated with SBP responses to high-salt and potassium supplementation. 【Conclusion】 miRNA gene polymorphisms are associated with BP response to sodium and potassium, suggesting that miRNA genes may be involved in the pathophysiological process of salt sensitivity and potassium sensitivity.

Associations of genetic variants in GLP-1R with blood pressure responses to dietary sodium and potassium interventions / 西安交通大学学报(医学版)

【Objective】 To investigate the association between genetic variations in the glucagon-like peptide-1 receptor (GLP-1R) gene and BP responses to sodium and potassium intake. 【Methods】 A total of 514 subjects from 124 families were recruited in Meixian County, Shaanxi Province, in 2004, resulting in the establishment of a "salt-sensitive hypertension study cohort" . The subjects followed a dietary regimen which involved a normal diet for 3 days, a low-salt diet for 7 days, a high-salt diet for 7 days, and a high-salt potassium-supplemented diet for 7 days. BP measurement was conducted at different intervention periods, and peripheral blood samples were collected. Additionally, eight single nucleotide polymorphisms (SNPs) of the GLP-1R gene were genotyped using the MassARRAY detection platform. 【Results】 The GLP-1R gene SNP rs9462472 exhibited a significant association with systolic BP, diastolic BP, and mean arterial pressure response to high-salt intervention. Similarly, SNP rs2268637 showed a significant association with systolic BP response to high-salt intervention. Furthermore, SNP rs2268637 was significantly associated with systolic BP and mean arterial pressure responses to high-salt plus potassium supplementation intervention. 【Conclusion】 Our findings indicate a significant association of genetic variations in the GLP-1R gene with BP responses to sodium and potassium intake. This suggests that the GLP-1R gene plays a role in the regulation of BP salt sensitivity and potassium sensitivity.

Association of genetic variants in NEDD4L with blood pressure responses to dietary salt and potassium intake / 西安交通大学学报(医学版)

【Objective】 4-like protein with down-regulated expression and development in neural precursor cells (NEDD4L) plays an important role in blood pressure (BP) regulation and sodium homeostasis by regulating epithelial sodium channel protein. In this study, we aimed to explore the relationship of NEDD4L gene polymorphisms with BP responses to sodium and potassium intake. 【Methods】 In 2004, 514 subjects from 124 families in Meixian County, Shaanxi Province, were recruited to establish a salt-sensitive hypertension study cohort. All the subjects received a 3-day baseline survey, a 7-day low-salt diet, a 7-day high-salt diet, and finally a 7-day high-salt and potassium supplementation. Their BP was measured and peripheral blood samples were collected at different intervention periods. The 14 gene polymorphisms of NEDD4L gene were genotyped and analyzed by MassARRAY platform. 【Results】 BP decreased on a low-salt diet, and significantly increased on a high-salt diet, and decreased again after potassium supplementation. NEDD4L SNPs rs74408486 were significantly associated with systolic BP, diastolic BP and mean arterial pressure responses to the low-salt diet. SNPs rs292449 and rs2288775 were significantly associated with pulse pressure response to the high-salt diet. In addition, SNPs rs563283 and rs292449 were significantly associated with diastolic BP, mean arterial pressure, and pulse pressure responses to high-salt and potassium supplementation diet. 【Conclusion】 NEDD4L gene polymorphisms were significantly associated with BP responses to sodium and potassium intake, suggesting that NEDD4L gene may be involved in the development of salt sensitivity and potassium sensitivity.

