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Is There Association between Altered Adrenergic System Activity and Microvascular Endothelial Dysfunction Induced by a 7-Day High Salt Intake in Young Healthy Individuals.
Stupin, A, Drenjančević, I, Šušnjara, P, Debeljak, Ž, Kolobarić, N, Jukić, I, Mihaljević, Z, Martinović, G, Selthofer-Relatić, K
Nutrients. 2021;(5)
Abstract
This study aimed to test the effect of a 7-day high-salt (HS) diet on autonomic nervous system (ANS) activity in young healthy individuals and modulation of ANS on microvascular endothelial function impairment. 47 young healthy individuals took 7-day low-salt (LS) diet (3.5 g salt/day) followed by 7-day high-salt (HS) diet (~14.7 g salt/day). ANS activity was assessed by 24-h urine catecholamine excretion and 5-min heart rate variability (HRV). Skin post-occlusive reactive hyperemia (PORH) and acetylcholine-induced dilation (AChID) were assessed by laser Doppler flowmetry (LDF). Separately, mental stress test (MST) at LS and HS condition was conducted, followed by immediate measurement of plasma metanephrines' level, 5-min HRV and LDF microvascular reactivity. Noradrenaline, metanephrine and normetanephrine level, low-frequency (LF) HRV and PORH and AChID significantly decreased following HS compared to LS. MST at HS condition tended to increase HRV LF/HF ratio. Spectral analysis of PORH signal, and AChID measurement showed that MST did not significantly affect impaired endothelium-dependent vasodilation due to HS loading. In this case, 7-day HS diet suppressed sympathetic nervous system (SNS) activity, and attenuated microvascular reactivity in salt-resistant normotensive individuals. Suppression of SNS during HS loading represents a physiological response, rather than direct pathophysiological mechanism by which HS diet affects microvascular endothelial function in young healthy individuals.
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Resequencing Epithelial Sodium Channel Genes Identifies Rare Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study.
Gu, X, Gu, D, He, J, Rao, DC, Hixson, JE, Chen, J, Li, J, Huang, J, Wu, X, Rice, TK, et al
American journal of hypertension. 2018;(2):205-211
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BACKGROUND A resequencing study of renal epithelial sodium channel (ENaC) genes was conducted to identify rare variants associated with blood pressure (BP) salt-sensitivity. METHODS The Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study was conducted among 1,906 participants who underwent a 7-day low-sodium followed by a 7-day high-sodium feeding-study. The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Three ENaC genes (SCNN1A, SCNN1B, and SCNN1G) were resequenced using capillary-based sequencing methods. Traditional burden tests were utilized to examine association between rare variants and BP salt-sensitivity. Associations of low-frequency and common variants were tested using single-marker analyses. RESULTS Carriers of SCNN1A rare variants had a 0.52 [95% confidence interval (CI): 0.32-0.85] decreased odds of BP salt-sensitivity compared with noncarriers. Neither SCNN1B nor SCNN1G associated with salt-sensitivity of BP in rare variant analyses (P = 0.65 and 0.48, respectively). In single-marker analyses, 3 independent common variants in SCNN1A, rs11614164, rs4764586, and rs3741914, associated with salt-sensitivity after Bonferroni correction (P = 4.4 × 10-4, 1.1 × 10-8, and 1.3 × 10-3). Each copy of the minor allele of rs4764586 was associated with a 1.36-fold (95% CI: 1.23-1.52) increased odds of salt-sensitivity, whereas each copy of the minor allele of rs11614164 and rs3741914 was associated with 0.68-fold (95% CI: 0.55-0.84) and 0.69-fold (95% CI: 0.54-0.86) decreased odds of salt-sensitivity, respectively. CONCLUSIONS This study demonstrated for the first time a relationship between rare variants in the ENaC pathway and BP salt-sensitivity. Future replication and functional studies are needed to confirm the findings in this study. CLINICAL TRIAL REGISTRY Trial Number NCT00721721.
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Increased salt consumption induces body water conservation and decreases fluid intake.
