ФУНКЦИИ ПОЧЕК [ functions of the kidneys ] Основными функциями (назначением, целью) почек, главных органов системы выделения, является образование мочи и выведение мочи.
В РАЗРАБОТКЕ = UNDER CONSTRUCTION
ПОЧКА: ОГЛАВЛЕНИЕ
1. Макроструктура почки.
2. Микроструктура почки.
3. Функции почки.
3.1. Образование мочи.
3.2. Выведение мочи.
3.3. Управление экскрецией натрия и воды.
3.3.1. Роль почек в регулировании системного давления крови = 104.
3.3.2. Роль почек в регулировании экскреции натрия = 110.
3.3.3. Роль почек в регулировании объёма и осмоляльности плазмы = .
3.3.4. Роль почек в экскреции воды = 131.
3.4. Роль почек в регулировании содержания в организме калия = .
3.4.1. Роль почек в регулировании соотношения содержания калия в интрацеллюлярных и экстрацеллюлярных жидкостях = 141.
3.4.2. Роль почек в экскреции калия = 143.
3.5. Регулирование содержания в организме ионов водорода = 155.
3.5.1. Кислотно-основное равновесие = 156.
3.5.2. Роль почек в регулировании кислотно-основного равновесия = 162.
3.5.3. Роль почек в экскреции кислот и оснований = 165.
3.5.4. Оценка экскреции ионов водорода по характеристикам буферов мочи = 167.
3.5.5. Фосфаты и органические кислоты как буферы = 169.
3.5.6. Оценка экскреции ионов водорода по содержанию аммония = 170.
3.5.7. Количественная оценка экскреции почками кислот и оснований = 174.
3.5.8. Регулирование выведения почками кислот и оснований = 176.
3.5.9. Участие почек в управлении метаболизмом глютамина и экскреции NH4 = 177.
3.5.10. Кровезамещающие растворы. Раствор Рингера с лактатом = 178.
3.5.11. Специфические нарушения кислотно-основного равновесия = 179.
3.5.12. Реакции почек на метаболический ацидоз и метаболический алкалоз = 180.
3.5.13. Факторы, способствующие созданию и поддержанию почками метаболического алкалоза = 181.
3.6. Регулирование равновесия в организме кальция и фосфатов = 185.
3.6.1. Эффекторы равновесия в организме кальция и фосфатов = 188.
3.6.2. Гормональная модуляция эффекторов равновесия в организме кальция и фосфатов = 192.
3.6.3. Паратиреоидный гормон = 193.
3.6.4. Экскреция почками фосфатов = 197.
4. Методики исследования функций почки.
ПОЧКА: ТАБЛИЦЫ И ИЛЛЮСТРАЦИИ.
Функции мочеобразования и мочевыведения являются непосредственным или опосредованным результатом ряда других сопряжённых функций систем организма.
1. Экскреция - в соответствии с потенциальными и актуальными потребностями организма, выведение с мочой: – негазообразных конечных продуктов метаболизма, которые не могут быть использованы в организме, – избытка воды в организме, – избытка минеральных компонентов плазмы крови и других жидкостей организма,
– чужеродных и токсических веществ.
2. Регулирование гомеостаза - вероятностной устойчивости характеристик внутренней среды для клеток и субклеточных структур организма:
– регулирование метаболизма белков, углеводов, липидов и их содержания в организме.
– регулирование метаболизма минеральных веществ и их содержания в организме.
– регулирование содержания воды в организме.
– регулирование осмотической концентрации веществ в жидкостях организма.
– регулирование кислотно-щёлочного равновесия в жидкостях организма.
3. Регулирование функций основных систем, специализированных для исполнения жизненно важных физических функций организма:
– регулирование объёма крови и внеклеточной жидкости.
– регулирование давления крови в организме.
– регулирование эритропоэза в организме.
– регулирование функций других систем.
3.3.1. Роль почек в регулировании системного давления крови.
KEY CONCEPTS
Multiple overlapping mechanisms regulate sodium and water excretion; most are
related to blood pressure.
The medullary vasomotor center regulates blood pressure on a moment-to moment
basis via the baroreceptor reflex and also regulates renal excretion of sodium
and water.
Angiotensin II is a crucial regulator of sodium excretion and blood pressure via its
actions in the kidneys, peripheral vasculature, and adrenal glands.
The regulation of sodium content is the ultimate determinant of blood pressure in
the long term via control of extracellular fluid (ECF) volume.
All the physiological controls in the proximal nephron affect the excretion of sodium
and water together, whereas the actions of aldosterone and ADH in the distal
nephron regulate sodium and water excretion independently.
Long-term regulation of sodium excretion and, therefore, blood pressure centers
on the actions of aldosterone.
ADH secretion is regulated both by blood pressure, via the baroreceptor-vasomotor
center system, and plasma osmolality via hypothalamic osmoreceptors.
REGULATION OF BLOOD PRESSURE
We choose to organize the control of sodium and water excretion around the topic
of blood pressure for 2 reasons. First, because pressures in various parts of the
vascular system have such a powerful influence on renal function, and second, because
renal actions so strongly affect blood pressures. In doing so, we will encounter
many important concepts and components. We briefly outline them here and
expand them in the ensuing discussion. First is the concept of a set-point, which is
the value that blood pressure should be at any moment (similar to the setting for
temperature on the thermostat in your house). Second are detectors of blood pressure
(“pressure gauges”), which assess the level of blood pressure at any moment.
Third are signals generated in response to changes in blood pressure sensed by the
detectors that regulate the fourth component: effectors, which change what they
do in response to the signals in order to raise or lower blood pressure and return it
to the setpoint. The effectors of blood pressure regulation are (1) the heart, which
has a variable contractility and beat rate; (2) peripheral arterioles, which determine
resistance to flow in the peripheral vasculature; (3) large veins, which change
their compliance to vary the capacity of the vascular system to hold blood; and (4)
the kidneys, which vary their output of salt and water. We will elaborate on the
renal involvement in these effectors as we go along.
The various blood pressure regulatory processes occur over different time spans.
There are immediate (within seconds) cardiovascular reflexes that are for the most
part nonrenal in nature. Then, there are slower processes spanning time scales of
minutes to days centered on renal regulation of salt and water (ie, fluid volume and
osmolality). We can arbitrarily divide regulation into short-term, intermediateterm,
and long-term processes, recognizing that those in one time domain overlap
with those in others and thus each process can interact with the others. Despite
this overlap between these systems, it still helps to conceptualize them, as we will
do below, as separate (but interacting) processes. Figure 7–1 summarizes these
relationships.
Short-Term Regulation of Blood Pressure: Cardiovascular Reflexes
Arterial blood pressure is regulated around a setpoint controlled by a set of
brainstem nuclei often called the vasomotor center. There are 2 major sets
of detectors for the short-term control of blood pressure. The most important
are baroreceptors that mediate the classic baroreceptor reflex. These are afferent
nerve cells (mechanoreceptors) with sensory endings located in the carotid arteries
and arch of the aorta. They report arterial blood pressure to the vasomotor
center via sensory neural pathways. They do this continuously on a heartbeat-byheartbeat
basis. The second set of baroreceptors is the cardiopulmonary baroreceptors.
These are also nerve cells, with sensory endings located in the cardiac atria and
parts of the pulmonary vasculature. They, like the arterial baroreceptors, send afferent
neural information to the brainstem vasomotor center. They are often called
low-pressure baroreceptors because they assess pressures in regions of the vascular
tree where pressures are much lower than in the arteries. The cardiopulmonary
Figure 7–1. Time span of arterial blood pressure regulation. Moment-to-moment regulation
is purely cardiovascular in nature (although the renal vasculature is affected because
it is part of the total peripheral resistance). Over time, control gradually shifts to
renal processes, centered on renin-angiotensin systems (RAS) control of total peripheral
resistance and excretion of sodium and water. Eventually, control is exerted chiefly by
regulating sodium and water excretion, with aldosterone as the central mediator.
baroreceptors serve as de facto blood volume detectors in the sense that pressures in
the atria and pulmonary vessels rise when blood volume increases and fall when
blood volume decreases. Their most important role lies in regulating salt and water
excretion, but their actions mix with those of the arterial baroreceptors.