Effects of sodium and potassium intervention on adult plasma levels of pentraxin-3 / 西安交通大学学报(医学版)

Objective: To explore the responses of plasma pentraxin-3 (PTX-3) to sodium and potassium supplementation so as to investigate the potential role of PTX-3 in salt-induced hypertension. Methods: We enrolled 48 volunteer participants from Liquan County, Shaanxi Province. All the subjects sequentially went through a 3-day normal diet, a 7-day low-sodium diet, a 7-day high-sodium diet, and a 7-day high-sodium plus potassium diet. Plasma concentration of PTX-3 was assessed by ELISA. Results: Subjects with lower PTX-3 tended to have higher body mass index (BMI), diastolic blood pressure (DBP), and mean arterial pressure (MAP). PTX-3 was negatively correlated with BMI, DBP, and MAP. During low-salt period, plasma PTX-3 significantly decreased compared with the baseline [(0.57±0.19)ng/mL vs. (0.72±0.33)ng/mL, P=0.012], but elevated during high-salt period [(0.68±0.26)ng/mL vs. (0.57±0.19)ng/mL, P=0.037]. Potassium supplementation significantly inhibited the salt-induced increase of PTX-3 [(0.56±0.21)ng/mL vs. (0.68±0.26)ng/mL, P=0.015]. PTX-3 was positively correlated with the sodium-to-potassium ratio (r=0.230, P=0.002). The response of PTX-3 was more prominent in salt-sensitive subjects. Conclusion: Dietary sodium and potassium interventions significantly affect circulating PTX-3. Low-salt intake contributes to the decrease of plasma PTX-3 while PTX-3 increases after high-salt intake. Potassium supplementation can inhibit salt-induced increase of PTX-3.

Salt sensitivity and its implication in clinical practice

Hypertension (HTN) is a complex multi-factorial disease and is considered one of the foremost modifiable risk factors for stroke, heart failure, ischemic heart disease and renal dysfunction. Over the past century, salt and its linkage to HTN and cardiovascular (CV) mortality has been the subject of intense scientific scrutiny. There is now consensus that different individuals have different susceptibilities to blood pressure (BP)-raising effects of salt and this susceptiveness is called as salt sensitivity. Several renal and extra-renal mechanisms are believed to play a role. Blunted activity of the renin–angiotensin–aldosterone system (RAAS), adrenal Rac1-MR-Sgk1-NCC/ENaC pathway, renal SNS-GR-WNK4-NCC pathway, defect of membrane ion transportation, inflammation and abnormalities of Na+/Ca2+ exchange have all been implicated as pathophysiological basis for salt sensitive HTN. While salt restriction is definitely beneficial recent observation suggests that treatment with Azilsartan may improve salt sensitivity by selectively reducing renal proximal tubule Na+/H+ exchange. This encourages the future potential benefits of recognizing and therapeutically addressing the salt sensitive phenotype in humans.

Effects of Chronic Salt Loading on Plasma Inflammatory Factors in Normotensive Adults / 中国循环杂志

Objectives: To observe the effects of dietary sodium intake on plasma inflammatory factors including tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (CRP) and monocyte chemoattractant protein -1 (MCP-1) in normotensive adults. Methods: Thirty normotensive volunteers, aged 18 to 60 years old, were selected to undergo baseline survey, low-sodium diet (51.3 mmol per day) for 7 days, followed by high-sodium diet (307.8 mmol per day) for 7days. Subjects were classified as salt sensitive (SS, 10 subjects) or non-salt sensitive (NSS, 20 subjects) based on their mean arterial blood pressure (MAP) increase (SS: more than 10 percent increase at the end of the high-sodium phase compared with the end of low-sodium phase). Fasting blood samples were taken on the first day of baseline and on the sixth day of the two intervention phases. Plasma TNF-α and MCP-1 concentration was measured using an enzyme-linked immunosorbent assay system, plasma hs-CRP concentration was measured by immune nephelometry. Results: The prevalence of SS is 33%. After salt loading, no significant change was found in the plasma hs-CRP concentrations; Whereas plasma TNF-α level increased significantly in both of the SS and NSS groups(pg/ml, [168.4±67.8 vs 42.1±26.7], P<0.01 and [129.8±24.1 vs 37.7±15.8], P<0.01, respectively) ; Plasma MCP-1 was also significantly higher during the high-sodium than the low-sodium phase in both SS and NSS groups(pg/ml, [205.2±64.2 vs 166.3±48.5], P<0.01and [212.3±52.2 vs 143.6±55.9], P<0.01). Conclusions: High-sodium diet can induce an inflammatory state independent of the salt sensitivity in normotensive subjects.

