Alterations In Sodium Balance Research Articles

Students lose balance over the yin-yang of sodium physiology

One of the major areas that students studying physiology stumble over is sodium homeostasis. In particular, there is often an unclear separation in their understanding to differentiate between sodium balance and sodium concentration (NaC) control. Functionally, students need to understand that NaC control involves the osmoreceptors that monitor changes in NaC in the extracellular fluid (ECF) since NaC is the dominant determinant of ECF osmolarity. This teaching note aims to address the common misconception regarding sodium physiology, specifically that ECF NaC is not regulated by the renin-angiotensin-aldosterone (RAAS) family of hormones. The RAAS is instead directed toward total body sodium or sodium balance. Different scenarios of ECF changes that alter sodium balance and/or NaC will be illustrated with a summary of “Tables of Salt.” Hopefully, both students and teachers will find this teaching note useful in their appreciation of the wonderful Yin Yang of sodium physiology.

Age‐related hypertension is associated with impairments in kidney dopamine D1 and angiotensin II AT1 receptor functions

The kidney dopamine D1 (D1R) and angiotensin II AT1 (AT1R) receptors by regulating sodium transporters maintain sodium homeostasis and blood pressure (BP). We have reported that the aging process is associated with changes in kidney function and increase in BP. Therefore, we hypothesized that impairments in kidney D1R and AT1R functions contribute to altered sodium balance and high BP in aging. To test this hypothesis, we measured BP and D1R and AT1R functions in adult (3‐month) and old (21‐month) Fischer 344 X Brown Norway F1 rats (a rat aging model). The D1R and AT1R functions were determined by administering D1‐like receptor agonist (SKF‐38393) and AT1 receptor antagonist (candesartan) respectively. We found that systolic, diastolic and mean arterial blood pressures were higher in old rats. SKF‐38393 increased urinary sodium excretion (UNaV) and fractional sodium excretion (FENa) in adult but not in old rats. While candesartan increased UNaV in both adult and old rats, the magnitude of natriuretic response was greater in old rats. Candesartan‐mediated increase in FENa over basal was also higher in old rats. Although the basal UNaV was similar in both groups, basal FENa was lower in old rats. These studies demonstrate the presence of diminished D1R and exaggerated AT1R functions in the aging kidneys, which may contribute to sodium retention and increase in blood pressure in old rats (NIH/NIA AG25056, AG29904).

High Sodium Diet Activated NFκB Signaling Plays an Important Role in Renal Medullary COX2 Induction

Renal medullary COX2 plays an important role in renal response to dietary sodium. NFκB is known as an important mediator of COX2 induction. The present study examined the role of NFκB in renal medullary COX2 induction following increased dietary sodium. High sodium diet (8% NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6J mice. Co‐immunofluorescence using a COX2 antibody and antibodies against AQP1, ClC‐K, AQP2 and CD31 showed that dietary sodium induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a 7±2 fold (P<0.05) increase of luciferase activity in renal medulla of the NFκB‐luciferase reporter mice following high sodium diet, and a robust induction of EGFP expression mainly localized in renal medullary interstitial cells of the NFκB‐EGFP reporter mice following high sodium diet. Treating C57Bl/6J mice with selective IκB kinase inhibitor IMD‐0354 (8mg/kg bw) substantially attenuated COX2 induction in renal medulla, and also significantly reduced urinary PGE2 following high sodium diet (from 1798±578 to 809±267 μg/24h, P<0.05). These data suggest a critical role of renal medullary NFκB signaling in the renal response to increased dietary sodium, which may account for the altered sodium balance observed in patients taking NFκB‐inhibiting drugs, such as Bortezomib. Research supported by NIH.