On the basis of the inputs from the arterial and cardiopulmonary baroreceptors,
the vasomotor center sends regulatory signals to effector systems: the heart,
blood vessels, and kidneys via the autonomic nervous system. Changes in the
activity of the brainstem vasomotor center lead to changes in sympathetic signals
that directly regulate the actions of our first effector system: cardiac contractility
and heart rate. At the same time, these signals are sent in parallel to our second
effector system: vasoconstriction or dilation of all systemic arterioles (including
those of the kidneys), with consequent changes in peripheral vascular resistance.
When we express mean arterial pressure (MAP) as the product of cardiac output
(CO) and total peripheral resistance (TRP), ie, MAP 5 CO Ч TPR, it becomes
clear that adjusting either CO or vascular resistance directly changes MAP.
Sympathetic output from the vasomotor center is also directed to our third
effector system: the large peripheral veins. These veins contain about two thirds
of the total blood volume. When blood volume changes, almost all the change
occurs in the volume of peripheral venous blood. The compliance of the veins
(ease of being stretched) allows them to accommodate moderate changes in blood
volume. Furthermore, their compliance is a regulated variable (via contraction
or relaxation of smooth muscle in their walls). Stimulatory sympathetic signals
reduce venous compliance, ie, make the veins less stretchy. This has the effect of
squeezing on the blood in the veins and raising its pressure, a de facto shrinkage
in the capacity of the venous tree to hold blood. In contrast, a reduction in sympathetic
signals raises the venous compliance, allowing the system to hold more
blood. These adjustments are very important in terms of keeping central venous
pressure (pressure at the right atrium) appropriate for filling the cardiac chambers
between beats.
A pathological increase in venous compliance, as in certain forms of circulatory
shock, has the same effect as a major hemorrhage, because this creates an overcapacity
of the vascular system relative to its actual volume, with a resulting drop in
central venous pressure and insufficient filling of the cardiac chambers.
All of these fast effector mechanisms of the heart, arterioles, and large veins
act very rapidly when pressure begins to change as a result of muscle activity or
simple changes in posture. The result is to stabilize arterial pressure at its setpoint,
the MAP, which for most people is slightly less than 100 mm Hg. The setpoint is
not rigidly fixed; however, it varies during the day, depending on the activity and
levels of excitement, and decreases about 20% during sleep.1 As we will expand on
shortly, a complication lies in the fact that the value of the setpoint over the long
term is highly influenced by renal processes because the kidneys regulate blood
volume. That is, the renal processing of salt and water, via its control of blood volume,
ultimately determines the average value of the setpoint for blood pressure
of the brainstem vasomotor center. As long as the kidneys regulate salt and water
excretion appropriately, the average value of blood pressure over the course of a
day will be normal. However, if renal excretion is inappropriate and remains so for
several days, then the setpoint becomes reset to a new value.
As the name implies, short-term control of blood pressure through the baroreceptor
reflex and signals from the cardiopulmonary baroreceptors is a rapidly acting
system that can respond to external perturbations in pressure on a time scale
of a few seconds (1 or 2 heartbeats). Both of these types of pressure detectors work
in concert to produce sympathetic signals that maintain blood pressure nearly
constant in the short term through fast vascular and cardiac effector responses.
However, besides initiating rapid responses, changes in the sympathetic signals
also have effects on the kidney that contribute to initiating the intermediate-term
regulation of blood pressure.
Intermediate-Term Regulation of Blood Pressure: Renal Control
of Vascular Resistance
In the event that the short-term regulation of blood pressure does not completely
restore blood pressure to its normal setpoint within a few tens of seconds, then the
kidneys are capable of strongly reinforcing the short-term vascular effects of the
1As an example of this variation, some patients experience “white coat hypertension,” a phenomenon in
which their blood pressure is normal while resting calmly at home but rises when a white-coated physician
measures it in an office setting.
vasomotor center if a deviation in blood pressure is maintained. This reinforcement
involves direct vascular actions. The major detectors involved in the kidney’s
ability to regulate vascular resistance are the previously described baroreceptors,
and another set of pressure-sensitive cells within the kidney, often referred to as
intrarenal baroreceptors. These baroreceptors sense renal afferent arteriolar pressure.
Anatomically, these structures are not neural baroreceptors (ie, they are not
nerve cells and do not send signals to the brainstem vasomotor center) but rather
are specializations of the cells of the afferent arteriole: granular cells (also called
juxtaglomerular cells) that form part of the juxtaglomerular apparatus. They act
entirely within the kidney.2 Although granular cells acting as intrarenal baroreceptors
do not send signals centrally, neural signals originating in the vasomotor
center (generated in response to vascular baroreceptors) reach the granular cells
via the renal sympathetic nerve. Thus, the activity of the granular cells is affected
both by direct sensing of pressure in the renal artery and by pressures sensed by
neural baroreceptors elsewhere in the body. Baroreceptors and their key actions
are summarized in Figure 7–2.
In response to changes in pressures sensed by baroreceptors, a number of renal
events are set in motion that have powerful effects on the vasculature and on
Figure 7–2. Baroreceptors and the major processes they influence. Arterial baroreceptors
sense pressures in the aorta and carotid arteries and send afferent information to the
brainstem vasomotor center, which then regulates cardiovascular and renal processes
via autonomic efferents. Cardiopulmonary baroreceptors sense pressure in the cardiac
atria and pulmonary arteries, thereby being responsive to the filling of the vascular tree.
They send afferent information in parallel with the arterial baroreceptors. Although there
is overlap between the influences of the two sets of baroreceptors, the cardiopulmonary
baroreceptors have a major influence on the hypothalamus, which regulates the secretion
of ADH.
2Although intrarenal baroreceptors are not neural afferents, there are afferent nerves originating in other
regions of the kidneys that impact autonomic function.
sodium excretion The most critical involve signaling pathways known as reninangiotensin
systems (RAS).
Renin-Angiotensin Systems
If it is possible to single out one substance as being the most important in
the control of sodium excretion and blood pressure, then that substance
would be angiotensin II. It is a potent vasoconstrictor and a mediator of
multiple actions in the kidneys that affect sodium excretion. Thus, it affects blood
pressure directly as a vasoconstrictor and indirectly via regulation of renal sodium
excretion.
There are many local RAS in individual tissues, including the kidneys, brain,
and the heart. There is also a global or systemic RAS which we normally consider
to be the major renal regulator of blood pressure. All RAS, whether global or local,
consist of a large protein substrate called angiotensinogen, several enzymes and
several products. The key product is angiotensin II. When angiotensin II binds to
cell surface receptors, it initiates actions that affect blood pressure and excretion
of sodium. The first key enzyme in all RAS is renin. It acts on angiotensinogen
to produce a small (10-amino-acid) product called angiotensin I. Angiotensin I
is acted upon by another enzyme, angiotensin-converting enzyme (ACE), to produce
the highly active 8-amino-acid peptide angiotensin II. In the global RAS, the
source of angiotensinogen circulating in the blood is the liver. The source of circulating
renin is the granule cells in the kidney. Renin is secreted both into the interstitium
of the kidney and into the lumen of the afferent arterioles, where it acts on
circulating angiotensinogen to produce circulating angiotensin I. ACE, which is
expressed on the luminal surface of endothelial cells in many parts of the vasculature,
particularly in the lungs, then converts angiotensin I to angiotensin II.