Salt Sensitivity Hypertension and Dietary Functional Factors / 中国医科大学学报

Of those who have hypertension,several patients are salt sensitive and need to restrict their salt intake. This article elucidates the physiological and pathological mechanisms of salt-sensitive hypertension (SSHT),including the dysfunction of the epithelial sodium channel (ENaC),epithelial damage,and the malfunction of the sodium pump,and relative genetic study,followed by a comparison of various salt-sensitivity examination methods. Another important discussion is about the influence of dietary factors (capsaicin,caffeine, apigenin,taurine,curcumin,menthol,and berberine) on SSHT. This review provides a solid foundation for understanding the biology of SSHT,screening of the salt-sensitive population,and prevention and cure of SSHT through everyday diet.

Effects of dietary high-salt intake on fibrosis and expression of microRNA133a in Dahl S rats’myocardium / 西安交通大学学报(医学版)

Objective To observe the influence of high-salt intake on the blood pressure,weight of left ventricle,myocardial microRNA133a and fibrosis levels by implementing the high-salt diet intervention trial in Dahl salt-sensitive rats and SD rats so as to explore the role of microRNA133a in salt-sensitive hypertensive cardiac fibrosis with high-salt intervention.Methods Sixteen 4-week male Dahl salt-sensitive rats are divided into two groups,8 in the SLS group and 8 in the SHS group.Similarly,sixteen 4-week male SD rats were divided into two groups. Systolic blood pressure of the rats was measured by the indirect tail-cuff method.Left ventricular mass index was measured after the rats were sacrificed. The expression levels of left ventricular myocardial tissue collagen I (LVMI),connective tissue growth factor (CTGF)expression and microRNA133a were observed.Results Blood pressure in high-salt groups both increased (P0.05).After the intervention,microRNA133a expression was significantly decreased in all high-salt groups compared with that in low-salt groups (P<0 .0 1 ),and the expression decreased more significantly in high-salt group of Dahl salt-sensitive rats than in high-salt group of SD rats (P<0.05).Conclusion High-salt diet is probably involved in salt-sensitive hypertension myocardial fibrosis by downregulating the expression of myocardial microRNA133a.

Upregulation of brain APJ receptor expression induced by high salt in pressure overload rats / 中国药理学通报

Aim To observe the effect of high salt stress on sympathetic nerve activity and brain Apelin and APJ system in pressure overload rats.Methods The suprarenal abdominal aorta was banded in male SD rats to create the pressure overload model.Four weeks later,the rats were fed a high-salt (8%NaCl)diet or a regular-salt (0.3% NaCl)diet for 1 week,and the hemodynamic changes of the rats were recorded.Sym-pathetic activity was evaluated by measuring 24 h uri-nary norepinephrine (NE)by ELISA.Real-time RCR and Western blot method were used to analyze the Ape-lin and APJ expression in the paraventricular nucleus of rats.In another protocol,ML22 1 or benzamil was intracerebroventricularly infused in the aorta banding rats fed with high-salt,and levels of 24 h urinary NE and cardiac index were recorded.In addition,normal SD rats were intracerebroventricularly infused with Na+-rich aCSF for 1 week,and the changes of blood pressure,24 h urine-NE and APJ expression levels were detected.Results In the pressure overload rats fed with high salt diet for 1 week,the mean arterial blood pressure (MAP),heart rate (HR),left ventric-ular end systolic pressure (LVESP),24 h urinary NE and APJ mRNA protein expression in paraventricular nuclear were significantly increased compared with those in control groups (P<0.05 ).However,the he-modynamics,24 h urinary NE and APJ expression showed no significant change in the sham rats fed a high salt diet.In addition,ICV infusion of APJ recep-tor antagonist ML221 or the ENaC antagonist benzamil significantly inhibited the 24 h urinary NE level and HW/BW ratio in the pressure overload rats fed high salt diet (P <0.01 ).Intracerebroventricular infusion of high Na+aCSF for 1 week in normotensive rats also significantly increased the MAP,HR,urinary-NE lev-els and brain APJ expression (P <0.0 1 ).Conclu-sions High salt increases the sympathetic nerve activ-ity in rats with pressure overload model, which is closely related to the brain APJ receptor expression and Na+sensitivity.Brain APJ receptor may be an impor-tant target in the development of salt sensitivity.

