Changes In Dietary Sodium Intake Research Articles

UROMODULIN - A LINK BETWEEN SODIUM EXCRETION AND ALTERATION IN CIRCADIAN BLOOD PRESSURE PATTERN IN PREHYPERTENSIVES.

Although changes in dietary sodium intake alter blood pressure (BP) in salt-sensitive individuals, pathophysiological mechanisms are still unknown. It has been reported that uromodulin is involved in sodium tubular transport, and genome-wide association studies pointed to UMOD gene as one of the most important gene candidates for arterial hypertension. Our aim was to analyze urinary uromodulin, salt intake and BP in 326 young middle-aged subjects (mean age 36±8 years, 49.4% male). In a subgroup of 175 individuals, ambulatory blood pressure monitoring and echocardiogram were performed. Uromodulin was determined by ELISA. According to the JNC-7 criteria, subjects were classified as optimal BP (n=103, men 72%), prehypertension (PHT) (n=143, men 43%) and hypertension (HT) (n= 80, men 38%). There were no differences in age, salt intake, estimated glomerular filtration rate, sodium excretion and uromodulin among BP groups. However, in PHT subjects, uromodulin was positively associated with fractional sodium excretion and negatively with 24-h sodium excretion and diastolic BP dip. These findings point to the effect of uromodulin on sodium reabsorption along the nephron and consequently circadian BP alteration in prehypertensives.

Blood Pressure Effects of Sodium Reduction: Dose-Response Meta-Analysis of Experimental Studies.

The relationship between dietary sodium intake and blood pressure (BP) has been tested in clinical trials and nonexperimental human studies, indicating a direct association. The exact shape of the dose-response relationship has been difficult to assess in clinical trials because of the lack of random-effects dose-response statistical models that can include 2-arm comparisons. After performing a comprehensive literature search for experimental studies that investigated the BP effects of changes in dietary sodium intake, we conducted a dose-response meta-analysis using the new 1-stage cubic spline mixed-effects model. We included trials with at least 4 weeks of follow-up; 24-hour urinary sodium excretion measurements; sodium manipulation through dietary change or supplementation, or both; and measurements of systolic and diastolic BP at the beginning and end of treatment. We identified 85 eligible trials with sodium intake ranging from 0.4 to 7.6 g/d and follow-up from 4 weeks to 36 months. The trials were conducted in participants with hypertension (n=65), without hypertension (n=11), or a combination (n=9). Overall, the pooled data were compatible with an approximately linear relationship between achieved sodium intake and mean systolic as well as diastolic BP, with no indication of a flattening of the curve at either the lowest or highest levels of sodium exposure. Results were similar for participants with or without hypertension, but the former group showed a steeper decrease in BP after sodium reduction. Intervention duration (≥12 weeks versus 4 to 11 weeks), type of study design (parallel or crossover), use of antihypertensive medication, and participants' sex had little influence on the BP effects of sodium reduction. Additional analyses based on the BP effect of difference in sodium exposure between study arms at the end of the trial confirmed the results on the basis of achieved sodium intake. In this dose-response analysis of sodium reduction in clinical trials, we identified an approximately linear relationship between sodium intake and reduction in both systolic and diastolic BP across the entire range of dietary sodium exposure. Although this occurred independently of baseline BP, the effect of sodium reduction on level of BP was more pronounced in participants with a higher BP level.

Pilot study to reduce interdialytic weight gain by provision of low-sodium, home-delivered meals in hemodialysis patients.

Patients with kidney failure undergoing maintenance hemodialysis (HD) therapy are routinely counseled to reduce dietary sodium intake to ameliorate sodium retention, volume overload, and hypertension. However, low-sodium diet trials in HD are sparse and indicate that dietary education and behavioral counseling are ineffective in reducing sodium intake. This study aimed to determine whether 4 weeks of low-sodium, home-delivered meals in HD patients reduces interdialytic weight gain (IDWG). Secondary outcomes included changes in dietary sodium intake, thirst, xerostomia, blood pressure, volume overload, and muscle sodium concentration. Twenty HD patients (55 ± 12 years, body mass index [BMI] 40.7 ± 16.6 kg/m2 ) were enrolled in this study. Participants followed a usual (control) diet for the first 4 weeks followed by 4 weeks of three low-sodium, home-delivered meals per day. We measured IDWG, hydration status (bioimpedance), standardized blood pressure (BP), food intake (3-day dietary recall), and muscle sodium (magnetic resonance imaging) at baseline (0 M), after the 4-week period of usual diet (1 M), and after the meal intervention (2 M). The low-sodium meal intervention significantly reduced IDWG when compared to the control period (-0.82 ± 0.14 kg; 95% confidence interval, -0.55 to -1.08 kg; P < 0.001). There were also 1 month (1 M) to 2 month (2 M) reductions in dietary sodium intake (-1687 ± 297 mg; P < 0.001); thirst score (-4.4 ± 1.3; P = 0.003), xerostomia score (-6.7 ± 1.9; P = 0.002), SBP (-18.0 ± 3.6 mmHg; P < 0.001), DBP (-5.9 ± 2.0 mmHg; P = 0.008), and plasma phosphorus -1.55 ± 0.21 mg/dL; P = 0.005), as well as a 0 M to 2 M reduction in absolute volume overload (-1.08 ± 0.33 L; P = 0.025). However, there were no significant changes in serum or tissue sodium (all P > 0.05). Low-sodium, home-meal delivery appears to be an effective method for improving volume control and blood pressure in HD patients. Future studies with larger sample sizes are needed to examine the long-term effects of home-delivered meals on these outcomes and to assess cost-effectiveness.

