Regulation of Extracellular Fluid Osmolarity and Sodium Concentration pdf - The Body Fluids and Kidneys

and collecting ducts to water, as discussed in Chapter 27. This allows large

gland secretes more ADH, which increases the permeability of the distal tubules

solutes in the body fluids become too concentrated), the posterior pituitary

When osmolarity of the body fluids increases above normal (that is, the

, also called

pendently of the rate of solute excretion. A primary effector of this feedback is

There is a powerful feedback system for regulating plasma osmolarity and

Antidiuretic Hormone Controls Urine Concentration

independently of solute excretion is necessary for survival, especially when fluid

solutes such as sodium and potassium. This ability to regulate water excretion

important, the kidney can excrete a large volume of dilute urine or a small

kidney can excrete urine with a concentration of 1200 to 1400 mOsm/L. Equally

when there is a deficit of water and extracellular fluid osmolarity is high, the

only about one sixth the osmolarity of normal extracellular fluid. Conversely,

excrete urine with an osmolarity as low as 50 mOsm/L, a concentration that is

is excess water in the body and body fluid osmolarity is reduced, the kidney can

of solutes and water in the urine in response to various challenges. When there

The normal kidney has tremendous capability to vary the relative proportions

a Dilute Urine

The Kidneys Excrete Excess Water by Forming

extracellular fluid volume, osmolarity, and sodium concentration.

anisms that determine the intakes of water and salt, which also help to control

sodium concentration and osmolarity; and (4) the thirst and salt appetite mech-

urine; (3) the renal feedback mechanisms that control the extracellular fluid

kidneys to eliminate excess water by excreting a dilute urine; (2) the mecha-

In this chapter, we discuss specifically (1) the mechanisms that cause the

that determine thirst, and (2) renal excretion of water, which is controlled by

body water in turn is controlled by (1) fluid intake, which is regulated by factors

tion and osmolarity are regulated by the amount of extracellular water. The

large extent, extracellular fluid sodium concentra-

by the volume of the extracellular fluid. Thus, to a

other solutes. The total concentration of solutes in

For the cells of the body to function properly, they

348

Regulation of Extracellular Fluid

Osmolarity and Sodium

Concentration

must be bathed in extracellular fluid with a rela-
tively constant concentration of electrolytes and

the extracellular fluid—and therefore the osmolar-
ity—is determined by the amount of solute divided

multiple factors that influence glomerular filtration and tubular reabsorption.

nisms that cause the kidneys to conserve water by excreting a concentrated

volume of concentrated urine without major changes in rates of excretion of

intake is limited.

sodium concentration that operates by altering renal excretion of water inde-

antidiuretic hormone (ADH)

vasopressin.

amounts of water to be reabsorbed and decreases urine volume but does not

tubular segment is impermeable to water, even in

are avidly reabsorbed. However, this portion of the

in the thick segment, sodium, potassium, and chloride

In the ascending limb of the loop of Henle, especially

Tubular Fluid Becomes Dilute in the Ascending Loop of Henle.

fore, the tubular fluid becomes more concentrated as

osmolarity of the original glomerular filtrate. There-

the descending loop of Henle, water is reabsorbed by

osmolarity of about 300 mOsm/L.As fluid passes down

tubule fluid remains isosmotic to the plasma, with an

little change in osmolarity occurs; that is, the proximal

water are reabsorbed in equal proportions, so that

fluid flows through the proximal tubule, solutes and

Tubular Fluid Remains Isosmotic in the Proximal Tubule.

follows.

than water, as shown in Figure 28–2, but this occurs

to dilute the filtrate as it passes along the tubule. This

(300 mOsm/L). To excrete excess water, it is necessary

When the glomerular filtrate is initially formed,

does not excrete excess amounts of solutes.

water, the kidney rids the body of the excess water but

about 100 mOsm/L. Thus, after ingestion of excess

However, the total amount of solute excreted remains

in a human after ingestion of 1 liter of water. Note that

Figure 28–1 shows the approximate renal responses

late distal tubule and the collecting ducts.

water in the distal parts of the nephron, including the

with a concentration as low as 50 mOsm/L. The kidney

kidney can excrete as much as 20 L/day of dilute urine,

When there is a large excess of water in the body, the

Dilute Urine

kidney excretes a dilute or a concentrated urine.

secretion determines, to a large extent, whether the

dilute urine to be excreted. Thus, the rate of ADH

lecting ducts to water, which causes large amounts of

ADH by the posterior pituitary decreases, thereby

cellular fluid osmolarity is reduced, the secretion of

When there is excess water in the body and extra-

solutes.

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

349

markedly alter the rate of renal excretion of the

reducing the permeability of the distal tubule and col-

Renal Mechanisms for Excreting a

performs this impressive feat by continuing to reab-
sorb solutes while failing to reabsorb large amounts of

urine volume increases to about six times normal
within 45 minutes after the water has been drunk.

relatively constant because the urine formed becomes
very dilute and urine osmolarity decreases from 600 to

its osmolarity is about the same as that of plasma

is achieved by reabsorbing solutes to a greater extent

only in certain segments of the tubular system as

osmosis and the tubular fluid reaches equilibrium with
the surrounding interstitial fluid of the renal medulla,
which is very hypertonic—about two to four times the

it flows into the inner medulla.

Drink 1.0 L H

Time (minutes)

180

Urinary solute

excretion

(mOsm/min)

1.2

0.6

120

Urine flow rate

(ml/min)

Osmolarity

(mOsm/L)

800

Urine

osmolarity

Plasma

osmolarity

400

prevent plasma osmolarity from decreasing markedly during

remains relatively constant. These responses of the kidneys

urine; however, the total amount of solute excreted by the kidneys

larity decreases, causing the excretion of a large volume of dilute

that after water ingestion, urine volume increases and urine osmo-

Water diuresis in a human after ingestion of 1 liter of water. Note

Figure 28–1

excess water ingestion.

100

Medulla

Cortex

NaCl

300

400

600

400

600

300

(Numerical values are in milliosmoles per liter.)

reabsorption of solutes lead to a large volume of dilute urine.

levels are very low. The failure to reabsorb water and continued

sodium chloride and the failure to reabsorb water when ADH

tubules, the tubular fluid is further diluted by the reabsorption of

fluid becomes very dilute. In the distal tubules and collecting

are very low. Note that in the ascending loop of Henle, the tubular

Formation of a dilute urine when antidiuretic hormone (ADH) levels

Figure 28–2

occur in the presence of high levels of ADH.

, which provides the

avidly reabsorb water, and (2)

to water, thereby allowing these tubular segments to

, which increases the

high level of ADH

The basic requirements for forming a concentrated

Concentrated Urine—High ADH Levels

However, a shipwreck victim’s pet Australian hopping

that occurs in shipwreck victims who drink seawater.

of seawater drunk, explaining the rapid dehydration

ingested in addition to other solutes such as urea. This

drunk, 2 liters of urine volume would be required to rid

about 600 mOsm/L. Thus, for every liter of seawater

centrated. Therefore, the maximum concentration of

excrete other solutes, especially urea, which contribute

dehydration? The answer is that the kidney must also

or 1.0 liter. Why then does drinking seawater cause

urine concentrating ability is 1200 mOsm/L, the amount

sodium chloride intake of 1200 milliosmoles. If maximal

1200 mOsm/L. Drinking 1 liter of seawater with a con-

per cent, with an osmolarity between about 1000 and

if one attempts to drink seawater. Sodium chloride

The limited ability of the human kidney to con-

ratory tract, and gastrointestinal tract, when water is not

dehydration, along with water loss from the skin, respi-

This minimal loss of volume in the urine contributes to

, can be calculated as

must excrete about 600 milliosmoles of solute each day.

ions that are ingested. A normal 70-kilogram human

The maximal concentrating ability of the kidney dic-

Obligatory Urine Volume

beaver, have minimal urine concentrating ability; they

Animals adapted to aquatic environments, such as the

survive in the desert without drinking water; sufficient

high as 10,000 mOsm/L. This allows the mouse to

tralian hopping mouse, can concentrate urine to as

ity of plasma. Some desert animals, such as the Aus-

1200 to 1400 mOsm/L, four to five times the osmolar-

decreasing the volume of urine formed. The human

When there is a water deficit in the body, the kidney

tant when water is in short supply.

tain homeostasis, a function that is especially impor-

intake is required to match this loss, but the ability of

and the kidneys through the excretion of urine. Fluid

feces, the skin through evaporation and perspiration,

expired air, the gastrointestinal tract by way of the

routes, including the lungs by evaporation into the

mammals that live on land, including humans. Water is

The ability of the kidney to form a urine that is more

by Excreting a Concentrated

The Kidneys Conserve Water

distal tubule and collecting ducts, and a large volume

absence of ADH, the urine is further diluted in the late

always dilute, regardless of the level of ADH. In the

sorb water. In healthy kidneys, fluid leaving the

To summarize, the mechanism for forming a dilute

of dilute urine.

