Comparative Roles of the Renal Apical Sodium Transport Systems in Blood Pressure Control

Abstract.Human genetic studies suggest that the genes encoding renal apical Na+transport proteins play an essential role in the control of extracellular fluid volume and BP. Mice with mutations in each of these genes provide the unique opportunity to directly assess their respective involvement in fluid homeostasis and BP controlin vivo. Inactivation of either the epithelial Na+channel (ENaC) or the Na+-Cl-cotransporter decreases BP to the same extent in mice fed a low-salt diet, despite a more pronounced perturbation of fluid homeostasis in ENaC-deficient mice. In contrast, inactivation of Na+/H+exchanger 3 (NHE3) or the Na+-K+-2Cl-contransporter reduces BP with a normal-salt diet and renders mice unable to survive with a low-salt diet. Therefore, the general conception that ENaC in the collecting duct is the main renal controller of Na+balance and extracellular fluid volume should be tempered. For example, NHE3 in the proximal convoluted tubule seems to play a more substantial role in the control of fluid homeostasis. The overall effect of NHE3 inacthvation on BP may also involve absorptive defects in the intestine and colon, where the exchanger normally reabsorbs significant amounts of Na+and water.

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Sodium uptake from the gut of freshwater- and seawater-acclimated ducks and gulls

Canadian Journal of Zoology ◽

10.1139/z88-200 ◽

1988 ◽

Vol 66 (6) ◽

pp. 1365-1370 ◽

Cited By ~ 11

Author(s):

M. R. Hughes ◽

J. R. Roberts

Keyword(s):

Extracellular Fluid ◽

Fluid Volume ◽

Extracellular Fluid Volume ◽

Ion Concentration ◽

Plasma Sodium ◽

Salt Glands ◽

Gut Epithelium ◽

Seawater Acclimation ◽

Na Uptake

The first possible regulator of plasma sodium ([Na]pl) and chloride ([Cl]pl) concentrations is the gut epithelium. Its in vivo role in uptake of ingested salt in birds with salt glands has not been evaluated. In the present study the anterior gut 22Na uptake rate was measured in freshwater-acclimated ducks (Anas platyrhynchos) and gulls (Larus glaucescens) and was then measured in the same birds after acclimation to 2/3 seawater. The 22Na was given orally in 7–10 mL of 171 mM NaCl. In ducks, seawater acclimation increased [Na]pl and [Cl]pl but not Na space; in gulls seawater acclimation increased Na space, but not plasma ion concentration. The rate of gut 22Na uptake was the same in ducks and gulls and was not affected by seawater acclimation in either species. As determined from the 22Na distribution between erythrocytes and plasma 3 h after i.v. 22NaCl injection, duck erythrocytes sequestered more (9.3% ± 0.4%) of the load than did gull erythrocytes (6.9% ± 0.3%) (P < 0.001). Although gulls are better hyperosmotic regulators than ducks, there was no difference between the two species in the entry of sodium into the extracellular fluid volume from the gut. Immediately after oral gut loading with dilute saline, freshwater-acclimated gull [Cl]pl, increased more (2P < 0.001) than could be accounted for by equilibration of the administered Cl within the extracellular fluid volume. After gut loading, the increase in [Cl]pl, of freshwater-acclimated ducks was less rapid and could be accounted for by extracellular distribution of the oral Cl load. In seawater-acclimated gulls, [Cl]pl decreased following gut loading, but was unchanged in seawater-acclimated ducks.

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Lithium clearance in man: Effects of dietary salt intake, acute changes in extracellular fluid volume, amiloride and frusemide

Clinical Science ◽

10.1042/cs0730645 ◽

1987 ◽

Vol 73 (6) ◽

pp. 645-651 ◽

Cited By ~ 41

Author(s):

J. C. Atherton ◽

R. Green ◽

S. Hughes ◽

V. McFall ◽

J. A. Sharples ◽

...

