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Dietary salt influences postprandial plasma sodium concentration and systolic blood pressure

2011; Elsevier BV; Volume: 81; Issue: 4 Linguagem: Inglês

10.1038/ki.2011.369

1523-1755

Rebecca Suckling, Feng J. He, Nirmala D. Markandu, Graham A. MacGregor,

Renal function and acid-base balance

The plasma sodium concentration has a direct effect on blood pressure in addition to its effects on extracellular volume regulated through changes in the endothelium. The mechanism for elevated blood pressure seen with habitually increased salt intake is unclear, especially the effect of salt in a single meal on plasma sodium concentration and blood pressure. To resolve this we compared the effect of soup with or without 6g of salt (an amount similar to that in a single meal) on the plasma sodium concentration and blood pressure in 10 normotensive volunteers using a randomized, crossover design. The plasma sodium concentration was significantly increased by 3.13±0.75mmol/l with salted compared with unsalted soup. Blood pressure increased in volunteers ingesting soup with added salt, and there was a significant positive correlation between plasma sodium concentration and systolic blood pressure. A 1-mmol/l increase in plasma sodium was associated with a 1.91-mmHg increase in systolic blood pressure by linear regression. Thus, changes in plasma sodium concentration occur each time a meal containing salt is consumed. A potential mechanism for the changes in blood pressure seen with salt intake may be through its effects on plasma sodium concentration. The plasma sodium concentration has a direct effect on blood pressure in addition to its effects on extracellular volume regulated through changes in the endothelium. The mechanism for elevated blood pressure seen with habitually increased salt intake is unclear, especially the effect of salt in a single meal on plasma sodium concentration and blood pressure. To resolve this we compared the effect of soup with or without 6g of salt (an amount similar to that in a single meal) on the plasma sodium concentration and blood pressure in 10 normotensive volunteers using a randomized, crossover design. The plasma sodium concentration was significantly increased by 3.13±0.75mmol/l with salted compared with unsalted soup. Blood pressure increased in volunteers ingesting soup with added salt, and there was a significant positive correlation between plasma sodium concentration and systolic blood pressure. A 1-mmol/l increase in plasma sodium was associated with a 1.91-mmHg increase in systolic blood pressure by linear regression. Thus, changes in plasma sodium concentration occur each time a meal containing salt is consumed. A potential mechanism for the changes in blood pressure seen with salt intake may be through its effects on plasma sodium concentration. There is increasing evidence that high salt intake has a direct effect on the cardiovascular system independent and additive to its effects on blood pressure (BP).1.He F.J. MacGregor G.A. Reducing population salt intake worldwide: from evidence to implementation.Prog Cardiovasc Dis. 2010; 52: 363-382Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar Despite this, the mechanisms whereby salt increases BP remain unclear. The prevailing hypothesis suggests that habitual salt intake increases extracellular volume (ECV) and this leads to high BP. Until recently the direct role of plasma sodium had been ignored, although it is the major component of plasma osmolality and is therefore important in stimulating thirst, as well as controlling ECV.2.He F.J. Markandu N.D. Sagnella G.A. et al.Plasma sodium: ignored and underestimated.Hypertension. 2005; 45: 98-102Crossref PubMed Scopus (132) Google Scholar Salt intake could influence BP through its direct effects on plasma sodium concentration.3.de Wardener H. He F. MacGregor G. Plasma sodium and hypertension.Kidney Int. 2004; 66: 2454-2466Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar This is supported through several lines of evidence. In two out of three large cohort studies there is a positive association between the level of plasma sodium and BP, with a 1-mmol/l increase in plasma sodium concentration being associated with 1-mmHg increase in systolic BP in hypertensive and normotensive individuals.4.Komiya I. Yamada T. Takasu N. et al.An abnormal sodium metabolism in Japanese patients with essential hypertension, judged by serum sodium distribution, renal function and the renin-aldosterone system.J Hypertens. 