Rakova, N, Kitada, K, Lerchl, K, Dahlmann, A, Birukov, A, Daub, S, Kopp, C, Pedchenko, T, Zhang, Y, Beck, L, et al
The Journal of clinical investigation. 2017;(5):1932-1943
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BACKGROUND The idea that increasing salt intake increases drinking and urine volume is widely accepted. We tested the hypothesis that an increase in salt intake of 6 g/d would change fluid balance in men living under ultra-long-term controlled conditions. METHODS Over the course of 2 separate space flight simulation studies of 105 and 205 days' duration, we exposed 10 healthy men to 3 salt intake levels (12, 9, or 6 g/d). All other nutrients were maintained constant. We studied the effect of salt-driven changes in mineralocorticoid and glucocorticoid urinary excretion on day-to-day osmolyte and water balance. RESULTS A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion. CONCLUSION Humans regulate osmolyte and water balance by rhythmical mineralocorticoid and glucocorticoid release, endogenous accrual of surplus body water, and precise surplus excretion. FUNDING Federal Ministry for Economics and Technology/DLR; the Interdisciplinary Centre for Clinical Research; the NIH; the American Heart Association (AHA); the Renal Research Institute; and the TOYOBO Biotechnology Foundation. Food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever.
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Elevation of Fasting Ghrelin in Healthy Human Subjects Consuming a High-Salt Diet: A Novel Mechanism of Obesity?
Zhang, Y, Li, F, Liu, FQ, Chu, C, Wang, Y, Wang, D, Guo, TS, Wang, JK, Guan, GC, Ren, KY, et al
Nutrients. 2016;(6)
Abstract
Overweight/obesity is a chronic disease that carries an increased risk of hypertension, diabetes mellitus, and premature death. Several epidemiological studies have demonstrated a clear relationship between salt intake and obesity, but the pathophysiologic mechanisms remain unknown. We hypothesized that ghrelin, which regulates appetite, food intake, and fat deposition, becomes elevated when one consumes a high-salt diet, contributing to the progression of obesity. We, therefore, investigated fasting ghrelin concentrations during a high-salt diet. Thirty-eight non-obese and normotensive subjects (aged 25 to 50 years) were selected from a rural community in Northern China. They were sequentially maintained on a normal diet for three days at baseline, a low-salt diet for seven days (3 g/day, NaCl), then a high-salt diet for seven days (18 g/day). The concentration of plasma ghrelin was measured using an immunoenzyme method (ELISA). High-salt intake significantly increased fasting ghrelin levels, which were higher during the high-salt diet (320.7 ± 30.6 pg/mL) than during the low-salt diet (172.9 ± 8.9 pg/mL). The comparison of ghrelin levels between the different salt diets was statistically-significantly different (p < 0.01). A positive correlation between 24-h urinary sodium excretion and fasting ghrelin levels was demonstrated. Our data indicate that a high-salt diet elevates fasting ghrelin in healthy human subjects, which may be a novel underlying mechanism of obesity.
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Effects of Salt Loading on Plasma Osteoprotegerin Levels and Protective Role of Potassium Supplement in Normotensive Subjects.
Liu, FQ, Liu, SQ, Zhang, Y, Wang, Y, Chu, C, Wang, D, Pan, S, Wang, JK, Yu, Q, Mu, JJ
Circulation journal : official journal of the Japanese Circulation Society. 2016;(1):77-81
Abstract
BACKGROUND Excess dietary salt is strongly correlated with cardiovascular disease, morbidity, and mortality. Conversely, potassium likely elicits favorable effects on cardiovascular disorders. In epidemiological studies, increased plasma osteoprotegerin (OPG) concentrations are associated with atherosclerosis and vascular deaths. Our study was designed to examine the effects of salt intake and potassium supplementation on plasma OPG levels in normotensive subjects.Methods and Results:The 18 normotensive subjects were selected from a rural community in China. They were sequentially maintained on low-salt diet for 7 days (3 g/day, NaCl), high-salt diet for 7 days (18 g/day), and high-salt diet with potassium supplementation for 7 days (18 g/day of NaCl+4.5 g/day of KCl). High-salt intake enhanced plasma OPG levels (252.7±13.9 vs. 293.4±16.1 pg/mL). This phenomenon was abolished through potassium supplementation (293.4±16.1 vs. 235.1±11.3 pg/mL). Further analyses revealed that the OPG concentration positively correlated with 24-h urinary sodium excretion (r=0.497, P<0.01). By contrast, OPG concentration negatively correlated with 24-h urinary potassium excretion (r=0.594, P<0.01). CONCLUSIONS Salt loading can enhance the production of circulating OPG. Potassium supplementation can reverse the effects of excessive OPG. Our study results may improve our understanding of the roles of salt and potassium in the risk of cardiovascular disorders.