SHORT-TERM CHANGES IN DIETARY SODIUM INTAKE INFLUENCE SWEAT SODIUM CONCENTRATION AND MUSCLE SODIUM CONTENT IN HEALTHY SUBJECTS

Objective: There is increasing evidence that sodium can be stored in the skin and muscles without being osmotically active, yet whether acute changes in dietary sodium intake alter sweat and muscle sodium content has not been investigated previously. Design and method: In a cross-over design, we assessed muscle sodium content by 23Na magnetic resonance imaging (MRI) in 38 healthy normotensive volunteers (aged 33.5 ± 11.1 years, 76.3% female) after 5 days of high sodium diet (HS) (6 g of salt added to their normal diet) and 5 days of a low-sodium diet (LS). Women performed each study visit during the same phase of the menstrual cycle. In a sub-group of 18 participants (72.2% female) we conducted quantitative pilocarpine iontophoretic sweat collections and measured the sodium concentration in sweat. Office blood pressure, electrolytes, creatinine and circulating aldosterone levels were measured in all participants, and 24 h urine was collected Results: Under HS conditions urinary sodium excretion, muscle sodium content and sweat sodium concentration all increased significantly (see Figure). Muscle sodium content by MRI (rm = 0.47, p = 0.03) and sodium sweat concentration (rm = 0.72, p < 0.001) correlated positively with salt intake as estimated by 24-hour urine sodium excretion. Age, gender or the phase of the menstrual cycle did not influence muscle or sweat sodium concentrations or their changes. In contrast, plasma aldosterone levels were strongly and negatively associated with both muscle sodium content (rs = −0.42, p = 0.0001) and sweat sodium (rs = −0.52, p = 0.002). Sweat and muscle sodium content were not different in participants with a salt-sensitive blood pressure compared to non-sensitives. Conclusions: Muscle and sweat sodium concentrations are significantly higher under high salt conditions in healthy male and female subjects, suggesting that muscle and sweat play a role in the dietary sodium balance in humans.

OR04-1 Dietary Sodium Intake, the Renin-Angiotensin-Aldosterone System, and the Risk for Incident Kidney Stones

Context: We previously reported that acute changes in dietary sodium intake and renin-angiotensin-aldosterone system (RAAS) activity could substantially modulate calcium homeostasis. We demonstrated that humans consuming a high sodium diet for one week, compared with a restricted sodium diet for one week, had suppression of the RAAS, a ~100% increase in calciuria (P<0.0001), and a ~10% decrease in serum calcium (P<0.0001). Whether these marked and acute changes induced by high dietary sodium intake are sustained chronically is not known. We hypothesized that a high dietary sodium intake over many years could increase calciuria and the risk for incident kidney stones. Methods: We studied 2496 participants from the Health Professionals Follow-up Study (HPFS) (all men) and the Nurses’ Health Study I (NHSI) (all women). 24-hour urine samples, collected from participants confirmed to have kidney stones and appropriate controls, were assessed for calcium, sodium, creatinine, as well as other factors. Participants were categorized by 24-hour urinary sodium excretion (<120, 120-139, 140-159, 160-179, 180-199, 200-219, >/=220 mEq/day) and the relative risk for developing kidney stones was assessed for each category of sodium excretion via adjusted logistic regression models. Models were adjusted for age, history of hypertension, and numerous urinary parameters (volume, creatinine, oxalate, uric acid, citrate, magnesium, potassium, phosphorus, and pH). Adjustment for urinary calcium was performed to evaluate the role of calciuria in modifying the relation between urinary sodium excretion and kidney stones. Results: Mean adjusted urinary calcium levels for individuals with urinary sodium excretion of <120 mEq/day compared to >/=220 mEq/day were 178 (SD=73) vs. 228 (SD=91) mg/day in men and 161 (SD=60) vs. 208 (SD=80) mg/day in women. When compared with a urinary sodium excretion of <120 mEq/day (relative risk=1.00), having a urinary sodium excretion of >/=220 mEq/day was associated with a higher risk for incident kidney stones in men [RR=1.90 (95% CI 1.18, 3.05)] and women [RR=2.02 (95% CI 1.19, 3.43)]. These associations were attenuated and no longer statistically significant after adjusting for urinary calcium excretion, thereby suggesting that developing kidney stones was mediated, in part, through an increase in urinary calcium excretion when urinary sodium excretion was higher. Conclusion: The combination of our physiology and epidemiology studies suggest that higher dietary sodium intake, and concomitant suppression of the RAAS, result in increased calciuria and an approximately two-fold higher risk for developing kidney stones. Studies to evaluate dietary sodium restriction, and/or RAAS inhibition, as potential methods to decrease calciuria and kidney stones are warranted.