1997; 15: 65-72Crossref PubMed Scopus (55) Google Scholar,5.Wannamethee G. Whincup P.H. Shaper A.G. et al.Serum sodium concentration and risk of stroke in middle-aged males.J Hypertens. 1994; 12: 971-979Crossref PubMed Scopus (37) Google Scholar A third study in 2,172 normotensive individuals found no association between plasma sodium concentration and BP, although the timing of the samples in relation to meals is not clear.6.Lago R.M. Pencina M.J. Wang T.J. et al.Interindividual variation in serum sodium and longitudinal blood pressure tracking in the Framingham Heart Study.J Hypertens. 2008; 26: 2121-2125Crossref PubMed Scopus (14) Google Scholar In intervention trials, large changes in salt intake have been found to change plasma sodium concentration by 3.0±0.3mmol/l and more modest reductions of dietary salt have been found to lower plasma sodium concentration by 0.4±0.2mmol/l, with these changes significantly correlating with falls in BP.2.He F.J. Markandu N.D. Sagnella G.A. et al.Plasma sodium: ignored and underestimated.Hypertension. 2005; 45: 98-102Crossref PubMed Scopus (132) Google Scholar In experimental studies, small increases in plasma sodium concentration were seen to increase the BP rapidly, despite reducing ECV.7.Friedman S.M. McIndoe R.A. Tanaka M. The relation of blood sodium concentration to blood pressure in the rat.J Hypertens. 1990; 8: 61-66Crossref PubMed Scopus (33) Google Scholar As yet the effect of acute consumption of salt, as is present in an average meal in the Western world, on plasma sodium is unclear. In this study the effects of 6g salt in a single meal in normotensive volunteers on plasma sodium and BP are described. This is compared with changes caused by an identical meal with no added salt. Soup with added salt increased the plasma sodium concentration by 2.12±0.46mmol/l, from 138.94±0.55 to 141.06±0.49mmol/l, whereas soup with no added salt lowered the plasma sodium concentration by 1.22±0.62mmol/l, from 139.72±0.66 to 138.49±0.79mmol/l at 120min. For added salt, the area under the curve (AUC) was significantly greater (added salt 400.35±78.59(mmol/l)min; no added salt 38.03±18.01(mmol/l)min; mean difference 362.32±79.72(mmol/l)min; P<0.01). Changes in plasma sodium concentration from baseline are illustrated in Figure 1. Soup with added salt increased the plasma osmolality by 3.80±0.58mosmol/l from 278.28±1.30 to 282.07±1.23mosmol/l at 60min (Figure 2). Soup with no added salt lowered the plasma osmolality by 4.37±1.02mosmol/l from 279.30±1.63 to 274.93±1.49mosmol/l at 120min. For added salt, the AUC was significantly greater (606.00±122.60(mosmol/l)min) compared with no added salt (32.25±24.23(mosmol/l)min); mean difference 573.75±114.92(mosmol/l)min; P<0.01. Soup with added salt increased the plasma chloride concentration by 2.87±0.40mmol/l from 105.76±0.56 to 108.63±0.83mmol/l at 120min and soup with no added salt lowered the plasma chloride concentration by 1.18±0.47mmol/l from 105.91±0.90 to 104.73±0.83mmol/l (Figure 3). For added salt the AUC was significantly greater (469.65±78.63(mmol/l)min) compared with the soup with no added salt (14.93±9.79(mmol/l)min); mean difference 454.73±78.01(mmol/l)min, P<0.01. There was an increase in BP following intake of both the soup with added salt and that with no added salt. This increase in BP was greater following intake of the soup with added salt compared with the soup with no added salt. For systolic BP, the AUC was 2499.00±560(mmHg)min with added salt, and 1488.00±453.59(mmHg)min with no added salt; mean difference 1011.00±420.36(mmHg)min, P<0.05. For diastolic BP, the AUC was 1665.00±499.22(mmHg)min with added salt and 1059.00±271.40(mmHg)min with no added salt; mean difference 606.00±416.84(mmHg)min. This difference was not statistically significant, P=0.180 (Figure 4). Although baseline BP was higher before intake of the soup with no added salt (108/70±6/2mmHg no added salt; 101/66±4/2mmHg added salt), there was no difference in pulse rate (70±5b.p.m. added salt; 67±3b.p.m. no added salt), 24-h urinary sodium (105±18mmol per 24h added salt; 106±16mmol per 24h no added salt) or other demographic or biochemical markers to explain for this difference. To examine the relationship between plasma sodium concentration and BP, we calculated the regression coefficient using linear regression analysis and the Pearson correlation coefficient between the change in plasma sodium concentration from baseline and the change in BP from baseline