Urine Concentration and Dilution PDF

CHAPTER 29 UNIT V Urine Concentration and Dilution; Regulation of Extracellular Fluid Osmolarity and Sodium Concentration For t...

CHAPTER 29 UNIT V Urine Concentration and Dilution; Regulation of Extracellular Fluid Osmolarity and Sodium Concentration For the cells of the body to function properly, they must of concentrated urine without major changes in rates of be bathed in extracellular fluid with a relatively constant excretion of solutes such as sodium and potassium. This concentration of electrolytes. The total concentration of ability to regulate water excretion independently of solute solutes in the extracellular fluid—and therefore the osmo- excretion is necessary for survival, especially when fluid larity—must also be precisely regulated to prevent the intake is limited. cells from shrinking or swelling. The osmolarity is deter- mined by the amount of solute (mainly sodium chloride) ANTIDIURETIC HORMONE CONTROLS divided by the volume of the extracellular fluid. Thus, to URINE CONCENTRATION a large extent, extracellular fluid osmolarity and sodium chloride concentration are regulated by the amount of The body has a powerful feedback system for regulating extracellular water. The total body water is controlled plasma osmolarity and sodium concentration that oper- by (1) fluid intake, which is regulated by factors that ates by altering renal excretion of water independently of determine thirst; and (2) renal water excretion, which is solute excretion rate. A primary effector of this feedback controlled by multiple factors that influence glomerular is antidiuretic hormone (ADH), also called vasopressin. filtration and tubular reabsorption. When osmolarity of the body fluids increases above In this chapter, we discuss the following: (1) mecha- normal (i.e., the solutes in the body fluids become too nisms that cause the kidneys to eliminate excess water by concentrated), the posterior pituitary gland secretes excreting a dilute urine; (2) mechanisms that cause the more ADH, which increases the permeability of the dis- kidneys to conserve water by excreting a concentrated tal tubules and collecting ducts to water, as discussed in urine; (3) renal feedback mechanisms that control the Chapter 28. This mechanism increases water reabsorp- extracellular fluid sodium concentration and osmolarity; tion and decreases urine volume but does not markedly and (4) thirst and salt appetite mechanisms that deter- alter the rate of renal excretion of the solutes. mine the intakes of water and salt, which also help con- When there is excess water in the body, and extracel- trol extracellular fluid volume, osmolarity, and sodium lular fluid osmolarity is reduced, secretion of ADH by the concentration. posterior pituitary decreases, thereby reducing the per- meability of the distal tubule and collecting ducts to water, which causes increased amounts of more dilute urine to KIDNEYS EXCRETE EXCESS WATER BY be excreted. Thus, the rate of ADH secretion determines, FORMING DILUTE URINE to a large extent, whether the kidney excretes dilute or Normal kidneys have a tremendous capability to vary concentrated urine. the relative proportions of solutes and water in the urine in response to various challenges. When there is excess RENAL MECHANISMS FOR EXCRETING water in the body, and body fluid osmolarity is reduced, DILUTE URINE the kidneys can excrete urine with an osmolarity as low as 50 mOsm/L, a concentration that is only about one-sixth When there is a large excess of water in the body, the the osmolarity of normal extracellular fluid. Conversely, kidney can excrete as much as 20 L/day of dilute urine, when there is a deficit of water in the body, and extra- with a concentration as low as 50 mOsm/L. The kidney cellular fluid osmolarity is high, the kidneys can excrete performs this impressive feat by continuing to reabsorb highly concentrated urine with an osmolarity of 1200 solutes without reabsorbing large amounts of water in the to 1400 mOsm/L. Equally important, the kidneys can distal parts of the nephron, including the late distal tubule excrete a large volume of dilute urine or a small volume and collecting ducts. 365 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys Drink 1.0 L H2O NaCl H2O NaCl 800 300 300 Osmolarity Urine 100 100 (mOsm/L) osmolarity 300 400 Plasma NaCl osmolarity Cortex 0 6 Urine flow rate (ml/min) 4 400 70 400 400 NaCl 2 Medulla H 2O NaCl 0 1.2 600 600 600 50 Urinary solute (mOsm/min) excretion 0.6 Figure 29-2. Formation of dilute urine when antidiuretic hormone (ADH) levels are very low. Note that in the ascending loop of Henle, 0 the tubular fluid becomes very dilute. In the distal tubules and collect- 0 60 120 180 ing tubules, the tubular fluid is further diluted by the reabsorption of sodium chloride and the failure to reabsorb water when ADH levels Time (minutes) are very low. The failure to reabsorb water and continued reabsorp- Figure 29-1. Water diuresis in a person after ingestion of 1 liter of tion of solutes lead to a large volume of dilute urine. (Numerical val- water. Note that after water ingestion, urine volume increases and ues are in milliosmoles per liter.) urine osmolarity decreases, causing excretion of a large volume of dilute urine; however, the total amount of solute excreted by the kidneys remains relatively constant. These responses of the kidneys Tubular Fluid Is Diluted in the Ascending Loop of prevent plasma