Plasma sodium is a concentration: sodium spread through a volume of water. So the number changes when the sodium changes, and it also changes when the water changes. The way to see how the body holds this number steady is to ask what sets each part of that ratio.
What sets the sodium number?
Body water is shared between the cells and the fluid outside them, as the body-water note showed. Sodium and its anions are the main solutes of the extracellular fluid (ECF), and potassium is the main solute of the intracellular fluid (ICF).
A first answer follows from this. Plasma sodium concentration depends on the amount of sodium in the blood and on the amount of ECF, so sodium concentration = [Na]/ECF. This is the right idea, because the number is sodium divided by the water that holds it. But it uses the wrong volume, because the cells also hold water. The first answer is therefore incomplete: sodium is not the only solute that matters for plasma sodium.
Does water stay where it is?
If sodium is not the only solute that matters, something else must move the water. The cell membrane is permeable to water, so water is not locked in the compartment where it started. It crosses the membrane and moves toward the side that holds more solute. Because of this, the ICF and the ECF settle at the same osmolality.
Potassium shows how this changes the plasma sodium. Suppose a large amount of potassium is added to the plasma. It moves into the cells and raises the intracellular osmolality. Water then shifts from the ECF into the ICF to equalise the two. The ECF has lost water, so the sodium left in it is more concentrated, and the plasma sodium concentration rises.
Water passes between plasma, interstitial fluid and cells, so plasma sodium concentration also reflects what happens to water across cell membranes. Plasma sodium therefore depends on more than the sodium and water in the plasma. Can the number change, then, when no sodium moves at all?
What does the number depend on?
Yes, as the potassium example shows, and that is why potassium has to appear in the sum. Plasma sodium depends on the exchangeable sodium, the exchangeable potassium and the total body water. Edelman’s relationship writes this as:
Plasma [Na+] ≈ (Na_e + K_e) / TBW
Here Na_e is exchangeable sodium, K_e is exchangeable potassium and TBW is total body water. The potassium adds solute to the same water, so it belongs in the numerator beside the sodium.
The amount of sodium in the ECF is one thing that sets plasma sodium concentration. It is the sodium part of the sum, so a change in how much sodium the ECF holds moves the number. The sodium held in the ECF is the part of the sum the body keeps steady. Which systems see to that?
Which systems hold the sodium in the ECF?
The sodium in the ECF is a term of the sum, so the body controls it. Three systems regulate how much sodium the ECF holds, and each has its own signal and direction.
- The renin–angiotensin–aldosterone system (RAAS) promotes sodium retention. Aldosterone acts on the late distal tubule and collecting duct to favour sodium and water reabsorption, so sodium stays in the ECF.
- Natriuretic peptides, for example atrial natriuretic peptide (ANP), promote sodium excretion. Their signal is stretch: when blood volume rises, the atria are stretched, and they are released when that stretch occurs. They act in the medullary collecting duct to reduce sodium reabsorption, so less sodium is kept and more is excreted.
- The sympathetic nervous system takes part in the control of sodium handling. Sympathetic nerves to the kidney reduce urinary sodium excretion and raise renin release, so they also hold sodium.
The RAAS and the natriuretic peptides pull in opposite directions: the RAAS retains sodium and ANP removes it. ANP also inhibits renin release, which adds to the opposition. If the systems push in opposite directions, what happens when one of them keeps going for a long time?
What keeps sodium steady once a system is pushed?
Primary aldosteronism is a useful example of this. Excess aldosterone retains sodium, and that might be expected to produce permanent hypernatremia. It does not. The reason is a protective mechanism called steady state, which exists for any ion excreted into the urine. After a change in intake or excretion of an ion that the kidney reabsorbs, only a few days are needed to bring intake and excretion back into balance. A continuous aldosterone effect therefore does not produce indefinite sodium retention: the body escapes from it, so retention stops rather than growing.
Primary aldosteronism tests this idea well, because the aldosterone is produced independently of renin, so the excess is not driven by the usual signal. Several mechanisms control the balance of the same ion, and here they can be seen working together. The sodium is retained with water, so the fluid expands rather than becoming more concentrated. After only a few days (less than 10), ANP rises and excretes the sodium that aldosterone retained, restoring balance. In this setting, escape from sodium retention is associated with raised ANP. A proposed explanation is that ANP drives the escape.
Taken together, the RAAS, the natriuretic peptides and the steady state hold the sodium content of the ECF stable. That settles how much sodium the ECF keeps. But water still needs a pull to cross the membrane, so what decides which dissolved particles provide it?
Which solutes pull the water?
Plasma sodium concentration also reflects water movement across cell membranes, and that movement depends on which solutes are counted. A solute exerts an osmotic force across a membrane when the membrane holds it back. So the osmolality that matters for water movement counts the solutes the membrane holds back, and the others do not pull water. Urea also adds to the measured osmolality, so does urea pull water too?