at each time point. This analysis was performed for each participant separately. Following Fisher r to z transformation, we then calculated the pooled regression coefficient and correlation coefficient using the random-effects model. Linear regression demonstrated a significant relationship between the change in plasma sodium concentration from baseline and the change in systolic BP following intake of soup with added salt (effect size 1.91mmHgpermmol/l, 95% CI: 0.16 to 3.66, P<0.05). This suggests that the greater the change in plasma sodium concentration, the greater the change in BP, with an increase in plasma sodium concentration of 1mmol/l being associated with an increase in systolic BP of 1.91mmHg (Figure 5). The pooled correlation coefficient was 0.42 (CI: 0.01–0.71). The relationship between change in plasma sodium concentration and change in systolic BP following intake of soup with no added salt was not significant (effect size 2.16mmHgpermmol/l (-1.07 to 5.40); r=0.29, CI: -0.13 to 0.63). There was no significant relationship between the change in plasma sodium and the change in diastolic BP (added salt: effect size 1.58mmHgpermmol/l (CI: -1.67 to 4.83); r=0.10, CI: -0.33 to 0.49; no added salt: effect size 0.83mmHgpermmol/l (-1.18 to 2.83); r=0.23, CI: -0.21 to 0.58). In this study, a soup containing 6g salt, a similar amount of salt that may be found in a single meal,8.Consensus Action on Salt and Health.CASH Surveys. 2010http://www.actiononsalt.org.uk/news/surveys/2010/index.htmlGoogle Scholar was shown to immediately increase plasma sodium concentration and BP. An identical soup with no added salt had the contrasting effect of reducing plasma sodium concentration. The change in plasma sodium concentration stimulates compensatory mechanisms to reduce the level of plasma sodium back to baseline levels. The raised plasma sodium concentration, and therefore osmolality, results in fluid movement from the intracellular to the extracellular space, stimulates thirst, and increases vasopressin secretion to reduce water excretion.3.de Wardener H. He F. MacGregor G. Plasma sodium and hypertension.Kidney Int. 2004; 66: 2454-2466Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Our study demonstrated that an increase in plasma sodium concentration was associated with an increase in BP. It is difficult to increase plasma sodium concentration without there being an associated expansion in ECV. However, experimental studies in animals have demonstrated a direct effect of plasma sodium on BP, and both plasma sodium concentration and ECV have an independent effect of BP.7.Friedman S.M. McIndoe R.A. Tanaka M. The relation of blood sodium concentration to blood pressure in the rat.J Hypertens. 1990; 8: 61-66Crossref PubMed Scopus (33) Google Scholar,9.Norman R. Coleman T.G. Wiley T.L. et al.Separate roles of sodium ion concentration and fluid volumes in salt-loading hypertension in sheep.Am J Physiol. 1975; 229: 1068-1072PubMed Google Scholar When plasma sodium concentration was increased by 10–15mmol/l in rats using peritoneal dialysis and ECV was reduced, BP rapidly increased.7.Friedman S.M. McIndoe R.A. Tanaka M. The relation of blood sodium concentration to blood pressure in the rat.J Hypertens. 1990; 8: 61-66Crossref PubMed Scopus (33) Google Scholar BP fell when plasma sodium concentration was lowered by the same amount and extracellular volume was increased. This could suggest that small increases in plasma sodium may independently regulate BP. It has been suggested that plasma sodium concentration may alter vascular function.2.He F.J. Markandu N.D. Sagnella G.A. et al.Plasma sodium: ignored and underestimated.Hypertension. 2005; 45: 98-102Crossref PubMed Scopus (132) Google Scholar, 3.de Wardener H. He F. MacGregor G. Plasma sodium and hypertension.Kidney Int. 2004; 66: 2454-2466Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 10.Oberleithner H. Riethmuller C. Schillers H. et al.Plasma sodium stiffens vascular endothelium and reduces nitric oxide release.Proc Natl Acad Sci USA. 2007; 104: 16281-16286Crossref PubMed Scopus (328) Google Scholar In cultured human endothelial cells, cell stiffness increased by 20% within minutes of raising plasma sodium concentration from 135 to 145mmol/l. This was associated with a reduction in nitric oxide formation and endothelial nitric oxide synthase activity, suggesting a functional link between nitric oxide metabolism and plasma sodium concentration.10.Oberleithner H. Riethmuller C. Schillers H. et al.Plasma