We will describe the regulation of RAS in terms of the global system, in part
because more is known about it. Investigators agree, however, that locally produced
angiotensin II (and some related peptides) is the more important source in
terms of regulating the kidneys because the levels of angiotensin II in renal tissues
are far higher than can be accounted for by a systemic source. It is presumed that
global angiotensin II arriving in the renal blood supply acts synergistically with
local angiotensin II as a regulator of function.
Circulating levels of angiotensinogen are usually fairly high and ACE activity
usually converts most angiotensin I into angiotensin II. Therefore, the primary
determinant of circulating levels of angiotensin II is the amount of renin available
to convert angiotensinogen to angiotensin I. Consequently, to understand
angiotensin II regulation of blood pressure, we require an understanding of the
regulation of renin secretion. What determines how much renin is secreted? Two
primary regulators have been described. The first are the neural baroreceptors,
which produce signals via the renal sympathetic nerves that stimulate granular
cells: Activation of .1-adrenergic receptors on the granular cells stimulates renin
secretion via a cyclic adenosine monophosphate and protein kinase A-dependent
process. (In addition, the activity of renal sympathetic nerves causes afferent arteriolar
constriction and reduction in renal blood flow.) The second regulators of
renin secretion are the intrarenal baroreceptors, ie, granular cells that deform in
response to changes in afferent arteriolar pressure; when the pressure falls, renin
production increases. Thus, as mentioned previously, granular cells act both as
detectors (of renal arteriolar pressure) and as signal generators (releasing renin)
in response to changes in pressure and sympathetic activity. The signals from the
vasomotor system to the renin-producing granular cells ensures that there is tight
coordination between the rapid activity of the baroreceptor reflex and the slower
acting RAS; ie, the short-term regulation and the intermediate-term regulation
have at least one common set of detectors. However, the intrarenal pressure detector
can function in the absence of renal innervation (eg, after a renal transplant).
There is also a third detector mechanism that regulates renin release. It is also
intrarenal, but it does not detect blood pressure. Rather, it measures the amount of
sodium chloride that leaves the thick ascending limb, directly bathing the macula
densa cells of the juxtaglomerular apparatus and delivered to the distal convoluted
tubule. This amount of sodium chloride depends on both the rate of filtration
and the rate of sodium reabsorption in all the nephron elements preceding the
macula densa. When sodium chloride delivery (a combination of concentration
and flow rate) to the luminal surface of macula densa cells increases, renin production
decreases. This is due to increased uptake of NaCl by the cells with subsequent
osmotic swelling. Osmotic swelling (Figure 7–3) causes the release of transmitter
agents (see later discussion) that inhibit renin release. This load detector, therefore,
does not generate signals that directly regulate blood pressure. However, it does
contribute to the regulation of renin secretion.
Figure 7–3. Responses of macula densa cells to changes in delivery of NaCl load. The
macula densa cells (arrowheads) are in close apposition to the glomerulus (G). Macula
densa cells swell in response to increasing tubular NaCl concentration from 25 (total osmolality
5 210 mOsm/kg H2O) on the left to 135 mmol (total osmolality 5 300 mOsm/
kg H2O). Bar 5 10 мm. (From Peti-Peterdi J et al, Am J Physiol Renal Physiol. 2002;283;F197.
Used with permission.)
Thus, there are three separate, redundant mechanisms regulating renin secretion
(neural signals, afferent arteriolar pressure, and NaCl at the macula densa).
This redundancy reflects the importance of the RAS and angiotensin II, in particular,
in regulating blood pressure. Among the most significant actions of circulating
angiotensin II produced by the global RAS is general arteriolar vasoconstriction.
This vasoconstriction acts in parallel with sympathetically mediated neural
control. This raises total peripheral resistance, thereby increasing blood pressure.
The importance of this system makes the RAS a natural target for pharmacological
intervention to reduce high blood pressure. A number of blood pressure–
lowering pharmacological agents are aimed at components of the RAS, including
ACE inhibitors and blockers of the arteriolar smooth muscle receptors for angiotensin
II. Figures 7–4 to 7–7 illustrate the various features of the RAS described
in the text and show how the system responds to a major fall in blood pressure
resulting from a hemorrhage.
Besides these primary mechanisms, angiotensin II acts in a negative feedback
manner to inhibit renin production by acting directly on granular cells (by interacting
with AT1 receptors on granular cells to increase intracellular Ca concentration,
which inhibits renin production).
Most of the time it is appropriate for the vasoconstrictive and sodium retaining
actions of angiotensin II to be exerted in parallel. However, by having both
a global and an intrarenal RAS, it is possible to separate these actions, such that
changes in sodium excretion can be effected without, at the same time, altering
vascular resistance elsewhere in the body.
CONTRIBUTION OF THE KIDNEY TO THE REGULATION OF
SODIUM EXCRETION AND BLOOD PRESSURE
Despite the strength and efficacy of the vascular baroreceptor reflex and the potency
of renin-induced angiotensin II in regulating vascular smooth muscle tone,
these mechanisms are not the ultimate determinants of blood pressure. That is,
the average value of blood pressure (or perhaps the average value of the setpoint
around which the baroreceptor reflex operates) is fixed not by the brainstem vasomotor
center but rather by the kidneys. Guyton and colleagues, in their classic
experiments, surgically cut the neural pathways between the baroreceptors and
the vasomotor center of anesthetized dogs. After recovery, the dogs’ blood pressure
varied widely from moment to moment, far more so than normal, but the mean
value eventually returned to baseline. Various investigators ultimately showed that
the kidneys are responsible for determining the setpoint for mean blood pressure.
It does this, as should be clear by now, by controlling the amount of sodium, and
hence volume, in the vascular space on a long-term basis.
It is worth emphasizing the time lag between volume changes and pressure
changes. For example, increasing volume by ingesting a large amount of liquid or
decreasing volume by sweating during a tennis match on a hot day does not immediately
cause changes in blood pressure. This is because tendencies to change
pressure are buffered immediately by the classic baroreceptor reflex and by renal
Figure 7–4. Control of renin secretion. There are 3 primary mechanisms by which renin
secretion is regulated. First, when blood pressure falls, renal sympathetic nerve activity
increases and activates в1-adrenergic receptors on granular cells of the afferent
arteriole to stimulate renin secretion. Second, the granular cells also act as “intrarenal
baroreceptors.” They respond to changes in pressure within the afferent arteriole, which,
except in cases of renal artery stenosis, is a reflection of changes in arterial blood pressure.
Deformation of the membranes of the granular cells alters renin secretion: When
pressure falls, renin production increases. Third, macula densa cells in the thick ascending
limb sense sodium chloride delivery by changing the uptake of salt, with subsequent
osmotic swelling. Changes in cell volume lead to the release of chemical transmitters that
alter renin secretion from the granular cells: When sodium chloride delivery increases,
renin production decreases.
output of salt and water. However, if the kidneys do not match their output to input,
and changes in extracellular fluid (ECF) volume are sustained, then pressure
gradually creeps toward a new elevated or depressed value. In the face of sustained
changes in volume, the baroreceptor reflex cannot forever keep pressure normal.
We are normally unaware of the kidneys’ role in the control of blood pressure
because the baroreceptor reflex is very effective on a short-term basis in buffering
changes and because healthy kidneys do such a good job of adjusting their volume
output in the face of changes in input.
Figure 7–5. Schematic diagram showing the increase in renin secretion and the increased
production of angiotensin II in response to a major hemorrhage. Three primary
mechanisms activate renin secretion: (1) increased renal sympathetic nerve activity; (2)
decreased pressure sensed by intrarenal baroreceptors; and (3) decreased sodium chloride
delivery to the macula densa. The first two mechanisms directly stimulate renin release,
whereas the third mechanism reduces inhibitory feedback, allowing more renin
release. Renin promotes the formation of angiotensin II, which produces strong vasoconstriction
and helps to correct the decrease in blood pressure that resulted from the
hemorrhage.