Dietary Sodium Modifies Serum Uric Acid Concentrations in Humans

Subjects with hypertension are frequently obese or insulin resistant, both conditions in which hyperuricemia is common. Obese and insulin-resistant subjects are also known to have blood pressure that is more sensitive to changes in dietary sodium intake. Whether hyperuricemia is a resulting consequence, moderating or contributing factor to the development of hypertension has not been fully evaluated and very few studies have reported interactions between sodium intake and serum uric acid. We performed further analysis of our randomized controlled clinical trials (Australian New Zealand Clinical Trials Registry #12609000161224 and #12609000292279) designed to assess the effects of modifying sodium intake on concentrations of serum markers, including uric acid. Uric acid and other variables (including blood pressure, renin, and aldosterone) were measured at baseline and 4 weeks following the commencement of low (60 mmol/day), moderate (150 mmol/day), and high (200-250 mmol/day) dietary sodium intake. The median aldosterone-to-renin ratio was 1.90 [pg/ml]/[pg/ml] (range 0.10-11.04). Serum uric acid fell significantly in both the moderate and high interventions compared to the low sodium intervention. This pattern of response occurred when all subjects were analyzed, and when normotensive or hypertensive subjects were analyzed alone. Although previously reported in hypertensive subjects, these data provide evidence in normotensive subjects of an interaction between dietary sodium intake and serum uric acid. As this interaction is present in the absence of hypertension, it is possible it could play a role in hypertension development, and will need to be considered in future trials of dietary sodium intake. The trials were registered with the Australian and New Zealand Clinical Trials Registry as ACTRN12609000161224 and ACTRN1260.

Abstract 82: Critical Role of Striatin in Vascular Responses to Sodium Intake

Striatin is a scaffolding protein that plays a role in vesicular trafficking in neurons. Striatin binds to regulatory proteins such as caveolin-1, Ca2+-calmodulin, Gαi and phosphatase 2A, thereby activating transduction molecules such as eNOS and mitogen-activated protein kinase. We have shown that striatin colocalizes with the minerlacorticoid receptor (MR), and that MR activation increases striatin levels in vascular cells in vivo and in vitro. To test the hypothesis that striatin is a critical regulator of vascular function, WT mice and heterozygous striatin-deficient mice lacking one allele for striatin (Strn-HET) were randomized in a crossover intervention to liberal salt (HS, 1.6% NaCl) and low salt (LS, 0.03% NaCl) diets for 7 days on each diet. Blood pressure (BP) and plasma aldosterone (ALDO) levels were measured and the aorta was excised to assess vascular function. Δ Systolic BP (BP on HS - BP on LS) was in Strn-HET &gt; WT (16.5±3.5 vs 3.7±6.1 mmHg). Plasma ALDO levels were higher during LS diet, but were similar in WT and Strn-HET mice (152.6±23.9 vs 131.5±47.6 ng/dL on LS; 72.9±7.7 vs 70.9±8.3 ng/dL on HS). Phenylephrine (Phe) caused vascular contraction that was in Strn-HET (max 0.31±0.07g) &gt; WT (0.23±0.07g). Also, high KCl (96 mM)-induced contraction was in Strn-HET (0.44±0.06g) &gt; WT mice (0.33±0.05g) on HS diet, suggesting that the enhanced vascular contraction is not limited to a particular receptor. Endothelium removal, NOS inhibitor L-NAME and guanylate cyclase inhibitor ODQ enhanced contraction and increased sensitivity to Phe in WT mice and to a greater extent in Strn-HET mice on HS but not LS diet. On HS, acetylcholine (ACh) relaxation was in Strn-HET (max 33.16±4.47%) &lt; WT (50.94±10.88%). ACh relaxation was blocked by endothelium removal, L-NAME and ODQ, supporting a role of the NO-cGMP pathway. Vascular relaxation to the exogenous NO donor sodium nitroprusside was not different between groups. Thus striatin deficiency during HS diet is associated with salt sensitivity of BP, enhanced vasoconstriction and decreased vascular relaxation. The results suggest a critical role for striatin, possibly through modulation of endothelium-dependent NO-cGMP pathway, in regulation of vascular function and BP during changes in dietary sodium intake.