Keyword(s):

Volume Expansion ◽

Salt Intake ◽

Extracellular Fluid ◽

Fluid Volume ◽

High Salt ◽

Extracellular Fluid Volume ◽

Lithium Clearance ◽

Dietary Salt ◽

Salt Diet ◽

Dietary Salt Intake

1. The effects of amiloride and frusemide on lithium clearance were studied during changes in dietary sodium chloride intake and during infusion of 0.9% NaCl in normal human volunteers. 2. Lithium and fractional lithium clearances were less on the low than on the high salt diet. Values for the medium salt diet were intermediate. Acute extracellular fluid volume expansion with 0.9% NaCl infusion and extracellular fluid volume contraction 3–4 h after intravenous frusemide caused lithium and fractional lithium clearances to increase and decrease respectively. 3. Amiloride caused small changes in lithium and fractional lithium clearances on a low salt diet, but was without effect when salt intake was medium or high. 4. Increases in lithium clearance occurred immediately after frusemide irrespective of dietary salt intake and in subjects infused with 0.9% NaCl. Only in salt-depleted subjects did frusemide cause a substantial increase in fractional lithium clearance. Changes induced under other circumstances were small. 5. It is concluded that the lithium clearance method for assessment of proximal tubule salt and water re-absorption can be used with some degree of confidence in certain circumstances (medium and high salt intake as well as in acute volume expansion) but may not be reliable when dietary salt intake is low.

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Influence of Volume Expansion on Renal Diluting Capacity in the Rat

Clinical Science ◽

10.1042/cs0460331 ◽

1974 ◽

Vol 46 (3) ◽

pp. 331-345

Author(s):

M. Martinez-Maldonado ◽

G. Eknoyan ◽

W. N. Suki

Keyword(s):

Volume Expansion ◽

Collecting Duct ◽

Isotonic Saline ◽

Extracellular Fluid ◽

Free Water ◽

Fluid Volume ◽

Extracellular Fluid Volume ◽

Sodium Reabsorption ◽

Water Excretion ◽

Hypotonic Saline

1. The functional capacity of Henle's loop was examined during hypotonic, isotonic and hypertonic extracellular fluid volume expansion. To eliminate a possible role of antidiuretic hormone (ADH) in the alteration of free water excretion, rats with congenital diabetes insipidus were used. The infusion of hypotonic saline resulted in a progressive rise in free water clearance (CH2O) throughout the range of urine flow (V) attained. Similar results were obtained in rats treated chronically with deoxycorticosterone acetate (DOCA). The infusion of isotonic saline (sodium chloride, 154 mmol/l) produced an initial rise in CH2O until V represented 10% of the filtered load, after which CH2O appeared to reach a plateau. The limitation of CH2O was more marked when hypertonic saline was infused. Medullary and papillary non-urea solute (NUS) concentration rose progressively with the increasing concentration of the saline solution infused. 2. The greater fractional sodium excretion (FENa) after acute isotonic and hypertonic volume expansion is probably the result of inhibition of sodium reabsorption in the collecting duct, although inhibition in the ascending limb cannot be entirely excluded. The depression of CH2O as a function of V seen during acute isotonic or hypertonic volume expansion can be attributed in part to enhanced water back-diffusion from the collecting duct consequent to the increasing medullary and papillary interstitial NUS concentration, even in the absence of ADH. 3. Chronic expansion of extracellular fluid volume by DOCA administration did not modify the response to hypotonic saline infusion.

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Mechanisms of proximal tubule sodium transport regulation that link extracellular fluid volume and blood pressure

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00002.2010 ◽

2010 ◽

Vol 298 (4) ◽

pp. R851-R861 ◽

Cited By ~ 120

Author(s):

Alicia A. McDonough

Keyword(s):