osmolarity from decreasing markedly during excess Henle. In the ascending limb of the loop of Henle, es- water ingestion. pecially in the thick segment, sodium, potassium, and chloride are avidly reabsorbed. However, this portion of Figure 29-1 shows the approximate renal responses in the tubular segment is impermeable to water, even in the a human after ingestion of 1 liter of water. Note that urine presence of large amounts of ADH. Therefore, the tubular volume increased to about six times normal within 45 min- fluid becomes more dilute as it flows up the ascending utes after the water had been ingested. However, the total loop of Henle into the early distal tubule, with the osmo- amount of solute excreted remained relatively constant larity decreasing progressively to about 100 mOsm/L by because the urine formed became dilute, and urine osmo- the time the fluid enters the early distal tubular segment. larity decreased from 600 to about 100 mOsm/L. Thus, after Thus, regardless of whether ADH is present or absent, fluid ingestion of excess water, the kidney rids the body of the leaving the early distal tubular segment is hypo-­osmotic, excess water but does not excrete excess amounts of solutes. with an osmolarity of only about one-third the osmolarity When the glomerular filtrate is initially formed, of plasma. its osmolarity is about the same as that of plasma (300 mOsm/L). To excrete excess water, the filtrate is diluted Tubular Fluid in Distal and Collecting Tubules Is as it passes along the tubule by reabsorbing solutes to a Further Diluted in Absence of ADH. As the dilute fluid greater extent than water, as shown in Figure 29-2. This in the early distal tubule passes into the late distal convo- dilution, however, occurs only in certain segments of the luted tubule, cortical collecting duct, and medullary col- tubular system, as described in the following sections. lecting duct, there is additional reabsorption of sodium chloride. In the absence of ADH, this portion of the tu- Tubular Fluid Remains Isosmotic in Proximal Tu- bule is also impermeable to water, and the additional re- bules. As fluid flows through the proximal tubule, solutes absorption of solutes causes the tubular fluid to become and water are reabsorbed in equal proportions, so little even more dilute, decreasing its osmolarity to as low as 50 change in osmolarity occurs. Thus, the proximal tubule mOsm/L. The failure to reabsorb water and continued re- fluid remains isosmotic to the plasma, with an osmolar- absorption of solutes lead to a large volume of dilute urine. ity of about 300 mOsm/L. As fluid passes down the de- To summarize, the mechanism for forming dilute scending loop of Henle, water is reabsorbed by osmosis, urine is to continue reabsorbing solutes from the distal and the tubular fluid reaches equilibrium with the sur- segments of the tubular system while reducing water rounding interstitial fluid of the renal medulla, which is reabsorption. In healthy kidneys, fluid leaving the ascend- very hypertonic—about two to four times the osmolarity ing loop of Henle and early distal tubule is always dilute, of the original glomerular filtrate. Therefore, the tubular regardless of the level of ADH. In the absence of ADH, the fluid becomes more concentrated as it flows into the in- urine is further diluted in the late distal tubule and collect- ner medulla. ing ducts, and a large volume of dilute urine is excreted. 366 https://ebook2book.ir/  Chapter 29 Urine Concentration and Dilution maximum concentration of sodium chloride that can be KIDNEYS CONSERVE WATER BY excreted by the kidneys is about 600 mOsm/L. Thus, for EXCRETING CONCENTRATED URINE every liter of seawater ingested, 1.5 liters of urine volume The ability of the kidney to form concentrated urine is would be required to rid the body of 1200 milliosmoles of essential for survival of mammals that live on land, includ- sodium chloride ingested in addition to 600 milliosmoles of other solutes, such as urea. This would result in a net ing humans. Water is continuously lost from the body UNIT V fluid loss of 0.5 liter for every liter of seawater, explain- through various routes, including the lungs by evapora- ing the rapid dehydration that occurs in shipwreck vic- tion into the expired air, the gastrointestinal tract by way tims who drink seawater. However, a shipwreck victim’s of the feces, the skin through evaporation and perspiration, pet Australian hopping mouse could drink seawater with and the kidneys through excretion of urine. Fluid intake is impunity. required to match this loss, but the ability of the kidneys to form a small volume of concentrated urine minimizes the Urine Specific Gravity fluid intake required to maintain homeostasis, a function Urine specific gravity is often used in clinical settings that is especially important when water is in short supply. to provide a rapid estimate of urine solute concentra- When there is a water deficit in the body, the kidneys tion. The more concentrated the urine, the higher the form concentrated urine by continuing to excrete solutes urine specific gravity. In most cases, urine specific grav- ity increases linearly with increasing urine osmolarity while increasing water reabsorption and decreasing the (Figure 29-3). Urine specific gravity, however, is a meas- urine volume. The human kidney can produce a maximal ure of the weight of solutes in a given volume of urine urine concentration of 1200 to 1400 