Salt sensitivity in middle-aged population with normal blood pressure and method for determining salt sensitivity / 第二军医大学学报

Objective To investigate the salt sensitivity of middle-aged population with normal blood pressure, and to observe the consistency of chronic sodium load test and cold pressor test in determining salt sensitivity. Methods Totally 68 middle-aged volunteers with normal blood pressure were divided into salt sensitivity (SS) group and non-salt sensitivity (NSS) group according to the results of chronic sodium load test, and the general data and increase amplitudes of blood pressure were compared between SS and NSS groups. The results of the two tests were compared by Χ2 test of fourfold table. Results According to the results of chronic sodium load test 22 (32. 4%) subjects were included in the SS group and 46 (67. 6%) were included in the NSS group. Compared with NSS group, SS group had a significantly elder age, higher proportion of family hypertension history (P0. 05). Conclusion The rate of salt sensitivity in the present normotensive middle-aged population is 32. 4%. Cold pressor test may be used as a substitute for the chronic sodium load test in determination of salt sensitivity.

Hypertension: Salt restriction, sodium homeostasis, and other ions.

Salt is composed of Sodium Chloride (NaCl) which in body water becomes essential electrolytes, viz., Sodium (Na + ) and Chloride (Cl - ) ions, including in the blood and other extracellular fluids (ECF). Na + ions are necessary cations in muscle contractions and their depletion will effect all the muscles in body including smooth muscle contraction of blood vessels, a fact which is utilized in lowering the blood pressure. Na+ ions also hold water with them in the ECF. Na + homeostasis in body is maintained by thirst (water intake), kidneys (urinary excretion) and skin (sweating). In Na + withdrawal, body tries to maintain homeostasis as far as possible. However, in certain conditions (e.g., during exercise, intake of drugs and in disorders causing Syndrome of Inappropriate Anti Diuretic Hormone Secretion (SIADH), diuretics, diarrhea) coupled with moderate or severe dietary salt restriction (anorexia nervosa), hyponatremia can get precipitated. Hyponatremia is one end point in the spectrum of disorders caused by severe Na + depletion whereas in moderate depletion it can cause hypohydration (or less total body water) and lower urinary volume (U v ). Moreover, salt sensitivity varies in various populations leading to different responses in relation to dietary Na + intake. Diabetes and Hypertension often co-exist but Na + withdrawal in salt sensitive subjects worsens diabetes though hypertension gets better and reverse occurs in salt loading. Therefore, Na + or salt restriction may be non-physiological. In hypertensive subjects other alternatives to Na + withdrawal could be Potassium (K + ) and Calcium (Ca 2+ ) supplementation. Further studies are required to monitor safety/side effects of salt restriction.