Blood Pressure ◽

Proximal Tubule ◽

Flow Rate ◽

Sodium Transport ◽

Extracellular Fluid ◽

Fluid Volume ◽

The Body ◽

Extracellular Fluid Volume ◽

Ang Ii ◽

Salt Diet

One-hundred years ago, Starling articulated the interdependence of renal control of circulating blood volume and effective cardiac performance. During the past 25 years, the molecular mechanisms responsible for the interdependence of blood pressure (BP), extracellular fluid volume (ECFV), the renin-angiotensin system (RAS), and sympathetic nervous system (SNS) have begun to be revealed. These variables all converge on regulation of renal proximal tubule (PT) sodium transport. The PT reabsorbs two-thirds of the filtered Na+ and volume at baseline. This fraction is decreased when BP or perfusion pressure is increased, during a high-salt diet (elevated ECFV), and during inhibition of the production of ANG II; conversely, this fraction is increased by ANG II, SNS activation, and a low-salt diet. These variables all regulate the distribution of the Na+/H+ exchanger isoform 3 (NHE3) and the Na+-phosphate cotransporter (NaPi2), along the apical microvilli of the PT. Natriuretic stimuli provoke the dynamic redistribution of these transporters along with associated regulators, molecular motors, and cytoskeleton-associated proteins to the base of the microvilli. The lipid raft-associated NHE3 remains at the base, and the nonraft-associated NaPi2 is endocytosed, culminating in decreased Na+ transport and increased PT flow rate. Antinatriuretic stimuli return the same transporters and regulators to the body of the microvilli associated with an increase in transport activity and decrease in PT flow rate. In summary, ECFV and BP homeostasis are, at least in part, maintained by continuous and acute redistribution of transporter complexes up and down the PT microvilli, which affect regulation of PT sodium reabsorption in response to fluctuations in ECFV, BP, SNS, and RAS.

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Pathophysiology of oedema in nephrotic syndrome

10.1093/med/9780199592548.003.0053 ◽

2015 ◽

Author(s):

Neil Turner ◽

Premil Rajakrishna

Keyword(s):

Nephrotic Syndrome ◽

Osmotic Pressure ◽

Serum Proteins ◽

Collecting Duct ◽

Extracellular Fluid ◽

Colloid Osmotic Pressure ◽

Fluid Volume ◽

Extracellular Fluid Volume ◽

Whole Body ◽

Sodium Retention

The mechanism by which loss of serum proteins into the urine causes expansion of extracellular fluid volume and oedema has become clearer. A key initiating abnormality is avid sodium retention by the kidney, leading to increased whole-body sodium and increased extracellular fluid volume. This appears to be driven primarily by overactivation of the amiloride-sensitive epithelial sodium channel (ENaC) in the collecting duct, activated proteolytically through abnormal filtration of plasminogen, and its activation to plasmin in the nephron. Conventional explanations for nephrotic oedema focused on low colloid osmotic pressure as a consequence of loss of serum proteins, leading to egress of extracellular fluid from the intravascular compartment. It was hypothesized that this led to underfilling of the circulation and a drive to sodium retention. While low osmotic pressure may play a part in the clinical picture of nephrotic syndrome, a variety of observations suggest that underfilling is not a common feature except in the most severe nephrotic syndrome. Furthermore the gradient in colloid osmotic pressure between serum and interstitium tends to be preserved in nephrotic syndrome. The distribution of excess extracellular fluid is markedly different in patients with nephrotic syndrome from that seen in patients who have reduced glomerular filtration rate as the cause of sodium retention. This is not fully understood but hypotheses centre on capillary permeability and colloid osmotic pressure effects.

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Body compostion in vivo. VIII. Some physiological implications with respect to extracellular fluid volume arising from the distribution of thiocyanate in sheep

Australian Journal of Agricultural Research ◽

10.1071/ar9650667 ◽

1965 ◽

Vol 16 (4) ◽

pp. 667 ◽

Cited By ~ 5

Author(s):

BA Panaretto

Keyword(s):

Body Weight ◽

Specific Activity ◽

Rumen Fluid ◽

Extracellular Fluid ◽

Fluid Volume ◽

Extracellular Fluid Volume

The distribution of [35S]-thiocyanate in sheep was studied. The specific activity in rumen fluid during the first 4 hr after injection was markedly less than in serum, and equilibration between rumen fluid and blood was not reached until 20–30 hr after injection. There were large urinary losses of the marker and approximately 50% of the dose was lost in 24 hr. Activity in rumen fluid and urine was due to [35S]-thiocyanate. The thiocyanate spaces, allowing for urinary losses, during the first 4 hr after injection were 25 –30% body weight, increasing to 35–40% body weight at 20–30 hr after injection. The physiological implications of the results with respect to measuring extracellular fluid volume in sheep are discussed.

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