sodium stiffens vascular endothelium and reduces nitric oxide release.Proc Natl Acad Sci USA. 2007; 104: 16281-16286Crossref PubMed Scopus (328) Google Scholar, 11.Oberleithner H. Kusche-Vihrog K. Schillers H. Endothelial cells as vascular salt sensors.Kidney Int. 2010; 77: 490-494Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 12.Li J. White J. Guo L. et al.Salt inactivates endothelial nitric oxide synthase in endothelial cells.J Nutr. 2009; 139: 447-451Crossref PubMed Scopus (78) Google Scholar These findings are supported by studies in cultured bovine endothelial cells, where an increase in sodium bath concentration from 135 to 142mmol/l reduced endothelial nitric oxide synthase activity by 25%.12.Li J. White J. Guo L. et al.Salt inactivates endothelial nitric oxide synthase in endothelial cells.J Nutr. 2009; 139: 447-451Crossref PubMed Scopus (78) Google Scholar Salt loading reduced endothelial vasodilation in hypertensives and healthy volunteers,13.Tzemos N. Lim P.O. Wong S. et al.Adverse cardiovascular effects of acute salt loading in young normotensive individuals.Hypertension. 2008; 51: 1525-1530Crossref PubMed Scopus (98) Google Scholar,14.Bragulat E. De la Sierra A. Antonio M. et al.Endothelial dysfunction in salt-sensitive essential hypertension.Hypertension. 2001; 37: 444-448Crossref PubMed Google Scholar and modest salt reduction increased endothelial vasodilation in obese normotensive women.15.Dickinson K.M. Keogh J.B. Clifton P.M. Effects of a low-salt diet on flow-mediated dilatation in humans.Am J Clin Nutr. 2009; 89: 485-490Crossref PubMed Scopus (107) Google Scholar Elevated plasma sodium concentration may have direct effects on vascular smooth muscle by way of increasing the vascular smooth muscle cell hypertrophy16.Gu J. Anand V. Shek E. et al.Sodium induces hypertrophy of cultured myocardial myoblasts and vascular smooth muscle cells.Hypertension. 1998; 31: 1083-1087Crossref PubMed Scopus (127) Google Scholar and through the direct effects of raised intracellular sodium concentration on vascular smooth muscle tension.17.Friedman S.M. The relation of cell volume, cell sodium and the transmembrane sodium gradient to blood pressure.J Hypertens. 1990; 8: 67-73Crossref PubMed Scopus (16) Google Scholar In our study, there was also a significant increase in plasma chloride concentration with salt loading. It is unclear as to how far plasma chloride concentration affects BP, although it is the effect of the combination of sodium and chloride that has the greatest effect on BP when compared with other sodium salts, for example, phosphate and bicarbonate.18.Shore A.C. Markandu N.D. MacGregor G.A. A randomized crossover study to compare the blood pressure response to sodium loading with and without chloride in patients with essential hypertension.J Hypertens. 1988; 6: 613-617Crossref PubMed Scopus (77) Google Scholar The relationship between plasma chloride concentration and BP is not consistent, and a strong relationship was seen between BP and plasma sodium concentration.18.Shore A.C. Markandu N.D. MacGregor G.A. A randomized crossover study to compare the blood pressure response to sodium loading with and without chloride in patients with essential hypertension.J Hypertens. 1988; 6: 613-617Crossref PubMed Scopus (77) Google Scholar, 19.Luft F.C. Zemel M.B. Sowers J.R. et al.Sodium bicarbonate and sodium chloride: effects on blood pressure and electrolyte homeostasis in normal and hypertensive man.J Hypertens. 1990; 8: 663-670Crossref PubMed Scopus (103) Google Scholar, 20.Sharma A.M. Kribeen A. Schattenfroh S. et al.Salt sensitivity in humans is associated with abnormal acid-base regulation.Hypertension. 1990; 16: 407-413Crossref PubMed Scopus (62) Google Scholar, 21.Schmidlin O. Forman A. Sebastian A. et al.Sodium-selective salt sensitivity, its occurrence in blacks.Hypertension. 2007; 50: 1085-1092Crossref PubMed Scopus (33) Google Scholar Our study had several limitations. We did not measure atrial natriuretic peptide (ANP), renin and aldosterone, or vasopressin. However, this has been explored in similar experiments. When plasma sodium concentration was increased using hypertonic saline, ANP levels were not affected by the loading procedures.22.Anderson L. Jenson T. Bestle M. et al.Gastrointestinal osmoreceptors and renal sodium excretion in humans.Am J Physiol Regul Integr Comp Physiol. 