Flow‐sensitive K+‐coupled ATP secretion modulates ENaC activity in the distal nephron

The epithelial Na+ channel (ENaC) in the aldosterone‐sensitive distal nephron (ASDN) is under tonic inhibition by paracrine purinergic signaling responding to changes in dietary sodium intake. Normal BK(Ca) channel function is required for ATP secretion in the ASDN. We test here whether ATP secreted through connexin channels in a coupled manner with K+ efflux through BK(Ca) channels is required for inhibitory purinergic regulation of ENaC in response to increases in sodium intake. Inhibition of connexin relieves purinergic inhibition of ENaC. Deletion of the BK‐β4 regulatory subunit, which is required for normal channel function and ATP secretion, mutes sodium intake‐dependent increases in urinary ATP resulting in inappropriately elevated ENaC activity. ENaC in BK‐β4 null mice, though, responds normally to exogenous ATP consistent with lower urinary ATP causing elevated activity. Moreover, disruption of purinergic regulation increases ENaC activity in wild type but not null mice. Consequently, sodium excretion is impaired in null mice. These results demonstrate that ATP secreted into the ASDN in a BK(Ca) channel‐dependent manner is physiologically available for inhibition of ENaC in response to changes in sodium intake. Impaired sodium excretion resulting form the loss of normal inhibitory purinergic control of ENaC likely contributes to the elevated blood pressure of BK‐β4 null mice.

Flow-sensitive K+-coupled ATP Secretion Modulates Activity of the Epithelial Na+ Channel in the Distal Nephron

The epithelial Na(+) channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN) is under tonic inhibition by a local purinergic signaling system responding to changes in dietary sodium intake. Normal BK(Ca) channel function is required for flow-sensitive ATP secretion in the ASDN. We tested here whether ATP secreted through connexin channels in a coupled manner with K(+) efflux through BK(Ca) channels is required for inhibitory purinergic regulation of ENaC in response to increases in sodium intake. Inhibition of connexin channels relieves purinergic inhibition of ENaC. Deletion of the BK-β4 regulatory subunit, which is required for normal BK(Ca) channel function and flow-sensitive ATP secretion in the ASDN, suppresses increases in urinary ATP in response to increases in sodium intake. As a consequence, ENaC activity, particularly in the presence of high sodium intake, is inappropriately elevated in BK-β4 null mice. ENaC in BK-β4 null mice, however, responds normally to exogenous ATP, indicating that increases in activity do not result from end-organ resistance but rather from lowered urinary ATP. Consistent with this, disruption of purinergic regulation increases ENaC activity in wild type but not BK-β4 null mice. Consequently, sodium excretion is impaired in BK-β4 null mice. These results demonstrate that the ATP secreted in the ASDN in a BK(Ca) channel-dependent manner is physiologically available for purinergic inhibition of ENaC in response to changes in sodium homeostasis. Impaired sodium excretion resulting form loss of normal purinergic regulation of ENaC in BK-β4 null mice likely contributes to their elevated blood pressure.

459 A ROLE FOR ANGIOTENSIN II TYPE 1A RECEPTORS IN PRINCIPAL CELLS OF THE COLLECTING DUCT IN THE INITIATION OF HYPERTENSION

Background: Actions of the renin-angiotensin system to control blood pressure(BP) are mediated by angiotensin type1 receptors(AT1R). The major murine AT1R isoform, AT1AR, is expressed throughout the nephron, including the dominant epithelial cell population of the collecting duct, the principal cells(PC). Between nephron segments, characteristics differ significantly resulting in distinctive regulatory consequences. Thus, this study examines the contribution of AT1AR in PC to regulation of BP. Methods: Mice lacking AT1Rs in PC(PC-KOs) were produced by intercrossing the Aqp-Cre mouse, which expresses Cre specifically in PCs with mice bearing a conditional allele for the Agtra1 gene, encoding the AT1AR. Mice were subjected to low and high-sodium diets followed by two-weeks of AngII(1000ng/kg/min) infusion via mini-osmotic pumps while BP was measured by radiotelemetry. Results: mRNA for AT1AR in inner medulla were reduced by ≈50% in PC-KO(P < 0.05). Baseline BP was identical between PC-KOs vs. controls. Following one-week of low-sodium(<0.002% NaCl) diet, MAP fell significantly(P < 0.05) and to a similar extent in both groups. Similarly, with a high-sodium(6% NaCl) diet, BP increased(P < 0.01), but was not different between groups. During first initial phase of AngII-hypertension, increase in BP was significantly attenuated in PC-KOs compared to controls(167 ± 7mmHg vs. 178 ± 3mmHg, P < 0.001). During established phase of hypertension (days 9-14), there was no significant difference in BPs between the groups. Conclusion: Our data suggests that AT1AR in principal cells of the collecting duct make a modest contribution to BP elevation in the early phase of AngII-hypertension but have negligible effects on basal BP or adaptation to changes in dietary sodium intake.