The Connection between Sodium, Water, and Blood Pressure
At this point, we have described signals affecting the first three effector
mechanisms for blood pressure control, ie, cardiac performance, vascular
resistance, and venous compliance. All of these three mechanisms can
generally be thought of as adjusting the properties of the vascular system to match
the available volume of blood. The fourth renal mechanism for controlling blood
pressure is to adjust the volume of blood to fit the vascular system. Because control
of blood volume is arguably the most complex of these effector systems, it is worth
elucidating the logical connection between renal sodium excretion and blood volume
before further describing the mechanisms of control per se.
Let us pose the following question: What does sodium have to do with blood
pressure? Pressures in the vascular tree require an appropriate volume of blood (to
fill both the highly elastic venous system and the chambers of the heart). With
insufficient volume, the heart can neither fill nor pump. Blood pressure in the long
term depends on blood volume. Blood volume, in turn, depends on total ECF
Figure 7–6. Schematic diagram showing the vascular response to a major hemorrhage.
The baroreceptor reflex increases sympathetic activity. Besides the effect of sympathetic
neurotransmitters on в1-adrenergic receptors to stimulate renin release, they also stimulate
б1-adrenoreceptors (like those present on other vascular smooth muscle cells) to
cause afferent arteriolar contraction and a reduction in renal blood flow. In the kidney,
most of this reduction in blood flow is blunted by tubuloglomerular feedback (see Figure
7–14). GFR, glomerular filtration rate.
volume (ie, the volume of blood plasma and fluid in the interstitial spaces of the
tissues throughout the body). Fluid in the interstitial spaces acts as a buffer for
plasma volume, protecting the vascular compartment from immediate changes
associated with drinking, sweating, and so on. However, over time, sustained
changes in ECF volume lead to parallel changes in blood volume and ultimately
arterial pressure. If the vascular system is inappropriately filled on a prolonged
basis, the setpoint gradually drifts. To keep arterial pressure normal, the ECF volume
must be kept normal. In many ways, regulating the ECF volume to a level appropriate
for the vascular system is the most important function of the kidneys.
The relationship between blood volume and total body water may appear obvious,
but the relationship between total body sodium content and blood volume
may not. However, as discussed in Chapter 4, there is a simple relation between
the volume of a compartment (essentially the amount of water) and its osmolarity:
osmolarity 5 total osmoles/volume.3 In other words, volume 5 total osmoles/
osmolarity. Therefore, the ECF volume is determined by the total osmotic content
3Here again, we use osmolarity for simplicity, recognizing that osmolality is actually the quantity that
governs osmotic flow.
Figure 7–7. The macula densa NaCl load sensor. Macula densa cells in the thick ascending
limb sense sodium chloride delivery by changing the uptake of salt with subsequent
osmotic swelling (see Figure 7–3). Changes in cell volume lead to the release of chemical
transmitters that alter renin secretion from the granular cells: When sodium chloride delivery
increases, renin production decreases. GFR, glomerular filtration rate.
and osmolarity. If the body regulates the total osmotic content of the ECF and
regulates its osmolarity, it has accomplished the task of regulating its volume. This
is precisely what the kidneys do. They regulate ECF osmolarity and total osmotic
content. Recall that more than 90% of the ECF osmotic content is accounted for
by sodium and the equal number of anions that must accompany it. To a first
approximation, total ECF osmotic content 5 sodium content 3 2. The other
10% of the ECF solute is accounted for by substances such as potassium, glucose,
urea, and so on. The regulation of solutes other than sodium occurs for purposes
unrelated to control of ECF osmolality, so that the regulation of osmotic content
amounts to the regulation of sodium content. Figure 7–8 shows how the ECF
volume changes when the body takes on sodium loads and Figure 7–9 shows the
excretory response to those loads.
In simple terms, long-term regulation of arterial blood pressure involves longterm
control of body sodium content. If the body controls sodium content and
plasma osmolarity (the water content containing the sodium), it controls volume.
Figure 7–7. The macula densa NaCl load sensor. Macula densa cells in the thick ascending
limb sense sodium chloride delivery by changing the uptake of salt with subsequent
osmotic swelling (see Figure 7–3). Changes in cell volume lead to the release of chemical
transmitters that alter renin secretion from the granular cells: When sodium chloride delivery
increases, renin production decreases. GFR, glomerular filtration rate.
and osmolarity. If the body regulates the total osmotic content of the ECF and
regulates its osmolarity, it has accomplished the task of regulating its volume. This
is precisely what the kidneys do. They regulate ECF osmolarity and total osmotic
content. Recall that more than 90% of the ECF osmotic content is accounted for
by sodium and the equal number of anions that must accompany it. To a first
approximation, total ECF osmotic content 5 sodium content 3 2. The other
10% of the ECF solute is accounted for by substances such as potassium, glucose,
urea, and so on. The regulation of solutes other than sodium occurs for purposes
unrelated to control of ECF osmolality, so that the regulation of osmotic content
amounts to the regulation of sodium content. Figure 7–8 shows how the ECF
volume changes when the body takes on sodium loads and Figure 7–9 shows the
excretory response to those loads.
In simple terms, long-term regulation of arterial blood pressure involves longterm
control of body sodium content. If the body controls sodium content and
plasma osmolarity (the water content containing the sodium), it controls volume.
Figure 7–8. Relation between sodium
and extracellular fluid (ECF)
volume. Each large rectangle represents
total-body water divided into
an ICF (open areas) and ECF (shaded
areas). The ECF is further subdivided
into interstitial and plasma volumes.
Excess sodium is almost always accompanied
by water, so that excess
sodium causes an expansion of the
ECF volume. If there is no change in
osmolality, as shown in the middle
example, the expansion is entirely
in the ECF and there is no change in
ICF volume. If there is excess sodium
without excess water, as shown in
the bottom example, water is drawn
from the ICF to maintain equal osmolalities between compartments. In both cases of
excess sodium, the increase in ECF volume causes an increase in both plasma and interstitial
volumes. ICF, intracellular fluid; ECF, extracellular fluid.
If it controls volume, then it controls pressure. This raises the following question:
How do the kidneys know about sodium content so that they can respond to
changes? Surprisingly, in detecting total body sodium, the primary variable that
the kidney monitors is not a direct measure of the amount of sodium in the body
or plasma sodium concentration but rather pressures in various parts of the vascular
tree and in the kidneys that we have already described. Pressure changes at any
of these sites are interpreted as a change in total body sodium because, except for
pathophysiological circumstances, blood pressure, blood volume, and total body
sodium march in lockstep.
Sodium content and blood pressure can be too high or too low. Some of the
mechanisms that control sodium excretion mainly serve to correct elevated pressure/
high sodium content, while others mainly correct low pressure/low sodium
content. Still others come into play with deviations in either direction. This bidirectional
responsiveness applies to the first control mechanism we discuss—
control of glomerular filtration rate (GFR).
Control of Glomerular Filtration Rate
Because sodium excretion represents the difference between filtration and reabsorption,
it is not surprising that one of the major controls over sodium excretion is
the regulation of GFR. A change in the amount of sodium filtered resulting from
a change in GFR is also accompanied by a change in the amount of water filtered.
Therefore, any change in GFR represents a mechanism for altering ECF volume.