50 mOsm/L. The failure to reabsorb water and the con-

more dilute, decreasing its osmolarity to as low as

impermeable to water, and the additional reabsorption

the absence of ADH, this portion of the tubule is also

there is additional reabsorption of sodium chloride. In

tubule, cortical collecting duct, and collecting duct,

Tubular Fluid in Distal and Collecting Tubules Is Further Diluted

only about one third the osmolarity of plasma.

regardless of whether

ascending loop of Henle into the early distal tubule,

the presence of large amounts of ADH. Therefore, the

350

Unit V

The Body Fluids and Kidneys

tubular fluid becomes more dilute as it flows up the

with the osmolarity decreasing progressively to about
100 mOsm/L by the time the fluid enters the early
distal tubular segment. Thus,
ADH is present or absent, fluid leaving the early distal
tubular segment is hypo-osmotic, with an osmolarity of

in the Absence of ADH.

As the dilute fluid in the early

distal tubule passes into the late distal convoluted

of solutes causes the tubular fluid to become even

tinued reabsorption of solutes lead to a large volume

urine is to continue reabsorbing solutes from the distal
segments of the tubular system while failing to reab-

ascending loop of Henle and early distal tubule is

of dilute urine is excreted.

Urine

concentrated than plasma is essential for survival of

continuously lost from the body through various

the kidney to form a small volume of concentrated
urine minimizes the intake of fluid required to main-

forms a concentrated urine by continuing to excrete
solutes while increasing water reabsorption and

kidney can produce a maximal urine concentration of

water can be obtained through the food ingested and

water produced in the body by metabolism of the food.

can concentrate the urine to only about 500 mOsm/L.

tates how much urine volume must be excreted each
day to rid the body of waste products of metabolism and

If maximal urine concentrating ability is 1200 mOsm/L,
the minimal volume of urine that must be excreted,
called the obligatory urine volume

available to drink.

centrate the urine to a maximal concentration of
1200 mOsm/L explains why severe dehydration occurs

concentration in the oceans averages about 3.0 to 3.5

centration of 1200 mOsm/L would provide a total

of urine volume needed to excrete 1200 milliosmoles
would be 1200 milliosmoles divided by 1200 mOsm/L,

about 600 mOsm/L when the urine is maximally con-

sodium chloride that can be excreted by the kidneys is

the body of 1200 milliosmoles of sodium chloride

would result in a net fluid loss of 1 liter for every liter

mouse could drink with impunity all the seawater it
wanted.

Requirements for Excreting a

and Hyperosmotic Renal Medulla

urine are (1) a
permeability of the distal tubules and collecting ducts

a high osmolarity of the

renal medullary interstitial fluid
osmotic gradient necessary for water reabsorption to

L day

1200 mOsm L

600 mOsm day

= 0 5

on, reducing the concentration inside the tubule and

thick ascending limb

3, step 1). Next, the active pump of

tubule (Figure 28

300 mOsm/L, the same as that leaving the proximal

becomes hyperosmotic. First, assume that the loop of

in mind, let us now discuss how the renal medulla

With these characteristics of the loop of Henle

Steps Involved in Causing Hyperosmotic Renal Medullary Inter-

ows toward the tip of the loop of Henle.

interstitium, and the tubular

renal medullary osmolarity. Therefore, water diffuses

the ascending limb, is very permeable to water, and the

s loop, in contrast to

The descending limb of Henle

water, adding further to the high solute concentration

s loop, which is also impermeable to

renal medullary interstitium. There is some passive

ow of water into the interstitium. Thus, the active

thick ascending limb is virtually impermeable to water,

uid. Because the

This pump is capable of establishing about a 200-

transport of potassium, chloride, and other ions from

The most important cause of the high medullary

inner medullary collecting ducts.

tubules, distal tubules, cortical collecting tubules, and

1, along with the characteristics of the proximal

istics of the loops of Henle are summarized in Table

The transport character-

Be Trapped in the Renal Medulla.

4. Diffusion of only small amounts of water from the

3. Facilitated diffusion of large amounts of urea

2. Active transport of ions from the collecting ducts

of potassium, chloride, and other ions out of the

1. Active transport of sodium ions and co-transport

The major factors that contribute to the buildup of

tion in the medulla is achieved, it is maintained by a

great excess of water. Once the high solute concentra-

pelvic tip of the medulla. This means that the renal

in the medulla of the kidney is much higher, increas-

282 mOsm/L.) The osmolarity of the interstitial

intermolecular attraction and repulsion, is about

corrected osmolar activity,

the plasma osmolarity. (As discussed in Chapter 25,

of the body is about 300 mOsm/L, which is similar to

The osmolarity of interstitial

Medullary Interstitium

osmotic renal medulla before it is excreted, also play

collecting ducts, which carry urine through the hyper-

nally, the

before returning to the renal cortex. And

the vasa recta, which also loop down into the medulla

renal pelvis. Paralleling the long loops of Henle are

the medulla before returning to the cortex. Some of

juxtamedullary nephrons,

. In the human, about 25 per

the specialized peritubular capillar-

The countercurrent mechanism depends on the

rent mechanism

This process involves the operation of the

but for now, what is the process by which renal

discuss the factors that control ADH secretion later,

degree of hyperosmolarity of the renal medulla. We

ability is limited by the level of ADH and by the

back into the blood. Thus, the urine concentrating

tium; from there it is carried away by the vasa recta

when ADH levels are high, water moves through the

collecting ducts normally is very hyperosmotic, so that

The renal medullary interstitium surrounding the

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

351

tubular membrane by osmosis into the renal intersti-

medullary interstitial fluid becomes hyperosmotic?

countercur-

special anatomical arrangement of the loops of Henle
and the vasa recta,
ies of the renal medulla
cent of the nephrons are
with loops of Henle and vasa recta that go deeply into

the loops of Henle dip all the way to the tips of the
renal papillae that project from the medulla into the

a critical role in the countercurrent mechanism.

Countercurrent Mechanism
Produces a Hyperosmotic Renal

fluid in almost all parts

the

which accounts for

fluid

ing progressively to about 1200 to 1400 mOsm/L in the

medullary interstitium has accumulated solutes in

balanced inflow and outflow of solutes and water in
the medulla.

solute concentration into the renal medulla are as
follows:

thick portion of the ascending limb of the loop
of Henle into the medullary interstitium

into the medullary interstitium

from the inner medullary collecting ducts into the
medullary interstitium

medullary tubules into the medullary interstitium,

far less than the reabsorption of solutes into the
medullary interstitium

Special Characteristics of Loop of Henle That Cause Solutes to

28–

osmolarity is active transport of sodium and co-

the thick ascending loop of Henle into the interstitium.

milliosmole concentration gradient between the
tubular lumen and the interstitial fl

the solutes pumped out are not followed by osmotic
fl
transport of sodium and other ions out of the thick
ascending loop adds solutes in excess of water to the

reabsorption of sodium chloride from the thin ascend-
ing limb of Henle’

of the renal medullary interstitium.

’

tubular fluid osmolarity quickly becomes equal to the

out of the descending limb of Henle’s loop into the

fluid osmolarity gradually

rises as it fl

stitium.

Henle is filled with fluid with a concentration of

–

the

on the loop of Henle is turned

Table 28–1

Summary of Tubule Characteristics—Urine Concentration

ADH

Thick ascending limb

Thin ascending limb

Thin descending limb

NaCl

Urea

Transport

Active NaCl

Permeability

Proximal tubule

Distal tubule

Cortical collecting

tubule

Inner medullary

++ADH

collecting duct

ADH, permeability to water or urea is increased by ADH.