Salt intake and depletion increase circulating levels of endogenous ouabain in normal men

High-salt diets elevate circulating Na+ pump inhibitors, vascular resistance, and blood pressure. Ouabain induces a form of hypertension mediated via the alpha2-Na+ pump isoform and the calcium influx mode of the vascular sodium calcium exchanger (NCX). Whereas elevated levels of an endogenous ouabain (EO) and NCX have been implicated in salt-sensitive hypertension, acute changes in sodium balance do not affect plasma EO. This study investigated the impact of longer-term alterations in sodium balance on the circulating levels and renal clearance of EO in normal humans. Thirteen normal men consumed a normal diet, high-salt diet, and hydrochlorothiazide (HCTZ), each for 5-day periods to alter sodium balance. EO and other humoral and urinary variables were determined daily. On a normal diet, urinary sodium excretion (140 +/- 16 meq/day), plasma EO (0.43 +/- 0.08 nmol/l) and urinary EO excretion (1.04 +/- 0.13 nmol/day) were at steady state. On the 3rd day of a high-salt diet, urine sodium excretion (315 +/- 28 meq/day), plasma EO (5.8 +/- 2.2 nmol/l), and the urinary EO excretion (1.69 +/- 0.27 nmol/day) were significantly increased, while plasma renin activity and aldosterone levels were suppressed. The salt-evoked increase in plasma EO was greater in older individuals, in subjects whose baseline circulating EO was higher, and in those with low renal clearance. During HCTZ, body weight decreased and plasma renin activity, aldosterone, and EO (1.71 +/- 0.77 nmol/l) rose, while urinary EO excretion remained within the normal range (1.44 +/- 0.31 nmol/day). Blood pressure fell in one subject during HCTZ. HPLC of the plasma extracts showed one primary peak of EO immunoreactivity with a retention time equivalent to ouabain. High-salt diets and HCTZ raise plasma EO by stimulating EO secretion, and a J-shaped curve relates sodium balance and EO in healthy men. Under normal dietary conditions, approximately 98% of the filtered load of EO is reabsorbed by the kidney, and differences in the circulating levels of EO are strongly influenced by secretion and urinary excretion of EO. The dramatic impact of high-salt diets on plasma EO is consistent with its proposed role as a humoral vasoconstrictor that links salt intake with vascular function in hypertension.

Blood pressure sensitivity to salt in rats with low urinary kallikrein excretion

We evaluated if a rat strain inbred for reduced urinary kallikrein excretion differs from normal-kallikrein Wistar rats regarding blood pressure in basal conditions and during alterations in sodium balance. Low-kallikrein rats showed greater systolic blood pressure values (125 ±3 vs. 114 ± 2mmHg in controls, P < 0.01) at 9 weeks of age. Systolic blood pressure was increased after 20 days of dietary sodium loading in the low-kallikrein group and remained unchanged in controls (150 ± 6vs.112 ± 2 mmHg, P < 0.01) and this effect was associated with a reduced cumulative excretion of sodium (23% less in the low-kallikrein group compared with controls, P < 0.01). Urinary creatinine excretion was decreased by sodium loading in both groups, and this effect was more pronounced in the low-kallikrein group. The group-difference in urinary kallikrein excretion found in basal conditions (2.49 ±0.10vs.7.78 ±0.53 Pkat/100 g body weight, P < 0.01) was enhanced by high salt diet (1.05 ±0.21vs.8.31 ±0.70 Pkat/100 g body weight, P < 0.01). The ratio of heart weight to body weight was significantly greater in low-kallikrein rats (331 ± 7vs.275 ± 4 mg/100 g body weight, P < 0.01), whereas the ratio of kidney weight to body weight was lower (329 ±5vs.370 ± 8 mg/100 body weight, P < 0.01). Our results indicate that a genetically-determined defect in urinary kallikrein excretion is associated with a greater blood pressure sensitivity to salt, possibly due to altered renal sodium handling.