mOsm/L, four to five and is therefore determined by the number and size of times the osmolarity of plasma. the solute molecules. In contrast, osmolarity is deter- Some desert animals, such as the Australian hop- mined only by the number of solute molecules in a given ping mouse, can concentrate urine to as high as 10,000 volume. mOsm/L. This ability allows the mouse to survive in the Urine specific gravity is generally expressed in grams desert without drinking water; sufficient water can be per milliliter (g/ml) and, in humans, normally ranges obtained through the ingested food and water produced from 1.002 to 1.028 g/ml, rising by 0.001 for every 35-­to in the body by metabolism of the food. Animals adapted 40-­mOsm/L increase in urine osmolarity. This relation- to freshwater environments usually have minimal urine-­ ship between specific gravity and osmolarity is altered when there are significant amounts of large molecules in concentrating ability. Beavers, for example, can concen- the urine, such as glucose, radiocontrast media used for trate the urine only to about 500 mOsm/L. diagnostic purposes, or some antibiotics. In these cases, urine specific gravity measurements may falsely suggest Obligatory Urine Volume a highly concentrated urine, despite a normal urine os- The maximal concentrating ability of the kidney dictates molality. how much urine volume must be excreted each day to rid Dipsticks are available that measure approximate urine the body of metabolic waste products and electrolytes that specific gravity, but most laboratories measure specific are ingested. A normal 70-­kg person must excrete about gravity with a refractometer. 600 milliosmoles of solute each day. If the maximal urine concentrating ability is 1200 mOsm/L, the minimal volume of urine that must be excreted, called the obligatory urine 1400 volume, can be calculated as follows: 600 mOsm/day = 0.5 L/day 1200 1200 mOsm/L This minimal loss of volume in the urine contributes to dehydration, along with water loss from the skin, res- 1000 piratory tract, and gastrointestinal tract, when water is not available to drink. Urine 800 The limited ability of the human kidney to concentrate Osmolarity (mOsm/L) the urine to only about 1200 mOsm/L explains why severe 600 dehydration occurs if one attempts to drink seawater. So- dium chloride concentration in the ocean averages about 3.0% to 3.5%, with an osmolarity between about 1000 and 400 1200 mOsm/L. Drinking 1 liter of seawater with a con- centration of 1200 mOsm/L would provide a total sodium 200 chloride intake of 1200 milliosmoles. If the maximal urine concentrating ability is 1200 mOsm/L, the amount of urine volume needed to excrete 1200 milliosmoles would be 1.0 1.010 1.020 1.030 1.040 liter. Why then does drinking seawater cause dehydration? Urine Specific Gravity (grams/ml) The answer is that the kidney must also excrete other sol- utes, especially urea, which contribute about 600 mOsm/L Figure 29-3. Relationship between specific gravity and osmolarity of the urine. when the urine is maximally concentrated. Therefore, the 367 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys The major factors that contribute to the buildup of sol- EXCRETING CONCENTRATED URINE ute concentration into the renal medulla are as follows: REQUIRES HIGH ADH LEVELS AND 1. Active transport of sodium ions and co-­transport of HYPEROSMOTIC RENAL MEDULLA potassium, chloride, and other ions out of the thick The basic requirements for forming a concentrated urine portion of the ascending limb of the loop of Henle are (1) a high level of ADH, which increases the perme- into the medullary interstitium ability of the distal tubules and collecting ducts to water, 2. Active transport of ions from the collecting ducts thereby allowing these tubular segments to avidly reab- into the medullary interstitium sorb water; and (2) a high osmolarity of the renal medul- 3. Facilitated diffusion of urea from the inner medul- lary interstitial fluid, which provides the osmotic gradient lary collecting ducts into the medullary interstitium necessary for water reabsorption to occur in the presence 4. Diffusion of only small amounts of water from the of high levels of ADH. medullary tubules into the medullary interstitium— The renal medullary interstitium surrounding the col- far less than the reabsorption of solutes into the lecting ducts is normally hyperosmotic, so when ADH medullary interstitium levels are high, water moves through the tubular mem- brane by osmosis into the renal interstitium; from there it is carried away by the vasa recta back into the blood. LOOP OF HENLE CHARACTERISTICS Thus, the urine-­concentrating ability is limited by the THAT CAUSE SOLUTES TO BE TRAPPED level of ADH and by the degree of hyperosmolarity of the IN THE RENAL MEDULLA renal medulla. We discuss the factors that control ADH The transport characteristics of the loops of Henle are secretion later, but for now, what is the process whereby summarized in Table 29-­1, along with the properties of renal medullary interstitial fluid becomes hyperosmotic? the proximal tubules, distal tubules, cortical collecting This process involves the operation of the countercurrent tubules, and inner medullary collecting ducts. multiplier mechanism. A major reason for the high medullary osmolarity is The countercurrent multiplier mechanism depends on active transport of sodium and co-­transport of potas- the special anatomical arrangement of the