, high level of active transport or permeability;

, moderate level of active

0, minimal level of active transport or permeability;

transport or permeability;

4). The early distal

about 100 mOsm/L (Figure 28

uid is dilute, with an osmolarity of only

cortex, the

When the tubular

Role of Distal Tubule and

arrived sodium chloride, thus

. The sodium chloride reabsorbed from

Thus, the repetitive reabsorption of sodium chloride

ity to 1200 to 1400 mOsm/L as shown in step 7

pumping of ions out of the thick ascending loop of

the concentration gradient established by the active

cient time,

in excess of water; with suf

These steps are repeated over and over, with the net

ows into the ascending limb, still

uid (step 6), and as the

500 mOsm/L (step 5). Then, once again, the

into the interstitium, with water remaining behind,

is in the ascending limb, additional ions are pumped

ow into the ascending limb. Once this

Henle from the proximal tubule, which causes the

ent, much less than that achieved by the countercur-

Henle. Thus, by itself, the active transport of sodium

out of the descending limb. The interstitial osmolarity

uid (step 2). The

raising the interstitial concentration; this pump estab-

352

Unit V

The Body Fluids and Kidneys

lishes a 200-mOsm/L concentration gradient between
the tubular fluid and the interstitial fl
limit to the gradient is about 200 mOsm/L because
paracellular diffusion of ions back into the tubule
eventually counterbalances transport of ions out of the
lumen when the 200-mOsm/L concentration gradient
is achieved.

Step 3 is that the tubular fluid in the descending limb

of the loop of Henle and the interstitial fluid quickly
reach osmotic equilibrium because of osmosis of water

is maintained at 400 mOsm/L because of continued
transport of ions out of the thick ascending loop of

chloride out of the thick ascending limb is capable of
establishing only a 200-mOsm/L concentration gradi-

rent system.

Step 4 is additional flow of fluid into the loop of

hyperosmotic fluid previously formed in the descend-
ing limb to fl

fluid

until a 200-mOsm/L osmotic gradient is established,
with the interstitial fluid osmolarity rising to

fluid in the

descending limb reaches equilibrium with the hyper-
osmotic medullary interstitial fl

hyperosmotic tubular fluid from the descending limb
of the loop of Henle fl
more solute is continuously pumped out of the tubules
and deposited into the medullary interstitium.

effect of adding more and more solute to the medulla

this process

gradually traps solutes in the medulla and multiplies

Henle, eventually raising the interstitial fluid osmolar-

by the thick ascending loop of Henle and continued
inflow of new sodium chloride from the proximal
tubule into the loop of Henle is called the countercur-
rent multiplier
the ascending loop of Henle keeps adding to the newly

“multiplying” its con-

centration in the medullary interstitium.

Collecting Ducts in Excreting a
Concentrated Urine

fluid leaves the loop of Henle and

flows into the distal convoluted tubule in the renal

–

300

400

300

200

400

300

400

200

400

300

400

300

400

200

400

350

500

300

350

500

150

300

700

300

1000

1200

300

700

1000

1200

100

500

800

1000

Repeat Steps 4-6

350

500

300

400

150

300

per liter.)

Countercurrent multiplier system in the loop of Henle for producing a hyperosmotic renal medulla. (Numerical values are in mill

Figure 28–3

iosmoles

(equal to the rate of urea production), despite the

centration increases markedly, returning the

have large reductions of GFR, the plasma urea con-

tration rate (GFR). In patients with renal disease who

determined mainly by two factors: (1) the concentra-

load of urea. In general, the rate of urea excretion is

impairment of urine concentrating ability.

whose protein intake and urea production are low.

people who ingest a high-protein diet, yielding large

The fundamental role of urea in contributing to

eventually, in the urine, even though urea is being

vated. The simultaneous movement of water and urea

collecting duct even more when ADH levels are ele-

urea transporters, UT-AI, is activated by ADH,

. One of these

into the renal interstitium. This diffusion is greatly

uid. This high concentration of

sorption takes place, causing an even higher concen-

inner medullary collecting ducts, still more water reab-

of the tubule. Then, as the tubular

1). In the presence of high concentrations of ADH,

these segments are impermeable to urea (see Table

cal collecting tubules, little urea is reabsorbed because

renal medulla is as follows: As water

The mechanism for reabsorption of urea into the

trations of ADH are high, large amounts of urea are

tubule. When there is water de

sodium chloride, urea is passively reabsorbed from the

is forming a maximally concentrated urine. Unlike

interstitium. However, urea contributes about 40

Thus far, we have considered only the contribution of

Renal Medullary Interstitium and to a

cits of body water.

the kidneys form a highly concentrated urine, excret-

3). Thus, by reabsorbing as much water as possible,

about 1200 mOsm/L (see Figure

the collecting ducts become permeable to water, so

venous blood. When high levels of ADH are present,

added to the cortex interstitium. The reabsorbed water

uid into the interstitium, but the total

lecting ducts, there is further water reabsorption from

owing peritubular capillaries.

tubule into the cortex interstitium, where it is swept

tubule becomes highly permeable to water, so that

high concentration of ADH, the cortical collecting

solutes and further dilutes the urine. When there is a

ADH, this segment is almost impermeable to water

the plasma concentration of ADH. In the absence of

ows into the cortical collecting tubule, the

atively impermeable to water.

segment, like the ascending loop of Henle, actively

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

353

tubule further dilutes the tubular fluid because this

transports sodium chloride out of the tubule but is rel-

As fluid fl

amount of water reabsorbed is critically dependent on

and fails to reabsorb water but continues to reabsorb

large amounts of water are now reabsorbed from the

away by the rapidly fl
The fact that these large amounts of water are reab-
sorbed into the cortex, rather than into the renal
medulla, helps to preserve the high medullary intersti-
tial fluid osmolarity.

As the tubular fluid flows along the medullary col-

the tubular fl
amount of water is relatively small compared with that

is quickly carried away by the vasa recta into the

that the fluid at the end of the collecting ducts has
essentially the same osmolarity as the interstitial fluid
of the renal medulla—
28–

ing normal amounts of solutes in the urine while
adding water back to the extracellular fluid and com-
pensating for defi

Urea Contributes to Hyperosmotic

Concentrated Urine

sodium chloride to the hyperosmotic renal medullary

to 50 per cent of the osmolarity (500-600 mOsm/L) of
the renal medullary interstitium when the kidney

ficit and blood concen-

passively reabsorbed from the inner medullary col-
lecting ducts into the interstitium.

flows up the

ascending loop of Henle and into the distal and corti-

28–
water is reabsorbed rapidly from the cortical col-
lecting tubule and the urea concentration increases
rapidly because urea is not very permeant in this part

fluid flows into the

tration of urea in the fl
urea in the tubular fluid of the inner medullary col-
lecting duct causes urea to diffuse out of the tubule

facilitated by specific urea transporters

increasing transport of urea out of the inner medullary

out of the inner medullary collecting ducts maintains
a high concentration of urea in the tubular fluid and,

reabsorbed.

urine concentrating ability is evidenced by the fact that

amounts of urea as a nitrogenous “waste” product,
can concentrate their urine much better than people

Malnutrition is associated with a low urea concentra-
tion in the medullary interstitium and considerable

Recirculation of Urea from Collecting Duct to Loop of Henle
Contributes to Hyperosmotic Renal Medulla.

A person

usually excretes about 20 to 50 per cent of the filtered

tion of urea in the plasma and (2) the glomerular fil-

filtered

urea load and urea excretion rate to the normal level

reduced GFR.

NaCl

Urea

1200

Medulla

Cortex

NaCl

300

100

300

600

1200

NaCl

600

1200

Urea

NaCl

600

300

1200 mOsm/L. (Numerical values are in milliosmoles per liter.)

the renal medullary interstitial fluid in the papilla, which is about

is dilute but becomes concentrated as water is absorbed from the

(ADH) levels are high. Note that the fluid leaving the loop of Henle

Formation of a concentrated urine when antidiuretic hormone

Figure 28–4

distal tubules and collecting tubules. With high ADH levels, the
osmolarity of the urine is about the same as the osmolarity of

solute exchange across the vasa recta, there is little net

Thus, although there is a large amount of

toward the cortex, it becomes progressively less

the medullary interstitium. As blood ascends back

centration of about 1200 mOsm/L, the same as that of

blood reaches the tips of the vasa recta, it has a con-

loss of water into the interstitium. By the time the

becomes progressively more concentrated, partly

descends into the medulla toward the papillae, it

the blood, except for the plasma proteins. As blood

other capillaries, are highly permeable to solutes in

of the cortex and renal medulla. The vasa recta, like

6): Blood enters and leaves the

follows (Figure 28

The countercurrent exchange mechanism operates as

The vasa recta serve as countercurrent exchangers

This sluggish blood

ow.