2000; 278: R287-R294PubMed Google Scholar In a study using a similar protocol, in individuals on a very-low-salt diet, plasma ANP levels were not affected by oral salt loading.23.Singer D.R.J. Markandu N.D. Buckley M.G. et al.Contrasting endocrine responses to acute oral compared with intravenous sodium loading in normal humans.Am J Physiol Renal Physiol. 1998; 274: F111-F119PubMed Google Scholar Salt loading led to an immediate fall in plasma concentration of angiotensin II, with suppression of plasma–renin activity and plasma aldosterone in both studies. Oral salt loading increases plasma vasopressin concentration.24.Spinelli L. Golino P. Piscione F. et al.Effects of oral salt load on arginine-vasopressin secretion in normal subjects.Ann Clin Lab Sci. 1987; 17: 350-357PubMed Google Scholar In conclusion, we have demonstrated that an increase in salt intake, which could occur with a single meal, rapidly increases plasma sodium concentration and BP. The significant positive relationship between plasma sodium concentration and BP levels is in agreement with previous studies.2.He F.J. Markandu N.D. Sagnella G.A. et al.Plasma sodium: ignored and underestimated.Hypertension. 2005; 45: 98-102Crossref PubMed Scopus (132) Google Scholar A potential mechanism whereby dietary salt could increase BP is through its effects on plasma sodium concentration. Ten healthy volunteers, six men and four women with a mean age of 39±4 years, provided written informed consent (see Table 1). The protocol was approved by the Local Research Ethics Committee and followed local institutional guidelines (LREC Approval Number 06/Q0803/323). Volunteers were advised to achieve a modest salt intake of 6g/day for a run-in period of 2 weeks and throughout the study. Dietary compliance was assessed with 24-h urinary sodium measurement. Volunteers were studied in fasting condition for 10h and were studied at 0800 hours. They were randomized to receive 400ml vegetable soup, which either contained 6g of salt or did not contain any salt. They were then crossed over to receive the other soup on the following visit. Soup was consumed over 20min and no other liquid was consumed during the study.Table 1Baseline demographic and clinical characteristics of all study participantsSaltNo saltDiffPWeight (kg)80.4±4.580.5±4.50.2±0.20.46Sitting BP (mmHg)101/66±4/2108/70±6/27/4±3/2<0.05Sitting pulse (min−1)70±567±33±40.46Sodium (mmol/l)138.9±0.6139.7±0.70.8±0.70.31Chloride (mmol/l)105.8±0.5105.9±0.90.2±0.70.84Osmolality (mosmol)278.2±1.4279.3±1.81.0±1.50.50Urine 24-h sodium (mmol/24h)105±18106±160.3±18.80.99Abbreviation: BP, blood pressure.Age (years), 39.4±4.5 years; body mass index (kg/m2), 26.6±1.1; male/female (n), 6/4.Data presented as mean±s.e.m. (n=10). Open table in a new tab Abbreviation: BP, blood pressure. Age (years), 39.4±4.5 years; body mass index (kg/m2), 26.6±1.1; male/female (n), 6/4. Data presented as mean±s.e.m. (n=10). Two 18-G intravenous cannulae were used to draw blood samples without stasis or a cuff at 15-min intervals for the first 90min, after which they were drawn half hourly. BP was measured using Omron HEM-705CP (Omron, Kyoto, Japan), and the mean of the second and third readings obtained at 1 to 2-min intervals was used for analysis. Plasma and urine sodium and chloride concentration were measured with an autoanalyzer with a coefficient of variation of 0.65% (ADVIA 2400 Chemistry System, Deerfield, IL). Osmolality was measured by freezing point depression with a coefficient of variation of 0.55% (Advanced Micro Osmometer Model 3300, Advanced Instruments, Norwood, MA). Results are reported as mean±s.e.m. We calculated the area under the curve above baseline for each analyte for each participant separately and compared the mean area under the curve between the no salt and salt visits using paired Student's t-tests. To study the relationship between plasma sodium concentration and BP, we calculated the regression coefficient using linear regression analysis and the Pearson correlation coefficient between change in plasma sodium concentration and change in BP for each participant separately. Correlation coefficients were transformed using Fisher r to z transformation. We then calculated the pooled regression coefficient and correlation coefficient using the random-effects model. The null hypothesis was rejected at P values of <0.05. Data were analyzed using SPSS for Windows, Rel. 15.0.0 (SPSS, Chicago, IL). We thank the nurses and laboratory technicians of the Blood Pressure Unit for their assistance in conducting these studies and the Clinical Pathology Department of St Helier Hospital, Carshalton, for their invaluable assistance.