Urinary kallikrein: A marker of blood pressure sensitivity to salt

We evaluated if a rat strain inbred for low urinary kallikrein excretion differs from normal-kallikrein Wistar rats regarding blood pressure levels in basal conditions and during alterations in sodium balance. Blood pressure was measured in unanesthetized rats on normal sodium intake. Then, blood pressure sensitivity to salt was evaluated over a period of 20 days of high sodium diet (0.84 mmol per g chow). Low-kallikrein rats showed greater systolic blood pressure levels (125 +/- 3 vs. 114 +/- 2 mm Hg in controls, P < 0.01) at nine weeks of age. Systolic blood pressure was increased after sodium loading in the low-kallikrein group and remained unchanged in controls (150 +/- 6 vs. 112 +/- 2 mm Hg, P < 0.01). This effect was associated with a reduced cumulative urinary excretion of sodium in the low-kallikrein rats. No group difference was found in the clearance of endogenous creatinine in basal conditions. Urinary creatinine excretion decreased during sodium loading, particularly in the low-kallikrein group. The group-difference in urinary kallikrein excretion found in basal conditions (6.85 +/- 0.31 vs. 20.74 +/- 1.71 nkat/24 hr in controls, P < 0.01) was enhanced by high salt diet (2.96 +/- 0.67 vs. 22.07 +/- 2.47 nkat/24 hr in controls, P < 0.01). In addition, renal kallikrein activity and content were reduced in low-kallikrein rats. The latter group showed a greater ratio of heart weight to body wt both in basal conditions and after sodium loading. The ratio of kidney weight to body wt was reduced after sodium loading. These results indicate that a genetically-determined defect in urinary kallikrein excretion is associated with a greater blood pressure sensitivity to salt, possibly due to altered renal sodium handling.

Role of endogenous central opioid mechanisms in maintenance of body sodium balance

The role of endogenous central opioids in the regulation of renal function was studied in Sprague-Dawley rats. In metabolism studies, changes in sodium balance were examined during normal dietary sodium intake (days 1-7; Na+ of 174 meq/kg) and sodium restriction (days 8-14; Na+ of 4.0 meq/kg). The influence of endogenous central opioids was investigated by repeating the protocol in the same rats during intracerebroventricular infusion of the opioid antagonist naltrexone methylbromide (NMBR). Intracerebroventricular NMBR did not alter sodium balance in rats fed normal sodium chow. In contrast, on low-sodium days 8 and 9, rats exhibited a more negative sodium balance during intracerebroventricular NMBR (day 8; -1,191 +/- 37 mu eq) compared with respective predrug control levels (day 8; -641 +/- 39 mu eq). Subcutaneous NMBR did not alter renal adaptation to sodium restriction. Thus central opioids are not involved in the maintenance of sodium balance during normal sodium intake. However, when dietary sodium is restricted, central opioid pathways are activated as a mechanism to maximally retain sodium.

Effect of sodium chloride supplementation on urinary endothelin-1 excretion in premature infants

We investigated the role of endothelin-1 in the renal adaptation to alterations in sodium balance in premature infants. The postnatal course of urinary endo thelin-1 excretion, an estimate of renal endothelin-1 production, was compared in premature infants receiving low or high sodium intake. Sodium supplementation was given in a dose of 3 to 5 mmol/kg per day and 1.5 to 2.5 mmol/kg per day at the postnatal ages of 8 to 21 and 22 to 35 days, respectively. Sodium balance and urinary endothelin-1 excretion were determined weekly up to the fifth week of life. Urinary endothelin-1 concentration (expressed in picomoles per liter) and urinary endothelin-1 excretion (expressed either in terms of picomoles per square meter per day or picomoles per millimole creatinine) were significantly lower in infants receiving a high sodium intake compared with those receiving low sodium intake (p < 0.001) in weeks 2 through 5. We conclude that in sodium-depleted premature infants with high urinary sodium excretion, an angiotensin II-mediated increase in renal endothelin-1 production occurs, which acts in concert with angiotensin II to restore sodium balance. (J PEDIATR 1994;125:793-7)

Lack of prostaglandin effect on sodium balance and hyperreninemia in adrenalectomized rats