loops of Henle sium, chloride, and other ions from the thick ascending and vasa recta, the specialized peritubular capillaries of loop of Henle into the interstitium. This pump is capable the renal medulla. In humans, about 25% of the nephrons of establishing about a 200-­mOsm/L concentration gra- are juxtamedullary nephrons, with loops of Henle and dient between the tubular lumen and interstitial fluid. vasa recta that go deeply into the medulla before return- Because the thick ascending limb is virtually imperme- ing to the cortex. Some of the loops of Henle dip all the able to water, the solutes pumped out are not followed way to the tips of the renal papillae that project from the by osmotic flow of water into the interstitium. Thus, the medulla into the renal pelvis. Paralleling the long loops of active transport of sodium and other ions out of the thick Henle are the vasa recta, which also loop down into the ascending loop adds solutes in excess of water to the renal medulla before returning to the renal cortex. And finally, the collecting ducts, which carry urine through the hyper- osmotic renal medulla before it is excreted, also play a Table 29-­1 Summary of Tubule Characteristics—Urine critical role in the countercurrent mechanism. Concentration Permeability Active NaCl COUNTERCURRENT MULTIPLIER Structure Transport H2O NaCl Urea MECHANISM PRODUCES Proximal tubule ++ ++ + + HYPEROSMOTIC RENAL MEDULLARY Thin descending 0 ++ + + INTERSTITIUM limb Thin ascending 0 0 + + The osmolarity of interstitial fluid in almost all parts of limb the body is about 300 mOsm/L, which is similar to the Thick ascending ++ 0 0 0 plasma osmolarity. (As discussed in Chapter 25, the cor- limb rected osmolar activity, which accounts for intermolecu- Distal tubule + +ADH 0 0 lar attraction, is about 282 mOsm/L.) The osmolarity of the interstitial fluid in the medulla of the kidney is much Cortical collecting + +ADH 0 0 tubule higher and may increase progressively to about 1200 to 1400 mOsm/L in the pelvic tip of the medulla. This means Inner medullary + +ADH 0 +ADH collecting duct that the renal medullary interstitium has accumulated solutes in great excess of water. Once the high solute con- ADH, Antidiuretic hormone; NaCl, sodium chloride; 0, minimal level of active transport or permeability; +, moderate level of ac- centration in the medulla is achieved, it is maintained by tive transport or permeability; ++, high level of active transport or a balanced inflow and outflow of solutes and water in the permeability; +ADH, permeability to water or urea is increased by medulla. ADH. 368 https://ebook2book.ir/  Chapter 29 Urine Concentration and Dilution medullary interstitium. There is some passive reabsorp- Step 4 is the additional flow of fluid into the loop of tion of sodium chloride from the thin ascending limb of Henle from the proximal tubule, which causes the hyper- Henle’s loop, which is also essentially impermeable to osmotic fluid previously formed in the descending limb water, adding further to the high solute concentration of to flow into the ascending limb. Once this fluid is in the the renal medullary interstitium. ascending limb, additional ions are pumped into the The descending limb of Henle’s loop, in contrast to the interstitium and water remains in the tubular fluid until UNIT V ascending limb, is very permeable to water, and the tubu- a 200-­mOsm/L osmotic gradient is established, and the lar fluid osmolarity quickly becomes equal to the renal interstitial fluid osmolarity rises to 500 mOsm/L (step 5). medullary osmolarity. Therefore, water diffuses out of Then, once again, fluid in the descending limb reaches the descending limb of Henle’s loop into the interstitium, equilibrium with the hyperosmotic medullary interstitial and the tubular fluid osmolarity gradually rises as it flows fluid (step 6) and, as the hyperosmotic tubular fluid from toward the tip of the loop of Henle. the descending limb of the loop of Henle flows into the ascending limb, still more solute is continuously pumped Steps Involved in Causing Hyperosmotic Renal Medul- out of the tubules and deposited into the medullary lary Interstitium. Keeping in mind these characteristics of interstitium. the loop of Henle, let us now discuss how the renal medulla These steps are repeated over and over, with the net becomes hyperosmotic (Video 29-1). First, assume that the effect of adding more and more solute to the medulla in loop of Henle is filled with fluid having a concentration of excess of water. With sufficient time, this process gradu- 300 mOsm/L, the same as that leaving the proximal tu- ally traps solutes in the medulla and multiplies the con- bule (Figure 29-4, step 1). Next, the active ion pump of centration gradient established by the active pumping of the thick ascending limb on the loop of Henle reduces the ions out of the thick ascending loop of Henle, eventually concentration inside the tubule and raises the interstitial raising the interstitial fluid osmolarity to 1200 to 1400 concentration; this pump establishes a 200-­mOsm/L con- mOsm/L, as shown in step 7. centration gradient between the tubular fluid and intersti- Thus, the repetitive reabsorption of sodium chlo- tial fluid (Figure 29-4, step 2). The limit to the gradient is ride by the thick ascending loop of Henle and continued about 200 mOsm/L because paracellular diffusion of ions inflow of new sodium chloride from the proximal tubule back into the tubule