, accounting for

The medullary blood flow is low

There are two special features of the renal

system, the solutes pumped into the renal medulla by

the kidney. Without a special medullary blood

of the Renal Medulla

Countercurrent Exchange in the Vasa

urea, and more urea is excreted in the urine.

levels of ADH, the inner medullary collecting ducts

When there is excess water in the body and low

is in short supply.

ucts that must be excreted by the kidneys, this mech-

This urea recirculation provides an additional mech-

excreted. Each time around the circuit contributes to

this way, urea can recirculate through these terminal

back down into the medullary collecting duct again. In

the distal tubule, the cortical collecting tubule, and

it passes upward through the ascending loop of Henle,

eventually diffuses into the thin loop of Henle, so that

into the medullary interstitium. A moderate share of

duct, the high tubular

uid concentration of urea. And as

of ADH are present, the reabsorption of water from

sorption occurs in these tubular segments. When the

tively impermeable to urea, and very little urea reab-

tubule, and the cortical collecting tubule are all rela-

The thick limb of the loop of Henle, the distal

loop of Henle from the medullary interstitium (Figure

segments of the loop of Henle, partly because of water

nearly as permeant as water. The concentration of urea

tered urea is reabsorbed, but even so, the tubular

In the proximal tubule, 40 to 50 per cent of the

354

Unit V

The Body Fluids and Kidneys

fil-

fluid

urea concentration increases because urea is not

continues to rise as the tubular fluid flows into the thin

reabsorption out of the descending loop of Henle but
also because of some secretion of urea into the thin

28–5).

kidney is forming a concentrated urine and high levels

the distal tubule and cortical collecting tubule further
raises the tubular fl
this urea flows into the inner medullary collecting

fluid concentration of urea

and specific urea transporters cause urea to diffuse

the urea that moves into the medullary interstitium

parts of the tubular system several times before it is

a higher concentration of urea.

anism for forming a hyperosmotic renal medulla.
Because urea is one of the most abundant waste prod-

anism for concentrating urea before it is excreted is
essential to the economy of the body fluid when water

have a much lower permeability to both water and

Recta Preserves Hyperosmolarity

Blood flow must be provided to the renal medulla to
supply the metabolic needs of the cells in this part of

flow

the countercurrent multiplier system would be rapidly
dissipated.

medullary blood flow that contribute to the preserva-
tion of the high solute concentrations:
1.

less than 5 per cent of the total renal blood fl

flow is sufficient to supply

the metabolic needs of the tissues but helps to
minimize solute loss from the medullary
interstitium.

minimizing washout of solutes from the medullary
interstitium.

–

medulla by way of the vasa recta at the boundary

by solute entry from the interstitium and partly by

concentrated as solutes diffuse back out into the
medullary interstitium and as water moves into the
vasa recta.

fluid and

dilution of the concentration of the interstitial fluid at
each level of the renal medulla because of the U shape

Urea

500

550

300

Urea

20% remaining

100% remaining

50% remaining

100%

remaining

4.5

Cortex

Outer

medulla

Inner

medulla

4.5

tubules are indicated in the boxes.)

present. Percentages of the filtered load of urea that remain in the

antidiuresis, when large amounts of antidiuretic hormone are

urea. (Numerical values are in milliosmoles per liter of urea during

ducts, indicate that these segments are not very permeable to

the thick ascending loop of Henle to the medullary collecting

hyperosmolarity of the renal medulla. The heavy dark lines, from

helps to trap urea in the renal medulla and contributes to the

passes back into the collecting duct. The recirculation of urea

Henle, and then passes through the distal tubules, and finally

into the interstitial fluid. This urea diffuses into the thin loop of

Recirculation of urea absorbed from the medullary collecting duct

Figure 28–5

becomes very dilute, falling to a concentration of

the tubule into the medullary interstitium. Therefore,

sium, and other ions are actively transported from

to water, but large amounts of sodium, chloride, potas-

The thick part of the

Thick Ascending Loop of Henle.

prevent its washout from the renal medulla. This

also diffuses into the ascending limb, thereby return-

remains in the tubule. Some of the urea absorbed into

Thus, the tubular

removal from the descending loop of Henle, there is

uid, owing to water

sodium chloride. Because of the high concentration of

The thin ascending limb is

Thin Ascending Loop of Henle.

volume of dilute urine.

larity also becomes less concentrated. This is due

consequently, the descending loop tubular

formed, owing to low ADH concentrations, the med-

tration of ADH is high. When a dilute urine is being

urea. Therefore, the osmolarity of the

medulla. The descending limb is highly permeable to

descending loop of Henle, water is absorbed into the

Descending Loop of Henle.

ltrate, 300 mOsm/L.

osmosis. Therefore, the osmolarity of the

able to water, so that whenever solutes are reabsorbed,

However, the tubular membranes are highly perme-

electrolytes are reabsorbed in the proximal tubule.

Proximal Tubule.

nephron are shown in Figure 28

The changes in osmolarity and volume of the tubular

of the Tubules

Osmolarity in Different Segments

Mechanism and Changes in

with maximal levels of ADH, urine concentrating

uid. Even

mined not only by the level of ADH but also by the

urine concentrating ability. As discussed earlier,

out the hyperosmotic interstitium, thereby reducing

ing maximum urine concentrating ability. Large

ow, thereby

ing Ability.

Increased Medullary Blood Flow Can Reduce Urine Concentrat-

absorbed from the medullary tubules, and the high

laries. Thus, under steady-state conditions, the vasa

The U-shaped structure of the vessels minimizes

rent exchangers.

of the vasa recta capillaries, which act as countercur-

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

355

Thus, the vasa recta do not create the

medullary hyperosmolarity, but they do prevent it from
being dissipated.

loss of solute from the interstitium but does not
prevent the bulk flow of fluid and solutes into the
blood through the usual colloid osmotic and hydro-
static pressures that favor reabsorption in these capil-

recta carry away only as much solute and water as is

concentration of solutes established by the counter-
current mechanism is maintained.

Certain vasodilators can markedly increase

renal medullary blood fl

“washing out”

some of the solutes from the renal medulla and reduc-

increases in arterial pressure can also increase the
blood flow of the renal medulla to a greater extent
than in other regions of the kidney and tend to wash

maximum concentrating ability of the kidney is deter-

osmolarity of the renal medulla interstitial fl

ability will be reduced if medullary blood flow
increases enough to reduce the hyperosmolarity in the
renal medulla.

Summary of Urine Concentrating

fluid as it passes through the different parts of the

–7.

About 65 per cent of the filtered

water also diffuses through the tubular membrane by

fluid remains

about the same as the glomerular fi

As fluid flows down the

water but much less permeable to sodium chloride and

fluid flowing

through the descending loop gradually increases until
it is equal to that of the surrounding interstitial fluid,
which is about 1200 mOsm/L when the blood concen-

ullary interstitial osmolarity is less than 1200 mOsm/L;

fluid osmo-

partly to the fact that less urea is absorbed into the
medullary interstitium from the collecting ducts when
ADH levels are low and the kidney is forming a large

essentially impermeable to water but reabsorbs some

sodium chloride in the tubular fl

some passive diffusion of sodium chloride from the
thin ascending limb into the medullary interstitium.

fluid becomes more dilute as the

sodium chloride diffuses out of the tubule and water

the medullary interstitium from the collecting ducts

ing the urea to the tubular system and helping to

urea

recycling is an additional mechanism that contributes
to the hyperosmotic renal medulla.

ascending loop of Henle is also virtually impermeable

fluid in the thick ascending limb of the loop of Henle

about 100 mOsm/L.