Glucocorticoids are known inhibitors of prostaglandin production. Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are promoters of natriuresis and renin release. Excessive prostaglandin production, therefore, might contribute to the altered sodium balance and renin release observed in primary adrenal insufficiency. To test this hypothesis, sodium balance and prostaglandin production were measured in adrenalectomized rats and in animals receiving prostaglandin inhibitors or replacement dexamethasone. Compared to sham-operated controls, adrenalectomized rats had decreased two-day sodium balance and elevated plasma renin concentration (PRC), renal PGE2 production, and renal 6-ketoprostaglandin F1 α (6 kPGF1 α, the nonezymatic metabolite of PGI2); however, no appreciable change in aortic 6 kPGF1 α production was observed. Dexamethasone given to adrenalectomized rats normalized PRC but had no effect on sodium balance or prostaglandin production. Likewise, prostaglandin inhibitors did not alter the sodium balance or decrease the PRC post adrenalectomy. These data confirm renal prostaglandin production is increased in adrenalectomized rats, but suggest that the elevation is not due directly to glucocorticoid deficiency. Further, PRC levels in adrenal insufficiency do not appear to be prostaglandin mediated. In conclusion, excessive renal prostaglandin production does not contribute to altered sodium balance or increased PRC in adrenalectomized rats.

Role of Endogenous Endothelin in Renal Function During Altered Sodium Balance

This study was conducted to determine the involvement of endogenous endothelin-1 (ET-1), a potent vasoconstricting peptide, in systemic and renal hemodynamics and in the renin-angiotensin system, by inhibiting ET-1 action with an infusion of specific ET-1 antiserum during altered sodium balance. Infusion of 1:50 diluted ET-1 antiserum, which completely inhibited renal vasoconstriction caused by exogenously administered ET-3 (0.25 to 1.0 nmol/kg), increased urinary sodium excretion (UNaV) and fractional excretion of sodium (FENa), and decreased the plasma renin concentration (PRC) without significant changes in blood pressure, heart rate, GFR, RPF, or urine volume (UV) in conscious rats fed a low-salt diet, but not those on a high-salt diet. A time-control study showed no significant changes in any of these parameters. These results suggest that during low salt intake, in comparison to high salt intake, endogenous ET is more potent. Endogenous ET may thus contribute to the adaptive modulation of sodium excretion by a renal tubular action, and of renin release in association with a change in sodium balance.

Role of endogenous endothelin on renal functions in rats

This study was conducted to determine the involvement of endogenous endothelin (ET), a novel potent vasoconstricting peptide, in systemic and renal hemodynamics and in the renin-angiotensin system by inhibiting ET action via infusion of a specific ET antiserum at a time of altered sodium balance. Infusion of 1:50 diluted ET antiserum, which completely inhibited renal vasoconstriction by the exogenously administered ET (0.25 to 1.0 nmol/kg), caused an increase in urinary sodium excretion and fractional excretion of sodium and a decrease in plasma renin concentration without significant changes in blood pressure, heart rate, glomerular filtration rate, renal plasma flow, and urine volume compared with the values with nonimmune serum in conscious rats fed a low-salt diet. A time control study showed no significant changes in all parameters. These results suggest that the state of low- compared to high-salt intake causes a relatively stronger activity of endogenous ET, and that the endogenous ET contributes to the adaptative modulations of sodium excretion via renal tubular action and renin release in association with the changed state of sodium balance.

Effect of a kinin antagonist on renal function and haemodynamics during alterations in sodium balance in conscious normotensive rats

1. To evaluate whether sodium intake can modulate the action of endogenous kinins on renal function and haemodynamics, a receptor antagonist of bradykinin was infused in conscious normotensive rats maintained on either a normal or a low sodium diet. 2. The antagonist inhibited the hypotensive effect of exogenously administered bradykinin. It did not change the vasodepressor effect of acetylcholine, dopamine or prostaglandin E2. 3. The antagonist did not affect mean blood pressure, glomerular filtration rate, renal blood flow or urinary sodium excretion, in rats on sodium restriction. It did not change mean blood pressure, glomerular filtration rate or urinary sodium excretion, but decreased renal blood flow, in rats on a normal sodium intake. 4. The kallikrein-kinin system has a role in the regulation of renal blood flow in rats on a normal sodium diet.