eventually counterbalances the trans- into the loop of Henle is called the countercurrent multi- port of ions out of the lumen when the 200-­mOsm/L con- plier. The sodium chloride reabsorbed from the ascending centration gradient is achieved. loop of Henle keeps adding to the newly arrived sodium Step 3 is that the tubular fluid in the descending limb chloride, thus “multiplying” its concentration in the med- of the loop of Henle and interstitial fluid quickly reaches ullary interstitium. osmotic equilibrium due to osmosis of water out of the descending limb. The interstitial osmolarity is maintained ROLE OF DISTAL TUBULE AND at 400 mOsm/L because of continued transport of ions out COLLECTING DUCTS IN EXCRETING of the thick ascending loop of Henle. Thus, by itself, active CONCENTRATED URINE transport of sodium chloride out of the thick ascending limb is capable of establishing only a 200-­mOsm/L con- When the tubular fluid leaves the loop of Henle and flows centration gradient, which is much less than that achieved into the distal convoluted tubule in the renal cortex, the by the countercurrent multiplier system. fluid is dilute, with an osmolarity of only about 100 to 300 300 300 300 200 300 200 300 300 200 1 300 300 300 2 300 400 200 3 400 400 200 4 300 400 200 300 300 300 300 400 200 400 400 200 400 400 400 300 300 300 300 400 200 400 400 200 400 400 400 300 150 300 150 300 300 100 5 300 350 150 6 350 350 150 Repeat steps 4 to 6 7 700 700 500 400 500 300 500 500 300 1000 1000 800 400 500 300 500 500 300 1200 1200 1000 Figure 29-4. Countercurrent multiplier system in the loop of Henle for producing a hyperosmotic renal medulla. (Numerical values are in mil- liosmoles per liter.) 369 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys NaCl H2O Urea H2O NaCl UREA CONTRIBUTES TO HYPEROSMOTIC 300 RENAL MEDULLARY INTERSTITIUM AND 100 300 300 FORMATION OF CONCENTRATED URINE NaCl Urea contributes about 40% to 50% of the osmolarity Cortex (500–600 mOsm/L) of the renal medullary interstitium when the kidney is forming a maximally concentrated urine. Unlike sodium chloride, urea is passively reab- sorbed from the tubule. When there is a water deficit and 600 600 600 600 blood concentration of ADH is high, large amounts of NaCl urea are passively reabsorbed from the inner medullary Medulla H2O H2O NaCl collecting ducts into the interstitium. Urea The mechanism for reabsorption of urea into the renal 1200 1200 1200 1200 medulla is as follows. As water flows up the ascending loop of Henle and into the distal and cortical collecting Figure 29-5. Formation of a concentrated urine when antidiuretic tubules, little urea is reabsorbed because these segments hormone (ADH) levels are high. Note that the fluid leaving the loop are impermeable to urea (see Table 29-­1). In the pres- of Henle is dilute but becomes concentrated as water is absorbed ence of high concentrations of ADH, water is reabsorbed from the distal tubules and collecting tubules. With high ADH levels, rapidly from the cortical collecting tubule, and the urea the osmolarity of the urine is about the same as the osmolarity of the renal medullary interstitial fluid in the papilla, which is about 1200 concentration increases rapidly because urea is not very mOsm/L. (Numerical values are in milliosmoles per liter.) permeant in this part of the tubule. As the tubular fluid flows into the inner medullary col- lecting ducts, still more water reabsorption takes place, 140 mOsm/L (Figure 29-5). The early distal tubule fur- resulting in an even higher concentration of urea in the ther dilutes the tubular fluid because this segment, like fluid. This high concentration of urea in the tubular fluid the ascending loop of Henle, actively transports sodium of the inner medullary collecting duct causes urea to dif- chloride out of the tubule but is relatively impermeable fuse out of the tubule into the renal interstitial fluid. This to water. diffusion is greatly facilitated by specific urea transporters, As fluid flows into the cortical collecting tubule, the UT-­A1 and UT-­A3. These urea transporters are activated amount of water reabsorbed is critically dependent on the by ADH, increasing transport of urea out of the inner plasma concentration of ADH. In the absence of ADH, medullary collecting duct even more when ADH levels this segment is almost impermeable to water and fails to are elevated. The simultaneous movement of water and reabsorb water but continues to reabsorb solutes and fur- urea out of the inner medullary collecting ducts maintains ther dilutes the urine. When there is a high concentration a high concentration of urea in the tubular fluid and, even- of ADH, the cortical collecting tubule becomes highly tually, in the urine, even though urea is being reabsorbed. permeable to water, so large amounts of water are now The fundamental role of urea in contributing to urine-­ reabsorbed from the tubule into the cortex interstitium, concentrating ability is evidenced by the fact that people where it is swept away by the rapidly flowing peritubu- who ingest a high-­protein diet, yielding large amounts of lar capillaries. Because large amounts of water are reab- urea as a nitrogenous waste product, can concentrate their sorbed into the cortex, rather than into the renal medulla, urine much better than people whose protein intake and this helps preserve the high medullary interstitial fluid urea production are low. Malnutrition is associated