Brain heterotrimeric Gαi 2 ‐subunit protein‐gated pathways mediate central sympathoinhibition to maintain fluid and electrolyte homeostasis during stress

Fluid and electrolyte homeostasis is integral to blood pressure regulation. However, the central molecular mechanisms regulating the neural control of sodium excretion remain unclear. We have demonstrated that brain Gαi(2)-subunit protein pathways mediate the natriuretic response to α(2)-adrenoreceptor activation in vivo. Consequently, we examined the role of brain Gαi(2) proteins in the neural mechanisms facilitating fluid and electrolyte homeostasis in response to acute [i.v. volume expansion (VE)] or chronic stressful stimuli (dietary sodium restriction vs. supplementation) in conscious Sprague-Dawley rats. Selective oligodeoxynucleotide (ODN)-mediated down-regulation of brain Gαi(2) proteins, but not a scrambled ODN, abolished the renal sympathoinhibitory response and attenuated the natriuresis to VE. In scrambled ODN-treated rats, chronic changes in dietary sodium intake evoked an endogenous, hypothalamic paraventricular nucleus (PVN)-specific, decrease (sodium deficiency) or increase (sodium excess) in PVN Gαi(2) proteins; plasma norepinephrine levels were inversely related to dietary sodium content. Finally, in rats treated with an ODN to prevent high salt-induced up-regulation of brain Gαi(2) proteins, animals exhibited sodium retention, global sympathoexcitation, and elevated blood pressure. Collectively, these data demonstrate that PVN Gαi(2) protein pathways play an endogenous role in maintaining fluid and electrolyte balance by controlling the influence the sympathetic nervous system has on the renal handling of sodium.

Abstract 18218: Vascular Dysfunction as a Primary Cause of Hypertension in Mice with Smooth Muscle Specific Deletion of RGS2

The etiology of hypertension in most cases is idiopathic. Current dogma states that all forms of hypertension arise from renal abnormalities of sodium handling. We have hypothesized that a primary abnormality of vascular smooth muscle cell (SMC) contraction can cause hypertension. To directly test this hypothesis we created and characterized inducible, SMC-specific RGS2 knockout mice (RGS2-SMC-KO) harboring a SMC-specific deletion of the PKGIα target the GTPase activating protein Regulator of G-protein Signaling 2. In these studies, SMC-specific deletion of RGS2 was induced at 7 weeks of age and Cre-negative mice treated identically as the RGS2-SMC-KO were used as controls. Telemetric blood pressure (BP) studies in ambulatory mice demonstrated that BP was significantly higher in RGS2-SMC-KO vs. control mice (135 ± 5 vs. 122 ± 7 mmHg, respectively. P &lt;0.01), with no change in heart rate. Ex vivo aortic rings of RGS2-SMC-KO mice were hypercontractile in response to phenylephrine (PE) (138 ± 6 vs. 124±4% of pre-existing tone at 6 mM PE, respectively. P &lt;0.05) Hemodynamic studies in anesthetized RGS2-SMC-KO mice revealed increased total systemic vascular resistance (SVR; 3.22x10 4 ± 0.01x10 4 vs. 1.61x10 4 ± 0.55x10 4 , respectively. P &lt;0.001), and significantly higher SBP (106 ± 5 vs. 93 ± 1 mmHg, respectively. P &lt;0.01). Following treatment with the NOS inhibitor L-NAME, BP decreased less in the RGS2-SMC-KO than in the control mice (⋔SBP: 38 ± 7 vs. 47 ± 3 mmHg, P &lt;0.001). We found identical BP responses to changes in dietary sodium intake in the RGS2-SMC-KO mice vs. control, supporting normal renal function in the RGS2-SMC-KO mice. These data support that SMC-specific deletion of RGS2 leads to hypertension, with accompanying loss of RGS2-dependent attenuation of contractile signaling in blood vessels, with increased SVR and hypercontractile arterial function. The hypertension in RGS2-SMC-KO mice together with normal sodium handling supports the hypothesis that high BP can arise from a primary abnormality of vascular smooth muscle cell contractile regulation. Taken together, these data have potentially important implications for the diagnosis and treatment of human vascular diseases and suggest RGS2 as a new therapeutic target for some forms of hypertension.

Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice

Changes in dietary sodium intake are associated with changes in vascular volume and reactivity that may be mediated, in part, by alterations in endothelial nitric oxide synthase (eNOS) activity. Caveolin-1 (Cav-1), a transmembrane anchoring protein in the plasma membrane caveolae, binds eNOS and limits its translocation and activation. To test the hypothesis that endothelial Cav-1 participates in the dietary sodium-mediated effects on vascular function, we assessed vascular responses and nitric oxide (NO)-mediated mechanisms of vascular relaxation in Cav-1 knockout mice (Cav-1-/-) and wild-type control mice (WT; Cav-1+/+) placed on a high-salt (HS; 4% NaCl) or low-salt (LS; 0.08% NaCl) diet for 16 days. After the systolic blood pressure was measured, the thoracic aorta was isolated for measurement of vascular reactivity and NO production, and the heart was used for measurement of eNOS expression and/or activity. The blood pressure was elevated in HS mice treated with NG-nitro-l-arginine methyl ester and more so in Cav-1-/- than WT mice and was significantly reduced during the LS diet. Phenylephrine caused vascular contraction that was significantly reduced in Cav-1-/- (maximum 0.25 +/- 0.06 g/mg) compared with WT (0.75 +/- 0.22 g/mg) on the HS diet, and the differences were eliminated with the LS diet. Also, vascular contraction in response to membrane depolarization by high KCl (96 mM) was reduced in Cav-1-/- (0.27 +/- 0.05 g/mg) compared with WT mice (0.53 +/- 0.12 g/mg) on the HS diet, suggesting that the reduced vascular contraction is not limited to a particular receptor. Acetylcholine (10(-5) M) caused aortic relaxation in WT mice on HS (23.6 +/- 3.5%) and LS (23.7 +/- 5.5%) that was enhanced in Cav-1-/- HS (72.6 +/- 6.1%) and more so in Cav-1-/- LS mice (93.6 +/- 3.5%). RT-PCR analysis indicated increased eNOS mRNA expression in the aorta and heart, and Western blots indicated increased total eNOS and phosphorylated eNOS in the heart of Cav-1-/- compared with WT mice on the HS diet, and the genotypic differences were less apparent during the LS diet. Thus Cav-1 deficiency during the HS diet is associated with decreased vasoconstriction, increased vascular relaxation, and increased eNOS expression and activity, and these effects are altered during the LS diet. The data support the hypothesis that endothelial Cav-1, likely through an effect on eNOS activity, plays a prominent role in the regulation of vascular function during substantial changes in dietary sodium intake.

Influence of Salt Intake on Renin–Angiotensin and Natriuretic Peptide System Genes in Human Adipose Tissue

We tested the hypothesis that changes in sodium intake modulate adipose-tissue renin-angiotensin and natriuretic peptide system gene expression in humans. We studied 9 healthy young men in a metabolic ward at constant room temperature, humidity, and water, potassium, and calcium intake. Subjects were submitted to 4 different periods of sodium intake, and blood samples, microdialysis samples (interstitial fluid), and biopsies from subcutaneous abdominal adipose tissue were obtained at the end of the low-sodium period (0.7 mmol Na/kg per day) and at the end of the high-sodium period (7.7 mmol Na/kg per day). Urinary sodium excretion was 64+/-4 mmol per day with the low-sodium diet and 521+/-8 mmol per day with the high-sodium diet. Systemic and microdialysate sodium concentrations were similar with both interventions. With high-sodium intake, systemic renin activity and aldosterone levels were suppressed, angiotensin-converting enzyme activity did not change, and systemic levels of the atrial natriuretic peptide increased. High-sodium diet increased angiotensin-converting enzyme and atrial natriuretic peptide gene expression in adipose tissue. None of the other genes tested were influenced by changes in dietary sodium intake. Our findings suggest that the adipose-tissue renin-angiotensin system is not part of a feedback mechanism regulating sodium homeostasis and blood pressure. Systemic and adipose-tissue renin-angiotensin systems are regulated at least in part independently from each other. In contrast, systemic atrial natriuretic peptide and adipose-tissue atrial natriuretic peptide respond similarly to changes in sodium intake.