Vasa recta

mOsm/L

Interstitium

mOsm/L

300

600

900

1200

600

1000

Solute

800

350

300

600

800

1000

600

800

1000

1200

in milliosmoles per liter.)

the U shape of the vasa recta capillaries. (Numerical values are

amounts of solutes would be lost from the renal medulla without

interstitial fluid and water diffuses back into the vasa recta. Large

ascending limb of the vasa recta, solutes diffuse back into the

of solutes from the renal interstitial fluid into the blood. In the

motic because of diffusion of water out of the blood and diffusion

the descending limb of the vasa recta becomes more hyperos-

Countercurrent exchange in the vasa recta. Plasma flowing down

Figure 28–6

large amounts of solute must be excreted, they must

amount of solute that must be excreted. Therefore, if

, which is dictated by the

nally, we should keep in mind that there is

This is accomplished by decreasing ADH secretion,

solutes to maintain the highly concentrated urine.

terone, which together cause avid sodium reabsorption

discussed in Chapter 29, low sodium intake stimulates

dehydration accompanied by low sodium intake. As

and creatinine. One condition in which this occurs is

other solutes, especially of waste products such as urea

. The hyperosmolarity of the urine in

sodium chloride

may not be obvious from this discussion. First,

There are several important points to consider that

centrating ability of the kidney.

medullary interstitium. This absorption of the urea

diffusion, much of the highly concentrated urea in

uid, and because the inner medullary collecting ducts

duced when ADH levels are high. Because water reab-

medullary interstitium (1200 to 1400 mOsm/L). Thus,

until osmotic equilibrium is reached, with the tubular

ADH, these ducts are highly permeable to water, and

rent mechanism. In the presence of large amounts of

depends on (1) ADH and (2) the osmolarity of the

The concentration of

Inner Medullary Collecting Ducts.

of ions from these segments.

cal collecting tubule; therefore, osmolarity decreases

excreted in the urine. In the absence of ADH, little

ducts, from which it is eventually reabsorbed or

concentration as water is reabsorbed. This allows most

this part of the nephron, resulting in increased urea

reabsorbed. Urea, however, is not very permeant in

able to water, and signi

high levels of ADH, these tubules are highly perme-

uid depends on the level of ADH. With

distal tubule and cortical collecting tubules, the osmo-

Late Distal Tubule and Cortical Collecting Tubules.

in the tubule.

Henle, so that further dilution of the tubular

The early distal tubule has proper-

Early Distal Tubule.

356

Unit V

The Body Fluids and Kidneys

ties similar to those of the thick ascending loop of

fluid

occurs as solutes are reabsorbed while water remains

In the late

larity of the fl

ficant amounts of water are

of the urea delivered to the distal tubule and collect-
ing tubule to pass into the inner medullary collecting

water is reabsorbed in the late distal tubule and corti-

even further because of continued active reabsorption

fluid in the inner medullary collecting ducts also

medullary interstitium established by the countercur-

water diffuses from the tubule into the interstitium

fluid having about the same concentration as the renal

a very concentrated but small volume of urine is pro-

sorption increases urea concentration in the tubular

fl
have specific urea transporters that greatly facilitate

the ducts diffuses out of the tubular lumen into the

into the renal medulla contributes to the high osmo-
larity of the medullary interstitium and the high con-

although sodium chloride is one of the principal
solutes that contributes to the hyperosmolarity of the
medullary interstitium, the kidney can, when needed,
excrete a highly concentrated urine that contains little

these circumstances is due to high concentrations of

formation of the hormones angiotensin II and aldos-

from the tubules while leaving the urea and other

Second, large quantities of dilute urine can be

excreted without increasing the excretion of sodium.

which reduces water reabsorption in the more distal
tubular segments without significantly altering sodium
reabsorption.

And fi

an obligatory urine volume
maximum concentrating ability of the kidney and the

be accompanied by the minimal amount of water

125 ml 44 ml

fect of

ADH

Osmolarity (mOsm/L)

Diluting segment

Late distal

Cortical

Medullary

1200

900

600

300

200

100

Proximal

tubule

25 ml

Distal

tubule

Collecting

tubule

and duct

Urine

20 ml

8 ml

0.2 ml

25 ml

Loop of Henle

ing along the different tubular

cal values indicate the approxi-

antidiuretic hormone (ADH) and

the presence of high levels of

the different tubular segments in

tubular fluid as it passes through

Figure 28–7

Changes in osmolarity of the

in the absence of ADH. (Numeri-

mate volumes in milliliters per
minute or in osmolarities in mil-
liosmoles per liter of fluid flow-

segments.)

positive.

free water,

in excess of solutes. Thus, water free of solutes, called

water clearance will be a positive value, denoting that

urine osmolarity is less than plasma osmolarity), free-

When the kidneys are forming a dilute urine (that is,

cits.

water back to the systemic circulation, as occurs during

excess of solutes, the kidneys are actually returning

1 ml/min. This means

rate is 1 ml/min and osmolar clearance is 2 ml/min,

Using the example discussed earlier, if urine

clearance is negative, excess solutes are being removed

water is being excreted by the kidneys; when free-water

kidneys. When free-water clearance is positive, excess

Thus, the rate of free-water clearance represents the

Free-

Assessed Using the Concept of “Free-Water Clearance.”

Relative Rates at Which Solutes and Water Are Excreted Can Be

being cleared of solute each minute.

(2.0 ml/min). This means that 2 milliliters of plasma are

0.6 mOsm/min divided by 300 mOsm/L, or 0.002 L/min

min), the rate of osmolar excretion is 0.6 mOsm/min

600 mOsm/L, and urine

plasma osmolarity is 300 mOsm/L, urine osmolarity is

is the plasma osmolarity. For example, if

rate, and P

is the urine osmolarity, V is the urine

volume of plasma cleared of solutes each minute, in

); this is the

expressed as the

The total clearance of solutes from the blood can be

is concentrated, solutes are excreted in excess of water.

excreted in excess of solutes. Conversely, when the urine

what independently. When the urine is dilute, water is

The process of concentrating or diluting the urine

“Free Water” and

liosmoles of solute must be excreted each day, this

necessary to excrete them. For example, if 1200 mil-

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

357

requires at least 1 liter of urine if maximal urine con-
centrating ability is 1200 mOsm/L.

Quantifying Renal Urine
Concentration and Dilution:

Osmolar Clearances

requires the kidneys to excrete water and solutes some-

osmolar clearance (C

osm

the same way that clearance of a single substance is cal-
culated:

where U

osm

flow

osm

flow rate is 1 ml/min (0.001 L/

(600 mOsm/L

¥ 0.001 L/min) and osmolar clearance is

water clearance (C

) is calculated as the difference

between water excretion (urine flow rate) and osmolar
clearance:

rate at which solute-free water is excreted by the

from the blood by the kidneys and water is being
conserved.

flow

free-water clearance would be

that instead of water being cleared from the kidneys in

water defi

Thus, whenever urine osmolarity is greater

than plasma osmolarity, free-water clearance will be neg-
ative, indicating water conservation.

water is being removed from the plasma by the kidneys

“

” is being lost from the body and the plasma

is being concentrated when free-water clearance is

H O

osm

V C

osm

(

)

(

)

osm

and tetracyclines (used as antibiotics), can impair the

urine concentrating ability. And certain drugs, such as

trolyte reabsorption by this segment, can compromise

loop of Henle, as occurs with diuretics that inhibit elec-

renal medulla. Also, impairment of the function of the

trating mechanism, especially those that damage the

formed, which tends to cause dehydration unless

ADH. In either case, large volumes of dilute urine are

kidneys. This abnormality can be due to either failure of

“nephrogenic” diabetes

This condition is referred to as

renal tubular segments cannot respond appropriately.

normal or elevated levels of ADH are present but the

There are circumstances in which

or orally, and rapidly restores urine output toward

Desmopressin can be given by injection, as a nasal spray,

permeability in the late distal and collecting tubules.

which acts selectively on V

istration of a synthetic analog of ADH,

The treatment for central diabetes insipidus is admin-

dehydration can rapidly occur.

scious (for example, because of a head injury), severe

intake is restricted, as can occur in a hospital setting

the large volume of dilute urine. However, if water

uid water do not occur. The primary abnormal-

as the person drinks enough water, large decreases in

excessive water is lost from the body; therefore, as long

nisms, discussed later in this chapter, are activated when

volumes that can exceed 15 L/day. The thirst mecha-

formation of a large volume of dilute urine, with urine

, results in the

“central” diabetes insipidus

dition, called

cannot reabsorb water in the absence of ADH, this con-

it can be congenital. Because the distal tubular segments

pituitary can be caused by head injuries or infections, or

inability to produce or release ADH from the posterior

collecting ducts to respond to ADH.

much ADH is present, maximal urine concentration

maximal urine concentrating ability. No matter how

Impairment of the countercurrent mechanism.

uid handling by the kidneys.

or too little ADH secretion results in abnormal

Inappropriate secretion of ADH.

Disorders of Urinary
Concentrating Ability

An impairment in the ability of the kidneys to concen-
trate or dilute the urine appropriately can occur with
one or more of the following abnormalities:
1.

Either too much

hyperosmotic medullary interstitium is required for

is limited by the degree of hyperosmolarity of the
medullary interstitium.

3. Inability of the distal tubule, collecting tubule, and

Failure to Produce ADH: “Central” Diabetes Insipidus.

body fl
ity observed clinically in people with this condition is

when fluid intake is restricted or the patient is uncon-

desmopressin,

receptors to increase water

normal.