with a osmolarity. low urea concentration in the medullary interstitium and As the tubular fluid flows along the medullary collect- considerable impairment of urine-­concentrating ability. ing ducts, there is further water reabsorption from the tubular fluid into the interstitium, but the total amount Recirculation of Urea from Collecting Duct to Loop of of water is relatively small compared with that added to Henle Contributes to Hyperosmotic Renal Medulla. the cortex interstitium. The reabsorbed water is carried A healthy person usually excretes about 20% to 60% of away by the vasa recta into the venous blood. When high the filtered load of urea, depending on urine flow rate and levels of ADH are present, the collecting ducts become state of hydration. In general, the rate of urea excretion is permeable to water, so the fluid at the end of the collect- determined mainly by the following: (1) concentration of ing ducts has essentially the same osmolarity as the inter- urea in the plasma; (2) glomerular filtration rate (GFR); stitial fluid of the renal medulla—about 1200 mOsm/L and (3) renal tubular urea reabsorption. In patients with (see Figure 29-4). Thus, by reabsorbing as much water renal disease who have large reductions in GFR, the plas- as possible, the kidneys form highly concentrated urine, ma urea concentration increases markedly, returning the excreting normal amounts of solutes in the urine while filtered urea load and urea excretion rate to the normal adding water back to the extracellular fluid and compen- level (equal to the rate of urea production), despite the sating for deficits of body water. reduced GFR. 370 https://ebook2book.ir/  Chapter 29 Urine Concentration and Dilution 100% remaining Henle, distal tubule, and cortical collecting tubule and back down into the medullary collecting duct again. In Urea this way, urea can recirculate through these terminal parts 4.5 Urea 4.5 of the tubular system several times before it is excreted. Each time around the circuit contributes to a higher con- Cortex 7 centration of urea. UNIT V 100% 50% remaining remaining This urea recirculation provides an additional mecha- 30 nism for forming a hyperosmotic renal medulla. Because 30 Outer H2O urea is one of the most abundant waste products that medulla 15 must be excreted by the kidneys, this mechanism for Urea concentrating urea before it is excreted is essential to Inner medulla 300 300 the economy of the body fluid when water is in short supply. UT-A2 UT-A1 When there is excess water in the body, urine flow rate 500 increases, and therefore the concentration of urea in the UT-A3 Urea 550 inner medullary collecting ducts decreases, causing less diffusion of urea into the renal medullary interstitium. ADH levels are also reduced when there is excess body 20% remaining water, and this reduction, in turn, decreases the perme- ability of the inner medullary collecting ducts to both Figure 29-6. Recirculation of urea absorbed from the medullary collecting duct into the interstitial fluid. This urea diffuses into the water and urea, and more urea is excreted in the urine. thin loop of Henle, then passes through the distal tubules, and finally passes back into the collecting duct. The recirculation of urea helps trap urea in the renal medulla and contributes to the hyperosmolarity COUNTERCURRENT EXCHANGE IN VASA of the renal medulla. The heavy lines, from the thick ascending loop RECTA PRESERVES HYPEROSMOLARITY of Henle to the medullary collecting ducts, indicate that these seg- OF RENAL MEDULLA ments are not very permeable to urea. The urea transporters UT-­A1 and UT-­A3 facilitate diffusion of urea out of the medullary collecting Blood flow must be provided to the renal medulla to sup- ducts while UT-­A2 facilitates urea diffusion into the thin descending ply the metabolic needs of the cells in this part of the kid- loop of Henle. (Numerical values are in milliosmoles per liter of urea ney. Without a special medullary blood flow system, the during antidiuresis, when large amounts of antidiuretic hormone are solutes pumped into the renal medulla by the countercur- present. Percentages of the filtered load of urea that remain in the tubules are indicated in the boxes.) rent multiplier system would be rapidly dissipated. Two special features of the renal medullary blood In the proximal tubule, 40% to 50% of the filtered urea flow contribute to the preservation of the high solute is reabsorbed but, even so, the tubular fluid urea concen- concentrations: tration increases because urea is not nearly as permeant 1. The medullary blood flow is low, accounting for as water. The concentration of urea continues to rise as less than 5% of the total renal blood flow. This slug- the tubular fluid flows into the thin segments of the loop gish blood flow is sufficient to supply the metabolic of Henle, partly because of water reabsorption out of the needs of the tissues but helps minimize solute loss descending loop of Henle but also because of some secre- from the medullary interstitium. tion of urea into the thin loop of Henle from the medul- 2. The vasa recta serve as countercurrent exchangers, lary interstitium (Figure 29-6). The passive secretion of minimizing the washout of solutes from the medul- urea into the thin loops of Henle is facilitated by the urea lary interstitium. transporter UT-­A2. The countercurrent exchange mechanism operates The thick limb of the loop of Henle, distal tubule, and as