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.