Inability of the Kidneys to Respond to ADH: “Nephrogenic”
Diabetes Insipidus.

insipidus because the abnormality resides in the

the countercurrent mechanism to form a hyperosmotic
renal medullary interstitium or failure of the distal and
collecting tubules and collecting ducts to respond to

fluid

intake is increased by the same amount as urine volume
is increased.

Many types of renal diseases can impair the concen-

lithium (used to treat manic-depressive disorders)

ability of the distal nephron segments to respond to
ADH.

cells in the supraoptic nuclei, which then relay

re, sending nerve signals to additional nerve

2. Shrinkage of the osmoreceptor cells causes them

nuclei, to shrink.

, located in

1. An increase in extracellular

example, this feedback system operates as follows:

cit, for

ity. When osmolarity (plasma sodium concentration)

osmoreceptor-ADH feedback system for control of

Figure 28

Osmoreceptor-ADH

uid: (1) the osmoreceptor-ADH system and

of sodium and water excretion by the kidneys, two

ion concentration at the same time.

ment across the cell membrane. Consequently, we can

pressure under steady-state conditions. Therefore, the

most cell membranes, it exerts little

osmoles. However, because urea easily permeates

per cent of the extracellular osmoles, with glucose and

Normally, sodium ions and associated anions (pri-

percentage points of those measured directly.

glucose and urea, should be included. Such estimates

renal disease, the contribution of two other solutes,

be more exact, especially in conditions associated with

from the formula above to be about 298 mOsm/L. To

142 mEq/L, the plasma osmolarity would be estimated

For instance, with a plasma sodium concentration of

solute in the extracellular compartment, plasma osmo-

routinely measured. However, because sodium and its

In most clinical laboratories, plasma osmolarity is not

Plasma Sodium Concentration

compartments.

discussed in Chapter 25, these variables must be pre-

2 to 3 per cent. As

L, with an average concentration of about 142 mEq/L.

compartment. Plasma sodium concentration is nor-

Control of Extracellular Fluid

diuretic.

enhances renal sodium excretion, such as a thiazide

disorder. The hypernatremia can also be attenuated by

insipidus is to correct, if possible, the underlying renal

betes insipidus. The treatment for nephrogenic diabetes

desmopressin, the synthetic analog of ADH. Lack of a

358

Unit V

The Body Fluids and Kidneys

Nephrogenic diabetes insipidus can be distinguished

from central diabetes insipidus by administration of

prompt decrease in urine volume and an increase in
urine osmolarity within 2 hours after injection of
desmopressin is strongly suggestive of nephrogenic dia-

a low-sodium diet and administration of a diuretic that

Osmolarity and Sodium
Concentration

Regulation of extracellular fluid osmolarity and
sodium concentration are closely linked because
sodium is the most abundant ion in the extracellular

mally regulated within close limits of 140 to 145 mEq/

Osmolarity averages about 300 mOsm/L (about
282 mOsm/L when corrected for interionic attraction)
and seldom changes more than

cisely controlled because they determine the distribu-
tion of fluid between the intracellular and extracellular

Estimating Plasma Osmolarity from

associated anions account for about 94 per cent of the

larity (P

osm

) can be roughly approximated as

osm

= 2.1 ¥ Plasma sodium concentration

of plasma osmolarity are usually accurate within a few

marily bicarbonate and chloride) represent about 94

urea contributing about 3 to 5 per cent of the total

effective osmotic

sodium ions in the extracellular fluid and associated
anions are the principal determinants of fluid move-

discuss the control of osmolarity and control of sodium

Although multiple mechanisms control the amount

primary systems are especially involved in regulating
the concentration of sodium and osmolarity of extra-
cellular fl
(2) the thirst mechanism.

Feedback System

–8 shows the basic components of the

extracellular fluid sodium concentration and osmolar-

increases above normal because of water defi

fluid osmolarity

(which in practical terms means an increase in
plasma sodium concentration) causes the special
nerve cells called osmoreceptor cells
the anterior hypothalamus near the supraoptic

to fi

Water deficit

Extracellular osmolarity

Osmoreceptors

Plasma ADH

ADH secretion

(posterior pituitary)

O permeability in

distal tubules,

collecting ducts

O reabsorption

O excreted

for regulating extracellular fluid osmolarity in response to a water

Osmoreceptor-antidiuretic hormone (ADH) feedback mechanism

Figure 28–8

deficit.

uid osmolarity.

ring and secretion of ADH.

neurons. These cells send nerve signals to the supraop-

uid osmolarity; hence, the

In the vicinity of the AV3V region and the supraop-

thirst, and sodium appetite.

ulation by angiotensin II can alter ADH secretion,

pressure. Electrical stimulation of this region or stim-

of ADH secretion, thirst, sodium appetite, and blood

the AV3V region cause multiple de

control centers in the medulla of the brain. Lesions of

median preoptic nucleus,

. Between these two

, and at the infe-

. At the upper part of this region is a

AV3V region

, called the

anteroventral region of the third ventricle

osmolarity and ADH secretion is located along the

means for altering renal excretion of water.

severalfold within minutes, thereby providing a rapid

lus is rapid, so that plasma ADH levels can increase

Secretion of ADH in response to an osmotic stimu-

response to increased calcium entry. The released

entry. ADH stored in the secretory granules (also

impulses pass down these nerve endings, changing

lated by increased osmolarity or other factors, nerve

tips, terminating in the posterior pituitary gland. When

the posterior pituitary. Once ADH is synthesized, it is

nuclei. Both of these nuclei have axonal extensions to

, about

magnocellular (large) neurons that synthesize

sized and released. The hypothalamus contains two

amus and the pituitary gland, where ADH is synthe-

Figure 28

Hypothalamus and ADH Release

of dilute urine is formed. This in turn concentrates the

for water, less water is reabsorbed, and a large volume

formed, the renal tubules decrease their permeability

uid osmolarity, less ADH is

For example, with excess water ingestion and a

The opposite sequence of events occurs when the

other solutes continue to be excreted in the urine. This

Thus, water is conserved in the body while sodium and

concentrated urine.

5. The increased water permeability in the distal

collecting tubules, and medullary collecting ducts.

permeability of the late distal tubules, cortical

to the kidneys, where it increases the water

4. ADH enters the blood stream and is transported

nerve endings.

pituitary stimulate the release of ADH, which is

3. These action potentials conducted to the posterior

to the posterior pituitary.

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

359

these signals down the stalk of the pituitary gland

stored in secretory granules (or vesicles) in the

nephron segments causes increased water
reabsorption and excretion of a small volume of

causes dilution of the solutes in the extracellular fluid,
thereby correcting the initial excessively concentrated
extracellular fluid.

extracellular fluid becomes too dilute (hypo-osmotic).

decrease in extracellular fl

body fluids and returns plasma osmolarity toward
normal.

ADH Synthesis in Supraoptic and
Paraventricular Nuclei of the

from the Posterior Pituitary

–9 shows the neuroanatomy of the hypothal-

types of
ADH in the supraoptic and paraventricular nuclei of
the hypothalamus

five sixths in the supraoptic

nuclei and about one sixth in the paraventricular

transported down the axons of the neurons to their

the supraoptic and paraventricular nuclei are stimu-

their membrane permeability and increasing calcium

called vesicles) of the nerve endings is released in

ADH is then carried away in the capillary blood of the
posterior pituitary into the systemic circulation.

A second neuronal area important in controlling

structure called the subfornical organ
rior part is another structure called the organum vas-
culosum of the lamina terminalis
organs is the

which has mul-

tiple nerve connections with the two organs as well as
with the supraoptic nuclei and the blood pressure

ficits in the control

tic nuclei are neuronal cells that are excited by small
increases in extracellular fl
term osmoreceptors has been used to describe these

tic nuclei to control their fi
It is also likely that they induce thirst in response to
increased extracellular fl

ADH

Urine:
decreased flow
and concentrated

Baroreceptors
Cardiopulmonary
receptors

Paraventricular
neuron

Osmoreceptors

Pituitary

Posterior
lobe

Anterior
lobe

Supraoptic

neuron

ADH is released.