follows (Figure 29-7). Blood enters and leaves the cortical collecting tubule are all less permeable to urea, medulla via the vasa recta at the boundary of the cortex and only small amounts of urea reabsorption normally and renal medulla. The vasa recta, like other capillaries, occur in these tubular segments. When the kidney is are highly permeable to solutes in the blood, except for forming concentrated urine, and high levels of ADH are the plasma proteins. As blood descends into the medulla present, reabsorption of water from the distal tubule and toward the papillae, it becomes progressively more con- cortical collecting tubule further raises the tubular fluid centrated, partly by solute entry from the interstitium and concentration of urea. As this urea flows into the inner partly by loss of water into the interstitium. By the time medullary collecting duct, the high tubular fluid concen- the blood reaches the tips of the vasa recta, it has a con- tration of urea and urea transporters UT-­A1 and UT-­A3 centration of about 1200 mOsm/L, the same as that of the cause urea to diffuse into the medullary interstitium. A medullary interstitium. As blood ascends back toward the moderate share of the urea that moves into the medullary cortex, it becomes progressively less concentrated as sol- interstitium eventually diffuses into the thin loop of Henle utes diffuse back out into the medullary interstitium and and then passes upward through the ascending loop of as water moves into the vasa recta. 371 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys Although large amounts of fluid and solute are high concentration of solutes established by the counter- exchanged across the vasa recta, there is little net dilution current mechanism is preserved. of the concentration of the interstitial fluid at each level of the renal medulla because of the U shape of the vasa recta Increased Medullary Blood Flow Reduces Urine-­ capillaries, which act as countercurrent exchangers. Thus, Concentrating Ability. Certain vasodilators can mark- the vasa recta do not create the medullary hyperosmolar- edly increase renal medullary blood flow, thereby wash- ity, but they do prevent it from being dissipated. ing out some of the solutes from the renal medulla and The U-­shaped structure of the vessels minimizes loss reducing the maximum urine-­concentrating ability. Large of solute from the interstitium but does not prevent bulk increases in arterial pressure may also increase the blood flow of fluid and solutes into the blood through the usual flow of the renal medulla to a greater extent than in other colloid osmotic and hydrostatic pressures that favor reab- regions of the kidney and tend to wash out the hyperos- sorption in these capillaries. Under steady-­state condi- motic interstitium, thereby reducing urine-­concentrating tions, the vasa recta carry away only as much solute and ability. As discussed earlier, maximum concentrating abil- water as is absorbed from the medullary tubules, and the ity of the kidney is determined not only by the level of ADH but also by the osmolarity of the renal medulla in- terstitial fluid. Even with maximal ADH levels, the urine-­ Vasa recta Interstitium mOsm/L mOsm/L concentrating ability will be reduced if medullary blood flow increases enough to reduce the hyperosmolarity in 300 350 300 the renal medulla. Solute H2O 600 Solute 600 SUMMARY OF URINE-­CONCENTRATING 600 600 MECHANISM AND CHANGES IN Solute H2O OSMOLARITY IN DIFFERENT TUBULAR 800 Solute 800 SEGMENTS 800 900 The changes in osmolarity and volume of the tubular fluid Solute H2O 1000 Solute as it passes through the different parts of the nephron are 1000 1000 shown in Figure 29-8. 1200 1200 Proximal Tubule. About 65% of most filtered electrolytes is reabsorbed in the proximal tubule. However, the proxi- Figure 29-7. Countercurrent exchange in the vasa recta. Plasma mal tubular membranes are highly permeable to water flowing down the descending limb of the vasa recta becomes more hyperosmotic because of diffusion of water out of the blood and so, whenever solutes are reabsorbed, water also diffuses diffusion of solutes from the renal interstitial fluid into the blood. In through the tubular membrane by osmosis. Water diffu- the ascending limb of the vasa recta, solutes diffuse back into the sion across the proximal tubular epithelium is aided by interstitial fluid, and water diffuses back into the vasa recta. Large the water channel aquaporin 1 (AQP-­1). Therefore, the amounts of solutes would be lost from the renal medulla without osmolarity of the fluid remains about the same as the glo- the U shape of the vasa recta capillaries. (Numerical values are in mil- liosmoles per liter.) merular filtrate—300 mOsm/L. 25 ml 0.2 ml 1200 Diluting segment Osmolarity (mOsm/L) Late distal Medullary Cortical 900 Effect of ADH 600 8 ml Figure 29-8. Changes in osmolarity of the tubular flu- 300 125 ml 44 ml id as it passes through the different tubular segments 200 in the presence of high levels of antidiuretic hormone 100 25 ml (ADH) and absence of ADH. (Numerical values indicate 20 ml 0 the approximate volumes in milliliters per minute or in Proximal Loop of Henle Distal Collecting Urine osmolarities in milliosmoles per liter of fluid flowing tubule tubule tubule along the different tubular segments.) and duct 372 https://ebook2book.ir/  Chapter 29 Urine Concentration and Dilution Descending Loop of Henle. As fluid flows down the