Natriuretic factors and lithium clearance in patients with the syndrome of inappropriate antidiuretic hormone (SIADH)

Abstract. Because the syndrome of inappropriate antidiuretic hormone (SIADH) is a state of disturbed body fluid volume regulation and altered sodium balance we sought to determine if recently described volume regulatory factors were stimulated in SIADH. We measured atrial natriuretic peptide (ANP), endogenous digitalis‐like natriuretic factor (EDNF) and urinary free dopamine in SIADH (n= 27). We also determined fractional clearance of lithium (FCLi). The data obtained in SIADH were compared with similar measurements performed in sodium retaining hyponatremias, such as those of heart failure (n= 26), liver cirrhosis (n= 19) and volume contraction (n= 28). We observed:ANP was 19.5 ± 2.7 µM/ml in SIADH; it was significantly lower than ANP in cardiac failure, but no different from ANP in volume contraction. Urinary free dopamine was 2.2 ± 0.8 µM/24 h in SIADH; this was significantly higher than in volume contraction and liver cirrhosis. EDNF (259 ± 42 nM/24 h) and FCLi (21.4 ± 2%) were both numerically higher in SIADH than in other hyponatremic disorders; however, the differences did not achieve significance. In conclusion, our observations did not establish a specific role of ANP in chronic stable SIADH. As to the importance of EDNF, dopamine and proximal tubular fluid reabsorption (FCLi) additional work using acute volume changes may demonstrate their participation in the renal sodium handling of SIADH more clearly than our study did.

Natriuretic factors and lithium clearance in patients with the syndrome of inappropriate antidiuretic hormone (SIADH)

Because the syndrome of inappropriate antidiuretic hormone (SIADH) is a state of disturbed body fluid volume regulation and altered sodium balance we sought to determine if recently described volume regulatory factors were stimulated in SIADH. We measured atrial natriuretic peptide (ANP), endogenous digitalis-like natriuretic factor (EDNF) and urinary free dopamine in SIADH (n = 27). We also determined fractional clearance of lithium (FCLi). The data obtained in SIADH were compared with similar measurements performed in sodium retaining hyponatremias, such as those of heart failure (n = 26), liver cirrhosis (n = 19) and volume contraction (n = 28). We observed: ANP was 19.5 +/- 2.7 fM/ml in SIADH; it was significantly lower than ANP in cardiac failure, but no different from ANP in volume contraction. Urinary free dopamine was 2.2 +/- 0.8 microM/24 h in SIADH; this was significantly higher than in volume contraction and liver cirrhosis. EDNF (259 +/- 42 nM/24 h) and FCLi (21.4 +/- 2%) were both numerically higher in SIADH than in other hyponatremic disorders; however, the differences did not achieve significance. In conclusion, our observations did not establish a specific role of ANP in chronic stable SIADH. As to the importance of EDNF, dopamine and proximal tubular fluid reabsorption (FCLi) additional work using acute volume changes may demonstrate their participation in the renal sodium handling of SIADH more clearly than our study did.

Effects of sodium depletion and angiotensin II on osmotic regulation of vasopressin.

After alterations in sodium balance, osmotic reactivity of vasopressin (AVP) release was evaluated in seven conscious dogs during bilateral intracarotid infusions of hypertonic saline. A low-sodium diet reduced plasma sodium concentration by 3%; deoxycorticosterone acetate (30 mg/day for 2 days) elevated the concentration by 1%. Neither treatment altered resting plasma AVP. Hypertonic intracarotid infusions increased jugular plasma osmolality by 20 +/- 2 mosmol/kg independent of manipulations. Plasma AVP values were significantly increased (P less than 0.05) in sodium-depleted dogs compared with values of the control animals. In addition, the osmotic reactivity of AVP release was evaluated during exogenous administration of angiotensin II (ANG II). Intravenous infusion of ANG II (5 ng . kg-1 . min-1) increased plasma concentration of ANG II but did not alter concentration of plasma AVP. The slope for the relationship of jugular plasma osmolality to plasma AVP during hypertonic intracarotid infusions was significantly increased with intravenous infusion of ANG II. Sodium depletion and intravenous ANG II potentiate the relationship of plasma osmolality and plasma AVP when evaluated with intracarotid hypertonic saline infusions in dogs.