The reflex control of GFR is mediated mainly by changing the resistance of
the afferent and efferent arteriolar resistance. The changes in resistance are produced
by changes in renal sympathetic nerve activity and circulating levels of
on by external signals. The high pressure reduces levels of intrarenal angiotensin
II. The number of Na-H exchangers in the apical membrane is strongly influenced
by angiotensin II. When its levels fall, Na-H exchangers are withdrawn, along
with a concomitant reduction in the activity of the basolateral Na-K-ATPase. The
result of the reduction in angiotensin II in response to high renal artery pressure
is less sodium absorption and more presentation of sodium to the loop of Henle,
and therefore more excretion (see Figure 7–10). Pressure natriuresis and diuresis
Figure 7–10. Response of the kidneys to an increase in blood pressure (natriuresis/
diuresis). Part of the intermediate-term response to increases in blood pressure is to reduce
blood volume (in an attempt to match blood volume with the capacity of the vascular
tree). There are several mechanisms for this response. By far, the most important is
a reduction in proximal tubular sodium reabsorption because of a reduction in the number
of functional transporters (Na-H antiporters) in the apical membrane of the proximal
tubule epithelial cells. The reduction is probably in response to reduced levels of angiotensin
II. There is also an increase (usually small) in glomerular filtration rate (GFR) and
an increase in peritubular hydrostatic pressure and renal interstitial pressure that favor
reduced absorption of salt and water in the cortex (particularly from the proximal nephron).
ECF, extracellular fluid.
serves as a kind of backup system that comes into play if fast-acting reflex systems
of regulating blood pressure fail to completely correct large increases.
If peritubular levels of angiotensin II are kept constant by experimental means,
pressure natriuresis and diuresis are strongly blunted or even eliminated. The effect
of maintaining constant sympathetic transmitters is similar but not so pronounced.
Thus, the same agents that directly affect vascular peripheral resistance
to correct blood pressure (sympathetic transmitters and angiotensin II) also affect
tubular reabsorption to correct ECF volume.
A key feature of pressure natriuresis and diuresis is that the degree of salt and
water excretion for a given rise in pressure varies with the volume status of the
body. Even though pressure natriuresis is turned on strictly by intrarenal mechanisms,
the amount that occurs can be dampened by external factors. If the ECF
volume is normal or high and the renal artery pressure rises, pressure natriuresis
and diuresis are very effective in increasing excretion of sodium and water and
reducing blood volume. On the other hand, if ECF volume is low and the renal
artery pressure rises, there is much less salt and water loss. It appears that the volume
status of the body acts as a gain control on pressure natriuresis and diuresis.4
There is potent pressure natriuresis and diuresis when ECF volume is high, and
much less pressure natriuresis and diuresis when ECF volume is depleted. Under
normal conditions, pressure natriuresis and diuresis is a proximal nephron mechanism
that is very important for dumping sodium and water when blood pressure
is too high. It does this by reducing isotonic reabsorption of salt and water from
the proximal convoluted and straight tubule.
Peritubular-Capillary Starling Factors and the Role of Renal
Interstitial Hydraulic Pressure
Changes in GFR, besides directly affecting the filtered volume, also affect reabsorption
of that volume. A rise in either peritubular capillary pressure or interstitial
pressure reduces net reabsorption (and therefore causes more excretion). From
the viewpoint of Starling forces acting on the capillary, it should be obvious that
high capillary pressure opposes reabsorption. But high interstitial pressure should
favor reabsorption, so why does it also oppose it? First, an increased interstitial
pressure causes back-leak of reabsorbed fluid from the interstitial space across the
tight junctions into the tubule. Thus, this pressure does not alter the cellular transport
mechanisms for sodium and water but rather reduces the net reabsorption
achieved by these mechanisms, particularly in the “leaky” proximal tubule. In
effect, if the interstitium gets “too full,” then it is difficult to transport more fluid
into it. Put another way, high interstitial pressure does more to oppose the movement
of fluid from tubule to interstitium than it does to promote the movement
of fluid from interstitium to capillary.
A decrease in peritubular-capillary oncotic pressure (рPC) also opposes reabsorption.
Of course, the new question is: How do changes in GFR cause changes
in PPC and рPC? We already know the answers to this question from Chapter 2:
4The only known way this can occur is via signals originating in cardiopulmonary baroreceptors and transmitted
to the kidneys via renal nerves. However, there are probably other factors.
PPC is set by (1) arterial pressure and (2) the combined vascular resistances of the
afferent and efferent arterioles, which determine how much of the arterial pressure
is lost by the time the peritubular capillaries are reached. рPC is set by (1)
arterial oncotic pressure and (2) filtration fraction (GFR/RPF), which determine
how much of the oncotic pressure increases from its original arterial value during
passage through the glomeruli.
Teleologically, it makes sense that PPC and рPC influence interstitial pressure
and, hence, sodium reabsorption because these phenomena are simply a logical
continuation of the flow diagrams we have used previously for studying the homeostatic
control of GFR. Events initiated by fluid loss from the body end with 3
changes that lower GFR: increased constriction of the afferent and efferent arterioles
(induced by the renal nerves and angiotensin II), decreased arterial hydraulic
pressure, and increased arterial oncotic pressure. Figure 7–10 illustrates how these
same 3 factors also decrease renal interstitial hydraulic pressure and, hence, increase
sodium reabsorption. Thus, homeostatic responses that tend to lower GFR
in response to a reduction in body sodium also usually increase sodium reabsorption,
the “desired” homeostatic event of preserving volume in response to bodily
fluid depletion.
The same logic applies when the desired homeostatic responses are increased
GFR and decreased sodium reabsorption so as to eliminate excess sodium from
the body. Thus, when a high-salt diet or expansion of the ECF volume from some
other physiological cause is the primary event, the following occurs: (1) decreased
plasma oncotic pressure (resulting from dilution of plasma proteins), (2) increased
arterial pressure, and (3) renal vasodilation secondary to decreased activity of the
renal sympathetic nerves and decreased angiotensin II. Simultaneously, then, the
GFR increases a small amount and so does interstitial pressure, which reduces
fluid reabsorption. Figure 7–10 illustrates these natriuretic responses to a rise in
arterial pressure.
Glomerulotubular Balance
As stated earlier, in the regulation of sodium excretion, the control of tubular
sodium reabsorption is more important than control of GFR. One reason for this
is that a change in GFR automatically induces a proportional change in the reabsorption
of sodium by the proximal tubules, so that the fraction reabsorbed (but
not the total amount) remains relatively constant (Table 7–1). This phenomenon
has the rather ungainly name of glomerulotubular balance. In response to a primary
change in GFR, the percentage of the filtered sodium reabsorbed proximally
remains approximately constant (about 65%). The fraction not reabsorbed
also remains approximately constant (about 35%). Therefore, a change in GFR is
still reflected as a change in the sodium and water presented to the loop of Henle.
Glomerulotubular balance does not mean that proximal reabsorption is always
exactly 65% of filtered sodium. It only says that when the fraction reabsorbed is
changed, the change is caused by processes other than changes in GFR. Several
mechanisms are manifested in the proximal tubule to stimulate sodium reabsorption
(raise the percentage reabsorbed above 65%) or inhibit sodium reabsorption
(lower the percentage below 65%).
Table 7–1. Effect of “perfect” glomerulotubular balance on the mass of
sodium leaving the proximal tubule
GFR
(L/min)
PNa
mmol/L)
Filtered
(mmol/min)
Reabsorbed
proximally (66.7% of
filtered; mmol/min)
Leaving proximal
(mmol/min)
0.124 145 18 12 6
0.165 145 24 16 8
0.062 145 9 6 3
The net result of fixed fractional reabsorption is to reduce the magnitude of difference in sodium
leaving the proximal tubule.
The mechanisms responsible for matching changes in tubular reabsorption to
changes in GFR are completely intrarenal (ie, glomerulotubular balance requires
no external neural or hormonal input; indeed, the presence of such input usually
obscures the existence of glomerulotubular balance, as described previously).
Glomerulotubular balance is actually a second line of defense preventing
changes in renal hemodynamics per se from causing large changes in sodium excretion.