A comparison between sphygmomanometer-based and ambulatory blood pressure monitoring in acute salt loading and depletion protocol

INTRODUCTION: Ambulatory blood pressure monitors have been used in salt loading and depletion protocols. However, the agreement between measurements made using ambulatory blood pressure monitors and those made with the sphygmomanometer has not been evaluated. OBJECTIVE: The objective of this study was to compare the concordance of the two methods of blood pressure measurements in protocols of acute salt loading and depletion. METHOD: Systolic blood pressure was measured using a sphygmomanometer at the completion of salt infusion (2 L NaCl 0.9 percent, 4 h) and salt depletion (furosemide, 120mg/day, p.o.) in 18 volunteers. Using the Pearson correlation coefficient (ρ), these readings were compared with the mean systolic blood pressure measured using the ambulatory blood pressure monitoring device during the following periods: 4 h of saline infusion and 12 h of salt depletion; 4 h of saline infusion and the last 6 h of salt depletion; 12 h of salt loading and the last 6 h of depletion; 12 h of salt loading and 12 h of depletion. Salt sensitivity was defined by a difference in the systolic blood pressure between salt loading and salt depletion greater than 10 mmHg when measured with the sphygmomanometer, and the Kappa analysis of concordance (K) was used with a significance level of P<0.05. RESULTS: Only the blood pressure readings obtained using the ambulatory blood pressure device during 4 h of intravenous NaCl and during 12 h of salt depletion showed a high correlation with the variation in the systolic blood pressure measured by the sphygmomanometer, with a full agreement with the salt sensitivity classification (p = 0.71; P = 0.001 and K=1). CONCLUSION: In acute salt loading and depletion protocols, an ambulatory blood pressure monitoring device should be used to record the blood pressure during the 4-h interval of salt infusion and 12-h interval of salt depletion.

Salt and insulin sensitivity after short and prolonged high salt intake in elderly subjects

Salt sensitivity and insulin resistance are correlated with higher cardiovascular risk. There is no information about changes in salt sensitivity (SS) and insulin sensitivity (IS) after a chronic salt overload in humans. The aim of this study was to evaluate these parameters in the elderly. Seventeen volunteers aged 70.5 ± 5.9 years followed a low-salt diet (LSD) for 1 week and a high-salt diet (HSD) for 13 weeks. We evaluated SS after one week (HSD1) and after 13 weeks (HSD13), and subjects’ IS and lipids on their usual diet (UD) at HSD1, and at HSD13. Blood pressure (BP) was measured at each visit and ambulatory blood pressure monitoring (ABPM) was performed twice. SS was the same at HSD1 and HSD13. Systolic BP was lower on LSD than on UD (P = 0.01), HSD1 (P < 0.01) and HSD13 (P < 0.01). When systolic and diastolic BP were evaluated by ABPM, they were higher at HSD13 during the 24-h period (P = 0.03 and P < 0.01) and during the wakefulness period (P = 0.02 and P < 0.01) compared to the UD. Total cholesterol was higher (P = 0.04) at HSD13 than at HSD1. Glucose and homeostasis model assessment (HOMA) were lower at HSD1 (P = 0.02 and P = 0.01) than at HSD13. Concluding, the extension of HSD did not change the SS in an elderly group. The higher IS found at HSD1 did not persist after a longer HSD. A chronic HSD increased BP as assessed by ABPM.

Óxido nítritico: sensibilidad a la sal y la obesidad / Nitric oxide: salt sensitivity and obesity

El óxido nítrico es una molécula neurotransmisora, mediadora de importantes funciones como la vasodilatación, estimulación de la síntesis de músculo liso vascular y antiagregación plaquetaria. El óxido nítrico es continuamente sintetizado y liberado desde el endotelio en condiciones fisiológicas. La inhibición crónica de la producción de óxido nítrico conduce a hipertensión arterial severa; por otra parte la hipertensión arterial se asocia con otros factores de riesgo, como lo es la sensibilidad a la sal. A pesar de que la hipertensión arterial inducida por sodio fue descrita hace medio siglo, aún se desconoce su etiología en humanos, y las implicaciones del óxido nítrico en su aparición. a) La ingesta elevada de sodio inhibe la producción del óxido nítrico; este efecto se revierte con la ingestión de sal. b) en sujetos obesos, la corrección de alteraciones metabólicas asociadas es capaz de corregir la sensibilidad a la sal y por lo tanto, de disminuir la hipertensión arterial en los individuos sal sensibles. También restablece la bioactividad normal del óxido nítrico. Estos hallazgos permiten afirmar que los factores de riesgo adquiridos juegan un papel importante en la patogénesis de la sensibilidad a la sal asociada a la obesidad, y que la corrección de la adiposidad abdominal mejora las anomalías metabólicas asociadas, reduce la reactividad de la presión arterial al sodio y mejora la producción de óxido nítrico.