(ADH) is synthesized, and the posterior pituitary gland, where

Neuroanatomy of the hypothalamus, where antidiuretic hormone

Figure 28–9

2. For example,

by various drugs and hormones, as shown in Table

Other Stimuli for ADH Secretion

osmolarity.

greatly enhances the ADH response to increased

plasma osmolarity. Decreased blood volume, however,

usual day-to-day regulation of ADH secretion during

play a major role in stimulating ADH secretion. The

decreases in blood volume, the cardiovascular re

volume, ADH levels rapidly increase. Thus, with severe

about 10 per cent. With further decreases in blood

contrast, after blood loss, plasma ADH levels do not

cient to increase ADH levels. By

For example, a change in plasma osmolarity of only

osmolarity than to similar changes in blood volume.

osmolarity stimulates ADH secretion. However, ADH

10, either a decrease in effec-

As shown in Figure 28

Osmolarity in Stimulating

uid reabsorption by the kidneys,

occurs during hemorrhage, increased ADH secretion

blood pressure and blood volume are reduced, such as

pressure and (2) decreased blood volume. Whenever

stimuli increase ADH secretion: (1) decreased arterial

Thus, in addition to increased osmolarity, two other

the tractus solitarius. Projections from these nuclei

atria. Afferent stimuli are carried by the vagus and

in the low-pressure regions, especially in the cardiac

culation, such as the aortic arch and carotid sinus, and

both of which are discussed in Chapter 18. These re

the cardiopulmonary reflexes

and (2)

ceptor reflexes

and/or blood volume, including (1) the

Blood Volume

of ADH Release by Decreased

tion of ADH and over thirst, as discussed later.

uid, exerting powerful control over the secre-

uid in this region. As a result, the osmoreceptors

tissue. This makes it possible for ions and other solutes

360

Unit V

The Body Fluids and Kidneys

Both the subfornical organ and the organum vascu-

losum of the lamina terminalis have vascular supplies
that lack the typical blood-brain barrier that impedes
the diffusion of most ions from the blood into the brain

to cross between the blood and the local interstitial
fl
rapidly respond to changes in osmolarity of the extra-
cellular fl

Cardiovascular Reflex Stimulation

Arterial Pressure and/or Decreased

ADH release is also controlled by cardiovascular
reflexes that respond to decreases in blood pressure

arterial barore-

flex

pathways originate in high-pressure regions of the cir-

glossopharyngeal nerves with synapses in the nuclei of

relay signals to the hypothalamic nuclei that control
ADH synthesis and secretion.

causes increased fl
helping to restore blood pressure and blood volume
toward normal.

Quantitative Importance of
Cardiovascular Reflexes and

ADH Secretion

–

tive blood volume or an increase in extracellular fluid

is considerably more sensitive to small changes in

1 per cent is suffi

change appreciably until blood volume is reduced by

flexes

simple dehydration is effected mainly by changes in

ADH secretion can also be increased or decreased by
other stimuli to the central nervous system as well as

28–

nausea is a potent stimulus for

0.1

AVP

Plasma ADH

(pg/ml)

Per cent change

= 2.5

Osm + 2.0

= 1.3 e

–

7 vol.

Isotonic volume depletion
Isovolemic osmotic increase

By copyright permission of the

lality and volume in regulating vasopressin secretion in the rat. J

Brennan TJ, Nelson AE, Robertson GL: The role of blood osmo-

called arginine vasopressin (AVP). (Redrawn from Dunn FL,

volume on the level of plasma (P) antidiuretic hormone (ADH), also

The effect of increased plasma osmolarity or decreased blood

Figure 28–10

Clin Invest 52(12):3212, 1973.
American Society of Clinical Investigation.)

Table 28–2

Nicotine

Clonidine (antihypertensive drug)

Morphine

Alcohol

Drugs:

Increase ADH

Decrease ADH

Regulation of ADH Secretion

≠ Plasma osmolarity

Ø Plasma osmolarity

Ø Blood volume

≠ Blood volume

Ø Blood pressure

≠ Blood pressure

Nausea
Hypoxia

Cyclophosphamide

Haloperidol (dopamine blocker)

person would continue to drink more and more, even-

were not temporarily relieved after drinking water, the

tributed throughout the body. If the thirst sensation

After a person drinks water, 30 to 60 minutes may be

The ability of animals and humans to

mechanisms is short-lived; the desire to drink is com-

stomach can relieve thirst. However, relief of thirst

thirst; for instance, simple in

drinking, although the relief is only temporary. Also,

into the blood, partial relief of thirst occurs after

. For example, in animals that have an esophageal

uid osmolarity.

immediately after drinking water, even though the

can elicit the sensation of thirst. As a result,

sure toward normal, along with the other actions

with hypovolemia and low blood pressure, its effect on

angiotensin II diffuse into the tissues. Because

outside the blood-brain barrier, and peptides such as

losum of the lamina terminalis. These regions are

A third important stimulus for thirst is angiotensin II

in plasma osmolarity. This probably occurs because of

osmolarity. Thus, blood volume loss by hemorrhage

obvious: it helps to dilute extracellular

the sensation of thirst. The value of this response is

, thereby stimulating

cellular fluid osmolarity, which causes intracellular

thirst. One of the most important is

Table 28

this response.

the AV3V region, is intimately involved in mediating

, which lies immediately

promote drinking. It is likely that the

release.

the same way that the osmoreceptors stimulate ADH

osmoreceptors to activate the thirst mechanism, in

ing behavior. These cells almost certainly function as

The neurons of the thirst center respond to injec-

lasts. All these areas together are called the

area that, when stimulated electrically, causes immedi-

motes ADH release also stimulates thirst. Located

9, the same area along

Referring again to Figure 28

Central Nervous System Centers

scious desire for water.

tion also increase thirst, which is de

Many of the same factors that stimulate ADH secre-

mechanism, maintains precise control of extracellular

anism, which, together with the osmoreceptor-ADH

nal tract. Fluid intake is regulated by the thirst mech-

uid intake, however, is necessary to coun-

through the osmoreceptor-ADH feedback system.

The kidneys minimize

Role of Thirst in Controlling

is due in part to inhibition of ADH release.

, inhibit ADH release. The

some drugs, such as

stimulate ADH release, whereas

times normal after vomiting. Also, drugs such as

ADH release, which may increase to as much as 100

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

361

nico-

tine and morphine

alcohol

marked diuresis that occurs after ingestion of alcohol

Extracellular Fluid Osmolarity
and Sodium Concentration

fluid loss during water deficits

Adequate fl
terbalance whatever fluid loss does occur through
sweating and breathing and through the gastrointesti-

fluid osmolarity and sodium concentration.

fined as the con-

for Thirst

–

the anteroventral wall of the third ventricle that pro-

anterolaterally in the preoptic nucleus is another small

ate drinking that continues as long as the stimulation

thirst

center.

tions of hypertonic salt solutions by stimulating drink-

Increased osmolarity of the cerebrospinal fluid in

the third ventricle has essentially the same effect to

organum vascu-

losum of the lamina terminalis
beneath the ventricular surface at the inferior end of

Stimuli for Thirst

–3 summarizes some of the known stimuli for

increased extra-

dehydration in the thirst centers

fluids and

returns osmolarity toward normal.

Decreases in extracellular fluid volume and arterial

pressure also stimulate thirst by a pathway that is inde-
pendent of the one stimulated by increased plasma

stimulates thirst even though there might be no change

neutral input from cardiopulmonary and systemic
arterial baroreceptors in the circulation.

Studies in animals have shown that angiotensin II acts
on the subfornical organ and on the organum vascu-

angiotensin II is also stimulated by factors associated

thirst helps to restore blood volume and blood pres-

of angiotensin II on the kidneys to decrease fluid
excretion.

Dryness of the mouth and mucous membranes of the

esophagus
a thirsty person may receive relief from thirst almost

water has not been absorbed from the gastrointestinal
tract and has not yet had an effect on extracellular
fl

Gastrointestinal and pharyngeal stimuli influence

thirst
opening to the exterior so that water is never absorbed

gastrointestinal distention may partially alleviate

flation of a balloon in the

sensations through gastrointestinal or pharyngeal

pletely satisfied only when plasma osmolarity and/or
blood volume returns to normal.

“meter” fluid

intake is important because it prevents overhydration.

required for the water to be reabsorbed and dis-

tually leading to overhydration and excess dilution of

Table 28–3

Increase Thirst

Decrease Thirst

Control of Thirst

≠ Osmolarity

Ø Osmolarity

Ø Blood volume

≠ Blood volume

Ø Blood pressure

≠ Blood pressure

≠ Angiotensin

Ø Angiotensin II

Dryness of mouth

Gastric distention

12. This

the experiment of Figure 28

This relative unimportance of aldosterone in regulat-

conditions.