The Effects of Enalapril on Blood Pressure and the Kidney in Normotensive Subjects under Altered Sodium Balance

Eight healthy volunteers received both oral enalapril (EN; MK-421) 20 mg and placebo (PL) under stable conditions of sodium repletion, 300 mmol sodium/day (HS) and sodium depletion, 10 mmol sodium/day (LS). During PL therapy, fivefold increases in the plasma concentrations of renin and aldosterone were observed when measurements under LS were compared with those under HS conditions. Basal blood pressure (BP) readings were consistently higher and the hypotensive response to EN greater under LS compared with HS conditions. After EN, renal plasma flow increased significantly over the first 4 h, while the glomerular filtration rate, measured both by inulin and creatinine clearances, did not change. A significant natriuretic response was observed within 2 h; further natriuresis between 6 and 12 h after EN was accompanied by increased phosphate excretion.

Changes in Leucocyte Sodium Transport with Alterations in Sodium balance: A Qualitative Difference in Normotensive Relatives of Hypertensives Compared to Controls

Changes in Leucocyte Sodium Transport with Alterations in Sodium balance: A Qualitative Difference in Normotensive Relatives of Hypertensives Compared to Controls

The ultrastructure of the macula densa during altered sodium intake. A morphometric study of the macula densa in the rabbit nephron.

Cells of the macula densa from sodium-depleted, sodium-loaded and normal rabbit kidneys were investigated morphometrically by light and electron microscopy. The total macula densa volume constituted 0.14 per cent of the cortical volume and was unchanged during altered sodium balance. Ultrastructurally the macula densa cells appeared similar at the three different levels of sodium intake investigated. However, the relative volume of Golgi apparatus in the cells of the macula densa decreased from the normal value of 1.54 per cent of the cytoplasmic volume to 1.25 per cent during sodium-load, indicating that functional changes take place in the cells of the macula densa under these conditions. The volume of the Golgi apparatus was unchanged in the sodium-depleted group. The volume of the cytoplasm, the nuclei and the intercellular space which normally constitute 56 per cent, 28 per cent and 15 per cent of the total volume of the macula densa, respectively, were unchanged during sodium-load and sodium-depletion. The mitochondria which normally constitute 25 per cent of the cytoplasmic volume were similarly unchanged.

Aldosterone response to antihypertensive treatment.

To investigate whether changes in aldosterone during antihypertensive treatment would be related to alterations in the renin-angiotensin system or to changes in sodium-fluid balance, 54 essential hypertensives were hospitalized. Sodium intake was restricted to 55 mmoles per day. Levels of renin, angiotensin II and aldosterone were measured before and after two weeks treatment with atenolol (n=15), prazosin (n=15), the converting enzyme inhibitor MK 421 (n=6), verapamil (n=9) and the vasodilator L 6150 (n=10). Daily sodium excretion was determined from 24 h urine collections. The results indicate that, when renin or angiotensin levels do not change, the aldosterone response depends on alterations in sodium balance. When the renin system is depressed, sodium loss may prevent a large drop in aldosterone levels. It is concluded that during antihypertensive treatment body sodium status in itself modifies aldosterone secretion, irrespective of the renin-angiotensin system.

The antihypertensive mechanism of sodium restriction.

Both sodium restriction and weight loss without alterations in sodium balance have reportedly resulted in blood pressure decrements in hypertensive man. The antihypertensive mechanism of short-term (5-day) sodium restriction was investigated in 38 essential hypertensive adults. The small decrement (6 mm Hg) that occurred in mean arterial pressure during low- as opposed to high-salt intake (35 and 177 mEq/day, respectively) correlated best with plasma volume contraction. Baroreflex sensitivity was unchanged during salt deprivation, while renal hemodynamics actually deteriorated. Inasmuch as rigorous sodium deprivation would result in (1) questionable compliance and (2) a small decrement in arterial pressure at the expense of (3) impaired renal perfusion, the merits of such a strategy as first-line therapy of hypertension should be questioned and confirmatory long-term studies initiated. It should be reiterated that these are short-term findings whose interpretation may not pertain to a period longer than a few days.