The first line of defense is autoregulation of GFR, described in Chapter
2 and in the prior discussion of tubuloglomerular feedback. GFR autoregulation
prevents GFR from changing too much in direct response to changes in blood
pressure, and glomerulotubular balance blunts the sodium-excretion response to
whatever GFR change does occur. Thus, tubuloglomerular feedback and glomerulotubular
balance mediated by GFR autoregulation are processes that allow a
large fraction of the responsibility for homeostatic control of sodium excretion to
reside in those primary inputs that act to influence tubular reabsorption of sodium
independently of GFR changes.
Before describing the mechanisms of long-term control in the next section we
want to point out 2 key features of the renal handling of sodium. First, interactions
between the various mechanisms we have described thus far allow the
kidneys to be true integrators of signals that are sometimes in conflict. A good
example is the case of prolonged aerobic exercise, specifically marathon running.
Well-trained, well-hydrated athletes running marathons on cool days (thus eliminating
excessive loss of sodium as a confounding factor) exercise intensely for well
over 2 h with an elevated blood pressure. Systolic pressure is typically elevated by
50%, while MAP is elevated about 20%. Acting alone this rise in pressure should
induce vigorous pressure natriuresis. But it does not. If anything, renal excretion
of sodium is decreased in these conditions because other signals override pressure
natriuresis.
We also want to point out that all the mechanisms described so far lead
to co-regulation of solute and water, ie, they tend by themselves to increase
or decrease the excretion of sodium and water in exact parallel. This is
very effective as a coarse control over ECF volume. However, sodium ingestion
and water ingestion are both highly variable and often unrelated to each other. If
one is ingested in excess of the other, the body has to excrete more of whichever
one is in excess. Such independent control requires additional mechanisms not
operative in the proximal tubule. Most of the processes for independent control of
sodium and water balance occur in the distal nephron (not surprising because the
distal nephron represents mammalian evolutionary adaptation to a terrestrial
environment).
Long-Term Control: Aldosterone Regulation of Sodium Balance
In the face of a constant rate of ingestion of salt and water, correction of
a sustained decrease in blood pressure requires a decrease in renal excretion
of salt and water until the transient positive fluid balance returns
blood volume to normal. A major control over the reabsorption of sodium in the
distal nephron involves the hormone aldosterone. The primary effect of aldosterone
is to increase sodium reabsorption in the connecting tubules and collecting
ducts. Aldosterone-stimulated sodium retention is an effector system that is vital
in correcting prolonged reductions in blood pressure. The most important physiological
factor controlling circulating levels of aldosterone is the circulating level
of angiotensin II. Thus, a decrease in blood pressure produces a rapid short-term
baroreceptor-mediated vascular response followed by the intermediate-term renalmediated
release of renin and production of angiotensin II, which reinforces the
initial short-term vascular response. However, even if the blood pressure returns
to near normal, the circulating angiotensin II will stimulate the adrenal cortex to
produce aldosterone.5 This targets the distal nephron to increase sodium reabsorption
and thus increase total body sodium and blood volume to produce a longterm
correction to total body sodium content and mean blood pressure.
Aldosterone stimulates sodium reabsorption mainly in the cortical connecting
tubule and cortical collecting duct, specifically by the principal cells. An action
on this late portion of the nephron is what one would expect for fine-tuning the
output of sodium, because more than 90% of the filtered sodium has already been
reabsorbed by the time the filtrate reaches the collecting-duct system.
The total quantity of sodium reabsorption dependent on the influence of aldosterone
is approximately 2% of the total filtered sodium. Thus, all other factors remaining
constant, in the complete absence of aldosterone, a person would excrete
2% of the filtered sodium, whereas in the presence of maximal plasma concentrations
of aldosterone, virtually no sodium would be excreted. Two percent of the
filtered sodium may seem small but is actually large because of the huge volume
of glomerular filtrate:
Total filtered Na/day 5 GFR 3 PNa
5 180 L/day 3 145 mmol/L
5 26,100 mmol/day
5Circulating angiotensin II has a very short plasma half-life; thus, continued stimulation of aldosterone
secretion requires the continued production of angiotensin II.
Thus, aldosterone controls the reabsorption of 0.02 3 26,100 mmol/day 5 522
mmol/day. In terms of sodium chloride, the form in which most sodium is ingested,
this amounts to the control of approximately 30 g NaCl/day, an amount
considerably more than the average person consumes. Therefore, by control of the
plasma concentration of aldosterone between minimal and maximal, the excretion
of sodium can be finely adjusted to the intake so that total-body sodium and
ECF volume remain constant. (Interestingly, aldosterone also stimulates sodium
transport by other epithelia in the body, namely, sweat and salivary ducts and the
intestine. The net effect is the same as that exerted on the kidney: movement of
sodium from lumen to blood. Thus, aldosterone is an all-purpose stimulator of
sodium retention.) In the kidney, aldosterone acts like many other steroid hormones.
As a molecule, it has enough lipid character to freely cross principal cell
membranes, after which it combines with mineralocorticoid receptors in the cytoplasm.
Aldosterone-bound receptors undergo a change in conformation that
reveals a formerly hidden nuclear localization signal. After being transported to
the nucleus, the receptor acts as a transcription factor that promotes gene expression
and synthesis of messenger RNA (mRNA). The mRNA mediates the translation
of specific proteins. The effect of these proteins is to increase the activity or
number of luminal membrane sodium channels and basolateral membrane Na-KATPase
pumps to exactly supply what is needed to promote increased reabsorption
of sodium (Figure 7–11).
Figure 7–11. Mechanism of aldosterone action. Aldosterone enters principal cells and
interacts with cytosolic aldosterone receptors. The aldosterone-bound receptors interact
with nuclear DNA to promote gene expression. The aldosterone-induced gene
products activate sodium channels and sodium pumps to increase sodium reabsorption.
Glucocorticoids such as cortisol are also capable of binding to the aldosterone receptor.
However, they are inactivated by 11в-hydroxysteroid dehydrogenase (11в-HSD).
Control of Aldosterone Secretion
Several inputs to the adrenal gland regulate aldosterone secretion and play a role
in electrolyte balance. The most important is angiotensin II produced by the
global RAS. In addition, elevated plasma potassium concentration, as described
in Chapter 8 in the context of the renal handling of potassium, stimulates aldosterone
secretion, while the atrial natriuretic factors (discussed later) inhibit aldosterone
secretion.
As described earlier, the plasma concentration of angiotensin II is determined
mainly by the plasma concentration of renin. Accordingly, control of aldosterone
secretion in sodium-regulating reflexes is determined by those factors that regulate
renin secretion (ie, intrarenal baroreceptors, macula densa, and renal sympathetic
nerves). Thus, when plasma volume is reduced, eg, by a low-sodium diet, hemorrhage,
or diarrhea, renin secretion is stimulated, which leads, via angiotensin II,
to an increased aldosterone secretion. This hormone then stimulates sodium reabsorption
(Figure 7–12). In contrast, when a person ingests a high-sodium diet,
renin secretion is reduced, which leads, via a reduced plasma angiotensin II, to
decreased aldosterone secretion.
Tubuloglomerular Feedback and Autoregulation Revisited
Responses to cardiopulmonary, arterial, and intrarenal baroreceptors are extremely
effective mechanisms for controlling blood volume. Part of this control causes
changes in GFR, mediated by changes in afferent arteriolar resistance. Although
this change in afferent resistance has the effect of altering GFR in a manner necessary
to correct blood volume, it has the additional effect of altering RBF and
pressure in the glomerular capillaries that may have the deleterious consequences
described in Chapter 2. Substantial reductions in RBF severely compromise already
oxygen-poor regions of the kidney like the medulla. Substantial increases
in glomerular capillary pressures are likely to damage the glomeruli. In addition,
the ability of the kidney to correct total body electrolyte and water imbalances depends
on keeping tubular flow (ie, GFR) within a certain limited range. Therefore,
the kidneys have specific mechanisms for blunting responses that would otherwise
lead to excessively large changes in GFR or RBF. These mechanisms are autoregulation
and tubuloglomerular feedback. It is important to emphasize that these
mechanisms do not block changes in GFR and renal blood flow; they simply keep
the changes from becoming excessive.