Nitric oxide, as a neurotransmitter molecule, is a mediator of important functions including vasodilatation, synthesis of vascular smooth muscle and anti-aggregation of platelets. Under physiological conditions nitric oxide is synthesized and released from the endothelium. The chronic inhibition of nitric oxide production leads to severe hypertension; moreover hypertension is associated with other risk factors, such as salt sensitivity. Although hypertension induced by sodium was described half a century ago, its etiology remains unclear as well as the involvement of nitric oxide. A) high sodium intake inhibits the production of nitric oxide; this effect is reversed by reducing salt intake. B) in obese subjects, the reduction of central adiposity and the correction of related metabolic abnormalities can alter the salt sensitivy, and thereby decrease blood pressure in salt-sensitive individuals. It also restores the normal bioactivity of nitric oxide. These findings confirm the important role of risk factors in the pathogenesis of salt sensitivy associated with obesity, and that the correction of abdominal fat improves metabolic abnormalities, leading to the lowering of salt sensitivy and to an improvement in the production of nitric oxide.

Salt-Sensitivity and Developement of Blood Pressure From Adolescents to Youth / 中华高血压杂志

Objective To study the effects of salt sensitivity on evolution of blood pressure and develope- ment to hypertension from adolescents to youth.Methods A baseline survey was carried out in 4623 adolescents aged 6-15 years old in Hanzhong rural area in 1987,310 of them were recruited for determination of salt sensitiv- ity using the tests of oral saline load and furosemide sodium-volume depletion.Salt sensitivity (SS) were diag- nosed in 101 while 209 subjects as no-sah sensitivity (NSS).This cohort of adolescents were followed up for av- erage 18 years.Results The response rate for this cohort of adolescents was 71.9%.At the end of follow up period,BP in subjects with baseline SS was higher in youth than that in NSS (SBP:122.9?13.1 vs 117.3?12.4, P

The Comparison of Renal Handling of Sodium and Potassium According to Salt Intake between Control and Hypertensive Group

The salt-sensitivity has been generally accepted as a mechnism of high blood pressure in elderly hypertensive patients, and so it may result in a difference of renal handling of sodium and potassium between normal healthy control and elderly hypertensive patient. So to evaluate an lbove difference, the amount of 24 hours' urinary excretion of Na+ & K+ were measured in healthy normotensive control (10 case) and elderly hypertensive group(10 case) according to normal diet (12-15gm of NaCl) for first 3 days and low salt diet (3~5)gm of NaCi) for next 3 days, also blood rewwure was mintored. The results were followed : 1) 24 hours' urinary excretion of NA+ was increased in hypertensive group more than control group at first day of normal diet and low salt diet significantly. 2) After a replacement of normal diet to low salt diet, a maximal decrement of 24 hours' urinary excretion of Na+ was 25% at first day in control but 40% at second day in hypertensive group only. 3) There was a similar pattern of urinary excretion of K+ as Na+ in hypertensive group, but it was not stastically significant. 4) There was no significant changes of blood pressure, serum electrolyte and BUN/creatinine according to salt intake in both group. From above findings. We can conclude that a urinary excretion of sodium is delayed in elderly hypertensive group, and it is suggested that a delayed excretion of sodium. is associated with retention of sodium in body. So a persistent restriction of sodium is recommended in elderly hypertensive patient.