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Common variants in the Na(+)-coupled bicarbonate transporter genes and salt sensitivity of blood pressure: the GenSalt study.
Guo, L, Liu, F, Chen, S, Yang, X, Huang, J, He, J, Jaquish, CE, Zhao, Q, Gu, CC, Hixson, JE, et al
Journal of human hypertension. 2016;(9):543-8
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The current study comprehensively examined the association between common variants in the Na(+)-coupled bicarbonate transporter (NCBT) genes and blood pressure (BP) responses to dietary sodium intervention. A 7-day low-sodium followed by a 7-day high-sodium dietary intervention was conducted among 1906 Han participants from rural areas of northern China. Nine BP measurements were obtained at baseline and each intervention using a random-zero sphygmomanometer. A mixed-effect model was used to assess the additive associations of 76 common variants in five NCBT genes, including SLC4A4, SLC4A5, SLC4A7, SLC4A8 and SLC4A10, with salt sensitivity phenotypes. The Bonferroni method was used to adjust for multiple testing. SLC4A4 marker rs4254735 was significantly associated with diastolic BP (DBP) response to low-sodium intervention (P=5.05 × 10(-4)), with mean (95% confidence interval (CI)) response of -2.91 (-3.21, -2.61) and -0.40 (-1.84, 1.05) mmHg for genotype AA and AG, respectively. In addition, BP responses to high-sodium intervention significantly increased with the number of minor C alleles of SLC4A4 marker rs10022637. Mean systolic BP responses among those with genotypes TT, CT and CC were 4.62 (4.29, 4.99), 5.94 (5.31, 6.58) and 6.00 (3.57, 8.43) mmHg (P=1.14 × 10(-4)); mean DBP responses were 1.72 (1.41, 2.03), 3.22 (2.52, 3.92) and 3.94 (1.88, 5.99) mmHg (P=2.26 × 10(-5)) and mean arterial pressure responses were 2.69 (2.40, 2.97), 4.13 (3.57, 4.70) and 4.61 (2.51, 6.71) mmHg (P=2.07 × 10(-6)), respectively. In brief, the present study indicated that common variants in the SLC4A4 gene might contribute to the variation of BP responses to dietary sodium intake in Han Chinese population.
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Salt Intake, Home Blood Pressure, and Perinatal Outcome in Pregnant Women.
Inoue, M, Tsuchihashi, T, Hasuo, Y, Ogawa, M, Tominaga, M, Arakawa, K, Oishi, E, Sakata, S, Ohtsubo, T, Matsumura, K, et al
Circulation journal : official journal of the Japanese Circulation Society. 2016;(10):2165-72
Abstract
BACKGROUND The relationship between salt (sodium chloride) intake and pregnancy-induced hypertension (PIH) remains unclear. The aim of this study was therefore to investigate the current status of salt intake during pregnancy and identify effective predictors for PIH. METHODS AND RESULTS Participants were 184 pregnant women who collected 24-h home urine as well as early morning urine samples. We investigated urinary salt excretion, home blood pressure (HBP) measurements for 7 consecutive days before the 20th and after the 30th gestational week, and the development of PIH. Urinary salt excretion according to early morning urine before the 20th gestational week was 8.6±1.7 g/day, and was significantly correlated with that measured from 24-h collected urine. Early morning urine estimated urinary salt excretion was slightly but significantly increased during pregnancy. HBP was 102±10/63±8 mmHg before the 20th gestational week and 104±12/64±10 mmHg after the 30th gestational week. On multiple regression analysis, serum uric acid and body mass index, but not urinary salt excretion, contributed to HBP both before the 20th and after the 30th gestational week. Fourteen participants (7.6%) developed PIH. On multivariate analysis, higher HBP and older age, but not urinary salt excretion, were significantly associated with PIH. CONCLUSIONS Higher HBP and older age, but not urinary salt excretion, are predictors of PIH. (Circ J 2016; 80: 2165-2172).
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Ambulatory blood pressure and blood pressure load responses to low sodium intervention in Han Chinese population.