Autoregulation of GFR involves local production of prostaglandins in conditions
when strong vasoconstriction might by itself reduce GFR and renal blood
flow too much (high sympathetic stimulation and high levels of angiotensin II).
Intrarenal (autoregulatory) prostaglandin production opposes the actions of angiotensin
II on the kidneys, ie, prostaglandins lead to vasodilation of arterioles
and relaxation of mesangial cells (Figure 7–8). Increased local (intrarenal) angiotensin
II concentrations associated with renin release and increased sympathetic
input stimulate the production of prostaglandins. The vasodilatory effect
Figure 7–12. Response of the RAS to a fall in blood pressure. Increased secretion of renin
leads via increased circulating angiotensin II to the stimulation of aldosterone secretion.
The aldosterone stimulates tubular sodium reabsorption, thereby preserving body
stores of sodium.
of prostaglandins dampens the effect of angiotensin II and sympathetic input
on renal arterioles and permits a reasonable, but reduced blood flow and GFR to
continue (see Figure 7–13).
Tubuloglomerular feedback, alternatively, is associated with the macula densa
sodium chloride load detector and plays a major role in conditions when GFR is
very high (eg, volume overload). Recall from the previous discussion that large
loads of sodium chloride in the thick ascending limb lead to inhibition of renin
release. The macula densa cells at the end of the thick ascending limb have Na-K-
2Cl symporters that can avidly take up Na, Cl, and K and cause the cells to swell
dramatically when GFR (NaCl delivery) is high (see Figure 7–9). The increased
Na and Cl in the lumen of the thick ascending limb stimulate the Na-H antiporter
and depolarizes the cells (as in thick ascending limb cells, the K recycles
via K channels). This depolarization leads to Ca entry across the basolateral membrane.
The rise in Ca leads to the release of ATP from the basolateral surface of
Figure 7–13. Prostaglandins mediate autoregulatory responses. Production of prostaglandins
(mostly PGE2) near the glomerulus relaxes the afferent arteriole and thus counteracts
the contractile effects of renal sympathetic nerve activation and angiotensin II.
the cells in close proximity to the glomerular mesangial cells. This ATP stimulates
purinergic P2 receptors on the mesangial cells and afferent arteriolar smooth
muscle cells. P2 receptor stimulation increases Ca in these cells and promotes
contraction. In addition, it is the increased Ca in the afferent arteriolar cells that
reduces renin secretion. The ATP may also be metabolized to adenosine, which
can stimulate adenosine receptors that produce the same result as the P2 receptors
(in contrast to the vasodilatory actions of adenosine in most other tissues).6
Contraction of mesangial cells decreases the effective filtration area, which decreases
GFR. Contraction of the afferent arteriolar smooth muscle cells increases
afferent resistance and decreases RBF and GFR7 (see Figures 7–14 and 7–15).
6=The actions of adenosine in a given cell depend on the type of purinergic receptor and the signaling
pathway initiated on binding of adenosine, similar to the situation with adrenergic receptors, in which an
array of receptor types permits a variety of responses to any given agonist.
7The increase in intracellular Ca of the granular cells inhibits their production of intrarenal renin, thus
reducing local production of angiotensin II and of prostaglandins, which would normally counteract the
vasoconstrictive effects of the purinergic agonists. Another mediator—nitric oxide (NO)—is not a factor
in initiating tubuloglomerular feedback but does appear to play a secondary role to sustain the tubuloglomerular
feedback once it has been initiated. The net effect of tubuloglomerular feedback is that the
pressure natriuretic and diuretic responses are blunted (but not eliminated).
Figure 7–14. Mechanism of tubuloglomerular feedback. Tubuloglomerular feedback
acts to prevent changes in renal artery pressure from causing extreme changes in sodium
delivery to the macula densa. This mechanism acts in the opposite direction to the
other reflexes and thus partially reduces or blunts their effectiveness. However, the overall
effect of an increase in renal artery pressure is still a net increase in sodium excretion
(compare with Figure 7–10). GFR, glomerular filtration rate; PGC, hydrostatic pressure in
glomerular capillaries.
The set of events just described is admittedly confusing, so the bottom line is
this: high salt content in the thick ascending limb of a given nephron generates
signals that reduce filtration in that nephron, thus blunting (but not eliminating)
the tendency to raise sodium excretion initiated by other process in conditions
(eg, volume expansion) where the appropriate overall response is increased sodium
excretion.
Figure 7–15. An example of tubuloglomerular feedback. Changes in juxtaglomerular
apparatus morphology during increasing tubular NaCl concentration from 25 (osmolality
5 210 mOsm/kg/H2O) to 135 mmol (osmolality 5 300 mOsm/kg/H2O). Macula densa
cell (arrowhead) swelling and parallel swelling/contraction of cells in the final part of the
afferent arteriole causes an almost complete closure of the arteriolar lumen (arrows), collapse
of capillary loops (CAP), and shrinkage of the entire glomerulus (G). *, mesangial
cells. Bar 5 10 мm. (From Peti-Peterdi J et al, Am J Physiol Renal Physiol. 2002;283:F197.
Used with permission.)
Other Mechanisms for Controlling Sodium Balance
Although there are several other renal mechanisms for controlling sodium balance
independent of water balance, under normal physiological circumstances none is
as important as aldosterone. Only under certain pathophysiological conditions
do these other mechanisms contribute significantly to the regulation of sodium
balance.
Natriuretic Peptides
Several tissues in the body synthesize members of a hormone family called natriuretic
peptides, so named because they promote excretion of sodium in the urine.
Key among these are atrial natriuretic peptide (ANP) and brain natriuretic peptide
(BNP; named as such because it was first discovered in the brain). The main
source of both natriuretic peptides is the heart. The natriuretic peptides have both
vascular and tubular actions. They relax the afferent arteriole, thereby promoting
increased filtration, and act at several sites in the tubule. They inhibit the release
of renin, inhibit the actions of angiotensin II that normally promote reabsorption
of sodium, and act in the medullary collecting duct to inhibit sodium absorption.
The major stimulus for increased secretion of the natriuretic peptides is distention
of the atria, which occurs during plasma volume expansion. This is probably the
stimulus for the increased natriuretic peptides that occurs in persons on a highsalt
diet. Although most experts assume that these peptides play some physiological
role in the regulation of sodium excretion in this and other situations in which
plasma volume is expanded, it is not currently possible to quantitate precisely their
contribution, although it is surely less than aldosterone. As described later, these
peptides are greatly elevated in patients with heart failure and serve as diagnostic
indicators.
Antidiuretic Hormone
As described in Chapter 6, the major function of ADH is to increase the permeability
of the cortical and medullary collecting ducts to water, thereby decreasing
the excretion of water. In addition to this effect, ADH also increases sodium reabsorption
by the cortical collecting duct, one of the same segments influenced by
aldosterone. This effect is particularly evident when plasma aldosterone is elevated,
and ADH’s action seems to synergize with the action of this steroid hormone. This
makes teleological sense because, as discussed later, the secretion of ADH, like
that of aldosterone, is stimulated when plasma volume is reduced.
Other Hormones
Many well-known hormones not normally associated with renal function can exert
an influence on sodium reabsorption. Cortisol, estrogen, growth hormone,
thyroid hormone, and insulin enhance sodium reabsorption, whereas glucagon,
progesterone, and parathyroid hormone decrease it. When the level of any of these
hormones is elevated (eg, estrogen during pregnancy), it will exert a significant
influence on sodium reabsorption and thus excretion. However, the secretion of
these hormones, unlike the hormones described earlier, is not reflexively controlled
specifically for the homeostatic regulation of sodium balance.