Serum electrolyte, serum protein, serum fat and renal responses to a dietary sodium challenge: Allostasis and allostatic load

Objective: The purpose of this study was to assess, in borderline hypertensive subjects, the homeostatic and allostatic responses of serum electrolytes, proteins, lipids, hematocrit and renal function to an extreme dietary sodium challenge, and to evaluate whether the responses in these clinical parameters were associated with a concomitant response in blood pressure.Subjects and methods: Data from middle-aged adults with a diagnosis of mild, uncomplicated borderline hypertension were collected at the end of 1-month randomized trials of low (24 ± 13 mmol/day) and high (309 ± 88 mmol/day) dietary sodium intake. A total of 48 subjects (38 men and 10 women) were examined.Results: Serum sodium increased (p<0.001), while all other serum electrolytes, except chloride, decreased (p<0.01) from the low to high sodium diets. Serum proteins (p<0.05) and hematocit (p<0.001) also declined among subjects on a high sodium diet. However, creatinine clearance (an indicator of glomerular filtration) increased with sodium intake (p = 0.004). None of these biochemical or renal functional responses was associated with a change in blood pressure.Conclusion: There are modest yet significant changes in serum electrolytes associated with changes in dietary sodium intake, suggesting that these ions are under an allostatic control mechanism. Serum proteins also appear to function as allostatic compensatory mechanisms, offsetting the net effect of increased serum salinity. It is speculated that the adaptive allostatic renal response to a high sodium diet (an increase in GFR) may result in loss of the ability to appropriately vary renal filtration if that diet is chronically maintained.

Disturbed Circadian Rhythm of Urinary Albumin Excretion in Non-Dipper Type of Essential Hypertension

Recently, we found that the circadian rhythms of natriuresis as well as of glomerular filtration rate were disturbed similar to the blood pressure in non-dipper type of essential hypertension during intake of a high-sodium diet. In this study, we examined circadian rhythms of the urinary albumin excretion rate (AER), which is recognized as a marker of glomerular capillary hydraulic pressure, in addition to those of urinary sodium excretion and blood pressure in 27 patients with essential hypertension. The patients were maintained on relatively high (10–12 g) on low (1–3 g) sodium (NaCl) diets for 1 week. On the last day of each diet, the 24-hour blood pressure was measured every 30 min noninvasively, and during the last 3 days, urine samples were collected for determination of both daytime (07:00–21.30 h) and nighttime (21.30–07.00 h) sodium and AER variations. During the high-sodium diet, nocturnal falls in urinary sodium excretion and blood pressure were observed in dippers (n = 7), while they were not observed in non-dipper (n = 20). The nocturnal decline in AER was also observed in dippers (day: 37 ×/÷ 6 µg/min vs. night: 22 ×/÷ 5 µg/min; p < 0.02), while it was not observed in non-dippers (day: 49 ×/÷ 6 µg/min vs. night: 40 ×/÷ 8 µg/min; NS). During intake of the low-sodium diet, on the other hand, a nocturnal decline in AER was observed in both types of hypertension. Sodium restriction significantly reduced only the nighttime AER in non-dippers (p < 0.01). These findings indicate that changes in dietary sodium intake modified the circadian rhythms of both blood pressure and AER in non-dippers. Renal sodium handling may contribute to determining the circadian rhythm of blood pressure, and furthermore an elevated glomerular capillary hydraulic pressure during the night may enhance the nocturnal albumin excretion in non-dippers.

Plasma-renin response to isotonic volume contraction in young salt-sensitive normotensive men

Salt-sensitive persons have lower plasma renin activity than salt-resistant persons and their plasma renin activity increases less with a low sodium diet or volume depletion, compared to salt-resistant individuals. However, the time course of the renin response to acute volume contraction has not been studied in humans. Therefore, we designed an acute study in salt-sensitive and salt-resistant normotensive volunteers, in which we examined the renin response to isotonic volume contraction. Twenty-four previously characterized salt-resistant ( n = 13) and salt-sensitive ( n = 11) persons were placed on a high salt diet containing 280 mmol NaCl/day for 3 days. After an overnight stay, volume depletion (total, 300 mmol Na) was induced by furosemide infusion. Free water deficits were replaced by 5% isotonic glucose infusion. Blood was obtained for electrolytes, plasma renin activity, and plasma aldosterone concentration. Blood pressure (BP) and heart rate were monitored during the experiment. Intravascular volume depletion resulted in a progressive increase in plasma renin activity that was both steeper and higher in salt-resistant than in the salt-sensitive subjects ( P < .001). There was a slight increase in BP in response to volume contraction in both groups. Although heart rate did not change in salt-sensitive persons, it increased significantly ( P < .001) in the salt-resistant group. These findings point to an intrinsic difference in the regulation of renin release between salt-sensitive and salt-resistant subjects that may account for the different BP responses to changes in dietary sodium intake.

Regulation of rat adrenal vasoactive intestinal peptide content: effects of adrenocorticotropic hormone treatment and changes in dietary sodium intake.