, except under extreme

Therefore,

sodium concentration. Although these hormones

kidneys, one might mistakenly infer that they also

versely, with high sodium intake, decreased formation of

may be reduced to as low as 10 per cent of normal. Con-

prevent large sodium losses, even though sodium intake

sodium reabsorption by the kidneys and, therefore,

is low, increased levels of these hormones stimulate

reabsorption by the renal tubules. When sodium intake

As discussed in Chapter 27, both angiotensin II and

Sodium Concentration

Aldosterone in Controlling

Role of Angiotensin II and

osmolarity.

occur. In the absence of the ADH-thirst mechanisms,

after blocking the total ADH-thirst system, relatively

controlled; thus, when sodium intake is increased

and thirst mechanisms fail simultaneously, plasma

gastrointestinal losses. However, if both the ADH

water losses caused by respiration, sweating, or

effectiveness, as long as there is enough

When either the ADH or the thirst mechanism fails,

are both functioning normally.

centration as long as the ADH and thirst mechanisms

osmolarity reasonably constant. Figure 28

intake, these feedback systems are able to keep plasma

Even with additional challenges, such as high salt

tion, despite the constant challenges of dehydration.

In a healthy person, the osmoreceptor-ADH and thirst

Mechanisms in Controlling

Integrated Responses of

and volume toward normal. In this way, the extracel-

intake, which restores extracellular

. Thus, even small increases

activated, causing a desire to drink water. This is called

about 2 mEq/L above normal, the thirst mechanism is

ity. When the sodium concentration increases only

tendency for dehydration, with resultant increased

sweating from the skin. Therefore, there is always a

olism. Water is also lost by evaporation from the lungs

uid, even in a dehydrated person, to rid the body of

The kidneys must continually excrete at least some

of Drinking

Threshold for Osmolar Stimulus

uids. Experimental studies have repeatedly

362

Unit V

The Body Fluids and Kidneys

the body fl
shown that animals drink almost exactly the amount
necessary to return plasma osmolarity and volume to
normal.

fl
excess solutes that are ingested or produced by metab-

and the gastrointestinal tract and by evaporation and

extracellular fluid sodium concentration and osmolar-

the threshold for drinking
in plasma osmolarity are normally followed by water

fluid osmolarity

lular fluid osmolarity and sodium concentration are
precisely controlled.

Osmoreceptor-ADH and Thirst

Extracellular Fluid Osmolarity and
Sodium Concentration

mechanisms work in parallel to precisely regulate
extracellular fluid osmolarity and sodium concentra-

–11 shows

that an increase in sodium intake to as high as six times
normal has only a small effect on plasma sodium con-

the other ordinarily can still control extracellular
osmolarity and sodium concentration with reasonable

fluid intake

to balance the daily obligatory urine volume and

sodium concentration and osmolarity are very poorly

large changes in plasma sodium concentration do

no other feedback mechanism is capable of ad-
equately regulating plasma sodium concentration and

Extracellular Fluid Osmolarity and

aldosterone play an important role in regulating sodium

these hormones permits the kidneys to excrete large
amounts of sodium.

Because of the importance of angiotensin II and

aldosterone in regulating sodium excretion by the

play an important role in regulating extracellular fluid

increase the amount of sodium in the extracellular fluid,
they also increase the extracellular fluid volume by
increasing reabsorption of water along with the sodium.

angiotensin II and aldosterone have little

effect on sodium concentration

ing extracellular fluid sodium concentration is shown by

–

figure shows the

effect on plasma sodium concentration of changing

Normal

ADH and
thirst
systems
blocked

120

150

180

Plasma sodium concentration (mEq/L)

Sodium intake (mEq/day)

136

152

148

144

140

feedback systems. (Courtesy Dr. David B. Young.)

). Note that control of extra-

and after the antidiuretic hormone (ADH) and thirst feedback

red line

sodium concentration in dogs under normal conditions (

Effect of large changes in sodium intake on extracellular fluid

Figure 28–11

)

systems had been blocked (blue line
cellular fluid sodium concentration is poor in the absence of these

Am J Physiol Regul Integr Comp Physiol 284:R1355, 2003.

ow.

Cowley AW Jr, Mori T, Mattson D, Zou AP: Role of renal

and salt appetite at the same time.

animals. Also, circulatory re

to be involved, because lesions in this region frequently

neuronal centers in the AV3V region of the brain seem

gous to that of the thirst mechanism. Some of the same

The neuronal mechanism for salt appetite is analo-

ciency. These are the same major stimuli that elicit thirst.

or blood pressure, associated with circulatory insuffi-

decreased sodium concentration; both of these changes

ciency of aldosterone secretion,

instance, there is de

s disease. In this

of sodium, such as occurs in Addison

ciency

urally eat a low-sodium diet, but salt craving may also

This is particularly important in herbivores, which nat-

ciency in the body.

cient. There is also a regulatory component

ostasis, and there is evidence that our usual high sodium

function normally on 10 to 20 mEq/day. Thus, most

200 mEq/day, even though humans can survive and

necessary for homeostasis. In fact, the average sodium

lizations, sodium intake is almost always greater than

sodium excretion and sodium intake. In modern civi-

and Volume

for Controlling Extracellular

with a functional ADH-thirst mechanism. Even so, the

cantly, even

Thus, there are extreme situations in which plasma

conditions.

exes. This leads to a

pressure, which can activate the thirst mechanism

reductions in plasma sodium concentration. One of the

dous loss of sodium by the kidneys, which can lead to

secretion or total lack of aldosterone), there is tremen-

patients with Addison

Under extreme conditions, caused by complete loss of

extremely high levels of aldosterone, the plasma sodium

, who have

ulating sodium concentration under normal conditions.

toward normal. The ADH-thirst system far overshad-

tion, which tends to dilute the extracellular

increased water intake or increased plasma ADH secre-

anism is functional, any tendency toward increased

Second, as long as the ADH-thirst mech-

concentrations.

tubules, leading to increases in extracellular

cussed earlier, angiotensin II and aldosterone increase

effect on plasma sodium concentration. First, as dis-

There are two primary reasons why changes in

conducted after blocking angiotensin II formation, with

well regulated. The same type of experiment has been

feedback system, plasma sodium concentration can be

changed only about 1 to 2 per cent in either case. This

intake was increased sixfold, plasma concentration

change upward or downward. Note that when sodium

Chapter 28

Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

363

sodium intake more than sixfold under two conditions:
(1) under normal conditions and (2) after the aldos-
terone feedback system has been blocked by removing
the adrenal glands and infusing the animals with aldos-
terone at a constant rate so that plasma levels could not

indicates that even without a functional aldosterone

the same result.

angiotensin II and aldosterone do not have a major

both sodium and water reabsorption by the renal

fluid

volume and sodium quantity but little change in sodium

plasma sodium concentration is compensated for by

fluid back

ows the angiotensin II and aldosterone systems for reg-

Even in patients with primary aldosteronism

concentration usually increases only about 3 to 5 mEq/L
above normal.

aldosterone secretion because of adrenalectomy or in

’s disease (severely impaired

reasons for this is that large losses of sodium eventually
cause severe volume depletion and decreased blood

through the cardiovascular refl
further dilution of the plasma sodium concentration,
even though the increased water intake helps to mini-
mize the decrease in body fluid volumes under these

sodium concentration may change signifi

ADH-thirst mechanism is by far the most powerful
feedback system in the body for controlling extracellu-
lar fluid osmolarity and sodium concentration.

Salt-Appetite Mechanism

Fluid Sodium Concentration

Maintenance of normal extracellular fluid volume and
sodium concentration requires a balance between

intake for individuals in industrialized cultures eating
processed foods usually ranges between 100 and

people eat far more sodium than is necessary for home-

intake may contribute to cardiovascular disorders such
as hypertension.

Salt appetite is due in part to the fact that animals and

humans like salt and eat it regardless of whether they
are salt-defi
to salt appetite in which there is a behavioral drive to
obtain salt when there is sodium defi

be important in humans who have extreme defi

’

which causes excessive loss of sodium in the urine and
leads to decreased extracellular fluid volume and

elicit the desire for salt.

In general, the two primary stimuli that are believed to

increase salt appetite are (1) decreased extracellular fluid
sodium concentration and (2) decreased blood volume

affect both thirst and salt appetite simultaneously in

flexes elicited by low blood

pressure or decreased blood volume affect both thirst

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210

110

Plasma sodium concentration

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100

120

130

140

150

Normal

Aldosterone system blocked

aldosterone feedback control. (Courtesy Dr. David B. Young.)

). Note that sodium concentration is maintained relatively

and after the aldosterone feedback system had been blocked

red line

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Effect of large changes in sodium intake on extracellular fluid

Figure 28–12

)

(blue line
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