Liu, F, Chen, P, Li, D, Yang, X, Huang, J, Gu, D
Clinical and experimental hypertension (New York, N.Y. : 1993). 2015;(7):551-6
Abstract
We aimed to illustrate ambulatory blood pressure monitoring parameters responses to low sodium intake and their differences between salt-sensitive and non-salt-sensitive individuals. A total of 186 participants were included in this analysis. Twenty-four hour, day-time and night-time blood pressure (BP) and BP load decreased during low sodium intervention, especially in salt-sensitive (SS) group. After multivariable adjustment, 24-h systolic BP, diastolic BP, mean arterial pressure and BP load responses to low sodium intervention of SS individuals were more pronounced than those of non-salt-sensitive individuals. Thus, reducing salt intake is potentially needed for the prevention of hypertension, especially in SS individuals.
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Using a low-sodium, high-potassium salt substitute to reduce blood pressure among Tibetans with high blood pressure: a patient-blinded randomized controlled trial.
Zhao, X, Yin, X, Li, X, Yan, LL, Lam, CT, Li, S, He, F, Xie, W, Sang, B, Luobu, G, et al
PloS one. 2014;(10):e110131
Abstract
OBJECTIVES To evaluate the effects of a low-sodium and high-potassium salt-substitute on lowering blood pressure (BP) among Tibetans living at high altitude (4300 meters). METHOD The study was a patient-blinded randomized controlled trial conducted between February and May 2009 in Dangxiong County, Tibetan Autonomous Region, China. A total of 282 Tibetans aged 40 or older with known hypertension (systolic BP≥140 mmHg) were recruited and randomized to intervention (salt-substitute, 65% sodium chloride, 25% potassium chloride and 10% magnesium sulfate) or control (100% sodium chloride) in a 1: 1 allocation ratio with three months' supply. Primary outcome was defined as the change in BP levels measured from baseline to followed-up with an automated sphygmomanometer. Per protocol (PP) and intention to treat (ITT) analyses were conducted. RESULTS After the three months' intervention period, the net reduction in SBP/DBP in the intervention group in comparison to the control group was -8.2/-3.4 mmHg (all p<0.05) in PP analysis, after adjusting for baseline BP and other variables. ITT analysis showed the net reduction in SBP/DBP at -7.6/-3.5 mmHg with multiple imputations (all p<0.05). Furthermore, the whole distribution of blood pressure showed an overall decline in SBP/DBP and the proportion of patients with BP under control (SBP/DBP<140 mmHg) was significantly higher in salt-substitute group in comparison to the regular salt group (19.2% vs. 8.8%, p = 0.027). CONCLUSION Low sodium high potassium salt-substitute is effective in lowering both systolic and diastolic blood pressure and offers a simple, low-cost approach for hypertension control among Tibetans in China. TRIAL REGISTRATION ClinicalTrials.gov NCT01429246.
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Blood pressure responses to dietary sodium and potassium interventions and the cold pressor test: the GenSalt replication study in rural North China.
Zhao, Q, Gu, D, Chen, J, Li, J, Cao, J, Lu, F, Guo, D, Wang, R, Shen, J, Chen, J, et al
American journal of hypertension. 2014;(1):72-80
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BACKGROUND In the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, we observed that blood pressure (BP) responses to dietary sodium and potassium interventions and the cold pressor test (CPT) varied greatly among individuals. We conducted a replication study to confirm our previous findings among 695 study participants. METHODS The dietary intervention included a 7-day low sodium (51.3 mmol/day), a 7-day high sodium (307.8 mmol/day), and a 7-day high sodium with potassium supplementation (307.8 mmol sodium and 60 mmol potassium/day). BP measurements were obtained during the baseline and each intervention phase. During the CPT, BP was measured before and at 0, 1, 2, and 4 minutes after the participants immersed their right hand in ice water for 1 minute. RESULTS Systolic and diastolic BP responses (mean ± SD (range), mm Hg) were 8.1±8.4 (-39.1 to 18.2) and -3.5±5.1 (-25.1 to 11.1) to low sodium, 9.1±8.4 (-13.3 to 33.1) and 4.0±5.4 (-16.0 to 20.7) to high sodium, and -4.6±5.8 (-31.8 to 11.6) and -1.9±4.3 (-16.9 to 14.2) to potassium supplementation, respectively (all P < 0.0001 for comparison with each former phase). The mean maximum systolic and diastolic BP responses to the CPT were 16.5±10.5 (-15.3 to 63.3) and 7.6±6.1 (-8.7 to 39.3), respectively (all P < 0.0001). CONCLUSIONS Our study indicates that there are large variations in BP responses to dietary sodium and potassium interventions and to the CPT among individuals.