Summary of the Control of Sodium Excretion
The control of sodium excretion depends on the control of 2 variables of renal function:
GFR and rate of sodium reabsorption (Tables 7–2 and 7–3). The latter is controlled
by the renin-angiotensin-aldosterone hormonal system, renal sympathetic
nerves, direct effects of arterial blood pressure on the kidneys (pressure natriuresis),
and atrial natriuretic factors. The renal interstitial hydraulic pressure and several
renal paracrine agents play important roles in regulating sodium reabsorption.
When considering mechanisms of sodium excretion, it is useful to consider 2
conceptually different categories of mechanisms: (1) proximal nephron mechanisms
(control of GFR, pressure natriuresis, and, to a lesser extent, changes in
Starling forces) that lead to coupled changes in sodium and water excretion and
(2) distal nephron effects in which sodium can be reabsorbed independently of
water. The proximal mechanisms are primarily involved in excreting excess ECF
volume, whereas the distal mechanisms alter sodium excretion when ingestion of
sodium is not balanced by ingestion of water. Both types of mechanisms can alter
blood pressure because of the intimate relationship among total body sodium and
water, blood volume, and blood pressure.
There is great flexibility in such a multifactor system. Thus, eg, although the
renal sympathetic nerves influence GFR, renin secretion, renal interstitial hydraulic
pressure, and the tubular cells themselves, a transplanted and, therefore,
denervated kidney maintains sodium homeostasis quite well because of the other
Table 7–2. Effects of renal nerve stimulation
1 Stimulates renin secretion via a direct action on в1-receptors of granular cells.
2 Stimulates sodium reabsorption via a direct action on tubular cells (multiple receptors);
one site affected is the proximal tubule.
3 Stimulates afferent and efferent arteriolar constriction (б-adrenergic receptors).
As a result:
a GFR and RBF both decrease, the latter much more than the former.
b The increased renal resistance decreases PPC, and the increased filtration fraction
increases рPC. These changes cause renal interstitial hydraulic pressure to decrease,
which stimulates sodium reabsorption, mainly in the proximal tubule.
c The decreased GFR and the increased proximal sodium reabsorption (Effects 2
and 3b) result in decreased delivery of fluid to the macula densa, which causes
increased renin secretion in addition to that of Effect 1 above.
The three categories of renal nerve effects are listed in the order in which they are elicited as the
frequency of renal nerve impulses is increased to higher and higher values. Nore that the direct
effects on both renin secretion and sodium reabsorption occur at lower stimulation levels than
those required elicit renal vasoconstriction. GFR, glomerular filtration rate; RBF, renal blood flow;
PPC, peritubular-capillary hydralic pressure; рPC peritubular capillary oncotic pressure.
Table 7–3. Changes in these factors influence sodium excretion in response
to changes in plasma volume
Filtration of sodium
GFR
Plasma sodium concentration (of minor importance except in severe disorders)
Tubular reabsorption of sodium
Arterial blood pressure effects on proximal reabsorption (pressure natriuresis)
Aldosterone
Peritubular capillary factors, acting via RIHP
Renal nerves (direct tubular effects and indirect effects via angiotensin II and RIHP)
Angiotensin II (direct tubular effects and indirect effect via RIHP)
GFR (glomerulotubular balance)
Atrial natriuretic factor
Antidiuretic hormone
GFR, glomerular filtration rate; RIHP, renal interstitial hydraulic pressure.
known nonneural factors involved. Overall, the one input whose absence causes
the greatest difficulty in sodium regulation is aldosterone.
In normal persons, the mechanisms for regulating sodium excretion are so precise
that sodium balance does not vary by more than a small percentage despite
marked changes in dietary intake or losses caused by sweating, vomiting, diarrhea,
hemorrhage, or burns.
131
CONTROL OF WATER EXCRETION
Over time, water excretion must meet the constraint of balance: matching
output to input. However, there is no physiological “water meter” to
measure input. So output is not controlled by input. Instead, output is
regulated by factors relating to the major “big picture” goals described in the introduction
to this chapter. That is, maintain a volume sufficient to fill the vascular
space, and set an osmolality appropriate for a healthy environment of tissue cells.
Then, it is not surprising that the major signals regulating water excretion originate
from baroreceptors that assess vascular fullness and osmoreceptors that assess
plasma osmolality
Water excretion conceptually consists of 2 major components: a proximal
nephron component, in which water is absorbed along with sodium as an isotonic
fluid, and a distal nephron component, in which water can be reabsorbed independent
of sodium. The proximal nephron component is primarily a mechanism
to regulate ECF volume in response to changes in blood pressure, while the distal
nephron rate of water reabsorption is independent of sodium reabsorption. It is
determined mainly by ADH, which increases the water permeability of the collecting
ducts, thereby increasing water reabsorption and, hence, decreasing water
excretion. Accordingly, total-body water is regulated mainly by reflexes that alter
the secretion of ADH.
ADH is a peptide produced by a discrete group of hypothalamic neurons whose
cell bodies are located in the supraoptic and paraventricular nuclei and whose axons
terminate in the posterior pituitary gland, from which ADH is released into
the blood. The most important of the inputs to these neurons are from cardiovascular
baroreceptors and osmoreceptors.
Baroreceptor Control of ADH Secretion
A decreased extracellular volume (eg, resulting from diarrhea or hemorrhage) reflexively
produces an increased aldosterone secretion. It also induces increased
ADH secretion. The reflex is mediated by neural input to the ADH-secreting
neurons from both cardiopulmonary and arterial baroreceptors.
Decreased cardiovascular pressures cause less firing by the baroreceptors. Via
afferent neurons from the baroreceptors and ascending pathways to the hypothalamus,
this decreased baroreceptor firing causes stimulation of ADH secretion.
Conversely, the baroreceptors are stimulated by increased cardiovascular pressures,
and this results in the inhibition of ADH secretion. The adaptive value of
these baroreceptor reflexes is to help restore ECF volume and, hence, blood pressure
(Figure 7–16).
There is a second adaptive value to this reflex: Large decreases in plasma volume
elicit, by way of the cardiovascular baroreceptors, such high concentrations of
ADH—much higher than those needed to produce maximal antidiuresis—that
the hormone is able to exert direct vasoconstrictor effects on arteriolar smooth
muscle. The result is increased total peripheral resistance, which helps raise arterial
blood pressure independently of the slower restoration of body fluid volumes.
3.3.1. Роль почек в регулировании системного давления крови = 104
Литература. Иллюстрации. References. Illustrations
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Руководство, подготовленное коллективом авторитетных специалистов. Доступ к данному источнику = Access to the reference. URL: http://www.tryphonov.ru/tryphonov/serv_r.htm#0 quotation
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«Я У Ч Е Н Ы Й И Л И . . . Н Е Д О У Ч К А ?» Т Е С Т В А Ш Е Г О И Н Т Е Л Л Е К Т А
Предпосылка: Эффективность развития любой отрасли знаний определяется степенью соответствия методологии познания - познаваемой сущности. Реальность: Живые структуры от биохимического и субклеточного уровня, до целого организма являются вероятностными структурами. Функции вероятностных структур являются вероятностными функциями. Необходимое условие: Эффективное исследование вероятностных структур и функций должно основываться на вероятностной методологии (Трифонов Е.В., 1978,..., ..., 2015, …).
Критерий: Степень развития морфологии, физиологии, психологии человека и медицины, объём индивидуальных и социальных знаний в этих областях определяется степенью использования вероятностной методологии.
Актуальные знания: В соответствии с предпосылкой, реальностью, необходимым условием и критерием...
... о ц е н и т е с а м о с т о я т е л ь н о: — с т е п е н ь р а з в и т и я с о в р е м е н н о й н а у к и, — о б ъ е м В а ш и х з н а н и й и — В а ш и н т е л л е к т !
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