How does vasopressin work?

From Lewis S. Blevins, Jr. MD  –

Vasopressin acts on the kidney to reabsorb water from the urine to restore plasma osmolarity to normal to prevent dehydration. Simple enough. Right? Hold on a minute!

Our bodies are 60 to 70% water. There are three water “compartments.” The first of these is the intracellular compartment which is, basically, the water that is located within our cells. The next is the extracellular fluid compartment. It accounts for about 20% of our body weight. This compartment is subdivided into two compartments: the blood plasma, or the water component of our blood, and the extracellular fluid that is located between our cells within our tissues. In an average 70 kg adult man (keep in mind that in today’s society 70 kg no longer an average weight), about 14 kg would be extracellular fluid. That’s roughly 31 pounds. Just about 6 kg would be the intravascular or blood plasma fluid. Remember that 1 kg of water is 1 L of water. So, think of about 14 kg, or 14 L, to be the rapidly or readily exchangeable extracellular fluid volume in an average adult. It is the osmolarity in this approximate 14 L that matters when we are measuring sodium and thinking about thirst and stimulation of arginine vasopressin secretion.

The kidneys receive about 22% of the cardiac output in a normal adult. That means that within a minute of time, 22% of the blood pumped by the heart flows through the kidneys. This is about 1.1 L per minute. The average adult has about 5 L of blood volume. Thus, in a five-minute period of time the average-sized adult has theoretically passed their entire blood volume through the kidneys to be cleansed at least once. Of course, it takes more than one pass to do all the proper cleansing.

Approximately 95% of the water is removed from the blood on every pass through the first part of the nephron of the kidney. Thus, the glomerulus, the first part of the nephron, is like a sieve. Water passes through it. Then enters a tubule of the nephron called the proximal collecting tubule, ultimately passes through a loop called the loop of Henle, then the distal tubule, and then the collecting duct. Different things happen to that water along its course. Potassium and sodium or exchanged. Bits of water might be resorbed. Things might be secreted. The nephrons also work to create a very hypertonic environment in the medulla of the kidney. The normal osmolarity of the blood is around 290 miliosmoles per kilogram of water. The kidney creates a situation where the renal interstitium has an osmolarity of about 1000 to 1200 miliosmoles per kilogram of water. This is critical to the action of vasopressin. Because of the actions of arginine vasopressin, in the last part of the distal tubule and the collecting duct, water is resorbed to an extent such that 80% of the filtered water is reclaimed in the kidney.

Imagine you are a cell in the proximal collecting duct of the nephron and you have the ability to respond to vasopressin. You live in a very harsh environment. On one side of you, urine is flowing at a high rate. On the other, is the very intense hypertonic renal medulla and lots of blood vessels. You have to defend yourself against both environments. And yet, you act as the grand mediator of water. You have vasopressin receptors on your cell membranes. You have genes in your nucleus and an ability to activate and encode those genes and a moments notice. At a very faraway place, as far as cells are concerned, a group of osmoreceptors have sensed a change in extracellular fluid osmolarity and stimulated the supraoptic and paraventricular nuclei to release vasopressin into the circulation. Arginine vasopressin ultimately finds its way to you. It binds to the vasopressin receptor, hey receptor that you made because that’s what collecting duct cells do, on your cell surface membranes. You internalize that receptor and a number of “second messenger” systems are activated. The second messengers affect your DNA and lead to the production of water channels known as aquaporins. The aquaporins that are inside of you are shuttled to and inserted into your cell membranes at the urinary space. Suddenly, your insides are flooded with water that passes from the urinary space because your tonicity is greater than that of the urine space. Thank goodness the renal interstitium is nearby. Its tonicity is much greater than yours, and it sucks the water from you into itself where the water is resorbed by the blood vessels called vasa recta. If it weren’t for this, you would surely burst from all of the water. Resorbed water lowers the osmolarity, the Osmo receptors become less active, less vasopressin is released, and you move around some aquaporins to slow down the tide and go back to your normal level of water conservation.

Normally, as mentioned, 80% of the filtered water is restored. Thus, the system is always partially “on.” Extra vasopressin gives the human the ability to resorb even more water. Excess water on board shuts down arginine vasopressin secretion and you resorb less water.

Patients with diabetes insipidus take an amount of vasopressin that balances their plasma osmolarity. Many patients have a plasma osmolarity that is at or near their thirst threshold as a consequence of treatment. Patients who ingest too much water will have hyponatremia because their vasopressin cannot be shut off, since it originated from outside the body when their osmolarity falls as a consequence of being”waterlogged.”

The hypertonicity of the renal medulla, created by the nephron, mentioned as essential to the action of vasopressin, can be altered by urine flow. Excessive urine flow dilutes out that particular hypertonic environment. What this means to you as a patient is that the more polyuria that you have, the less effective will be a dose of DDAVP. Thus, you must control your polyuria to be able to respond adequately to DDAVP. This explains why people might be somewhat resistant to vasopressin at first after a new diagnosis and then are more sensitive to doses over the first few weeks of treatment.

People who have nephrogenic diabetes insipidus have a problem responding to vasopressin. They might have a mutation in the vasopressin receptor. They could have a mutation in the aquaporins and, thus, unable to insert those water channels into their cell surface membranes to permit water to be resorbed.

Photo by Tim  Geers

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