Vasoactive intestinal peptide (VIP) is well established as a paracrine regulator of adrenal function. It is present in nerves supplying the adrenal cortex, although previous studies have found that the amount of VIP in the outer zones of the rat adrenal is not affected by ligating the splanchnic nerve supplying the adrenal gland. The present studies were designed to investigate the mechanisms involved in regulating the VIP content of the rat adrenal gland. This study examined the effects of changes in electrolyte balance and adrenocorticotropic hormone (ACTH) administration on the adrenal content of VIP as measured by radioimmunoassay. Rats on a low sodium diet had a significantly increased capsular/zona glomerulosa immunoreactive VIP (irVIP) level, while rats on a high sodium diet had suppressed levels relative to controls. Changes in dietary sodium did not affect inner zone/medullary VIP content. Administration of ACTH caused a decrease in irVIP levels in the capsular/zona glomerulosa portion of the adrenal gland but had no effect on the inner zone/medulla. Analysis of mRNA encoding VIP revealed a large increase in expression of VIP in the sodium-deplete group compared with the control, with no change in VIP expression in the sodium-loaded group. ACTH treatment was found to significantly decrease VIP mRNA levels in the capsular portion. Neither ACTH treatment nor changes in sodium intake affected inner zones/medullary VIP message. These data suggest that VIP in the capsule and zona glomerulosa region of the adrenal cortex is regulated in response to the physiological status of the animal, with changes in capsular/zona glomerulosa VIP correlating with changes in zona glomerulosa function.

Peripheral and central interactions between the renin-angiotensin system and the renal sympathetic nerves in control of renal function.

Increases in renal sympathetic nerve activity (RSNA) regulate the functions of the nephron, the vasculature, and the renin-containing juxtaglomerular granular cells. As increased activity of the renin-angiotensin system can also influence nephron and vascular function, it is important to understand the interactions between RSNA and the renin-angiotensin system in the control of renal function. These interactions can be intrarenal, that is, the direct (via specific innervation) and indirect (via angiotensin II) contributions of increased RSNA to the regulation of renal function. The effects of increased RSNA on renal function are attenuated when the activity of the renin-angiotensin system is suppressed or antagonized with angiotensin-converting enzyme inhibitors or angiotensin II-type AT1 receptor antagonists. The effects of intrarenal administration of angiotensin II are attenuated following renal denervation. These interactions can also be extrarenal, that is, in the central nervous system, wherein RSNA and its arterial baroreflex control are modulated by changes in activity of the renin-angiotensin system. In addition to the circumventricular organs, the permeable blood-brain barrier of which permits interactions with circulating angiotensin II, there are interactions at sites behind the blood-brain barrier that depend on the influence of local angiotensin II. The responses to central administration of angiotensin II type AT1 receptor antagonists, into the ventricular system or microinjected into the rostral ventrolateral medulla, are modulated by changes in activity of the renin-angiotensin system produced by physiological changes in dietary sodium intake. Similar modulation is observed in pathophysiological models wherein activity of both the renin-angiotensin and sympathetic nervous systems is increased (e.g., congestive heart failure). Thus, both renal and extrarenal sites of interaction between the renin-angiotensin system and RSNA are involved in influencing the neural control of renal function.

Nervous kidney. Interaction between renal sympathetic nerves and the renin-angiotensin system in the control of renal function.

Increases in renal sympathetic nerve activity regulate the functions of the nephron, the vasculature, and the renin-containing juxtaglomerular granular cells. Because increased activity of the renin-angiotensin system can also influence nephron and vascular function, it is important to understand the interactions between the renal sympathetic nerves and the renin-angiotensin system in the control of renal function. These interactions can be intrarenal, for example, the direct (by specific innervation) and indirect (by angiotensin II) contributions of increased renal sympathetic nerve activity to the regulation of renal function. The effects of increased renal sympathetic nerve activity on renal function are attenuated when the activity of the renin-angiotensin system is suppressed or antagonized with ACE inhibitors or angiotensin II-type AT(1)-receptor antagonists. The effects of intrarenal administration of angiotensin II are attenuated after renal denervation. These interactions can also be extrarenal, for example, in the central nervous system, wherein renal sympathetic nerve activity and its arterial baroreflex control are modulated by changes in activity of the renin-angiotensin system. In addition to the circumventricular organs, whose permeable blood-brain barrier permits interactions with circulating angiotensin II, there are interactions at sites behind the blood-brain barrier that depend on the influence of local angiotensin II. The responses to central administration of angiotensin II-type AT(1)-receptor antagonists into the ventricular system or microinjected into the rostral ventrolateral medulla are modulated by changes in activity of the renin-angiotensin system produced by physiological changes in dietary sodium intake. Similar modulation is observed in pathophysiological models wherein activity of both the renin-angiotensin and sympathetic nervous systems is increased (eg, congestive heart failure). Thus, both renal and extrarenal sites of interaction between the renin-angiotensin system and renal sympathetic nerve activity are involved in influencing the neural control of renal function.