de- tubule to pass into the inner medullary collecting ducts, scending loop of Henle, water is absorbed into the medul- from which it is eventually reabsorbed or excreted in la. The descending limb also contains AQP-­1 and is highly the urine. In the absence of ADH, little water is reab- permeable to water but much less permeable to sodium sorbed in the late distal tubule and cortical collecting chloride and urea. Therefore, the osmolarity of the fluid tubule; therefore, osmolarity decreases even further flowing through the descending loop gradually increases because of continued active reabsorption of ions from UNIT V until it is nearly equal to that of the surrounding intersti- these segments. tial fluid, which is about 1200 mOsm/L when the blood concentration of ADH is high. Inner Medullary Collecting Ducts. The concentration of When dilute urine is being formed, as a result of low fluid in the inner medullary collecting ducts also depends ADH concentrations, the medullary interstitial osmolarity on the following: (1) ADH; and (2) the surrounding med- is less than 1200 mOsm/L; consequently, the descending ullary interstitium osmolarity established by the counter- loop tubular fluid osmolarity also becomes less concen- current mechanism. In the presence of large amounts of trated. This decrease in concentration is due partly to the ADH, these ducts are highly permeable to water, and wa- fact that less urea is absorbed into the medullary intersti- ter diffuses from the tubule into the interstitial fluid un- tium from the collecting ducts when ADH levels are low, til osmotic equilibrium is reached, with the tubular fluid and the kidney is forming a large volume of dilute urine. having about the same concentration as the renal med- ullary interstitium (1200–1400 mOsm/L). Thus, a small Thin Ascending Loop of Henle. The thin ascending volume of concentrated urine is produced when ADH limb is essentially impermeable to water but reabsorbs levels are high. Because water reabsorption increases urea some sodium chloride. Because of the high concentration concentration in the tubular fluid, and because the inner of sodium chloride in the tubular fluid as a result of wa- medullary collecting ducts have specific urea transporters ter removal from the descending loop of Henle, there is that greatly facilitate diffusion, much of the highly con- some passive diffusion of sodium chloride from the thin centrated urea in the ducts diffuses out of the tubular lu- ascending limb into the medullary interstitium. Thus, the men into the medullary interstitium. This absorption of tubular fluid becomes more dilute as the sodium chloride the urea into the renal medulla contributes to the high diffuses out of the tubule and water remains in the tubule. osmolarity of the medullary interstitium and high con- Some of the urea absorbed into the medullary inter- centrating ability of the kidney. stitium from the collecting ducts also diffuses into the Several important points to consider may not be obvi- ascending limb, thereby returning the urea to the tubular ous from this discussion. First, although sodium chlo- system and helping prevent its washout from the renal ride is one of the principal solutes that contribute to the medulla. This urea recycling is an additional mechanism hyperosmolarity of the medullary interstitium, the kidney that contributes to the hyperosmotic renal medulla. can, when needed, excrete a highly concentrated urine that contains little sodium chloride. The hyperosmolarity of Thick Ascending Loop of Henle. The thick part of the the urine in these circumstances is due to high concentra- ascending loop of Henle is also virtually impermeable to tions of other solutes, especially of waste products such water, but large amounts of sodium, chloride, potassium, as urea. One condition in which this occurs is dehydra- and other ions are actively transported from the tubule tion accompanied by low sodium intake. As discussed into the medullary interstitium. Therefore, fluid in the in Chapter 30, a low sodium intake stimulates formation thick ascending limb of the loop of Henle becomes very of the hormones angiotensin II and aldosterone, which dilute, falling to a concentration of about 140 mOsm/L. together cause avid sodium reabsorption from the tubules while leaving the urea and other solutes to maintain the Early Distal Tubule. The early distal tubule has properties highly concentrated urine. similar to those of the thick ascending loop of Henle, so Second, large quantities of dilute urine can be excreted further dilution of the tubular fluid to about 100 mOsm/L without increasing sodium excretion. This feat is accom- occurs as solutes are reabsorbed while water remains in plished by decreasing ADH secretion, which reduces the tubule. water reabsorption in the more distal tubular segments without significantly altering sodium reabsorption. Late Distal Tubule and Cortical Collecting Tubules. Finally, there is an obligatory urine volume dictated In the late distal tubule and cortical collecting tubules, by the maximum concentrating ability of the kidney and the osmolarity of the fluid depends on the level of ADH. amount of solute that must be excreted. Therefore, if With high ADH levels, these tubules are highly perme- large amounts of solute must be excreted, they must be able to water, and significant amounts of water are reab- accompanied by the minimal amount of water necessary sorbed. Urea, however, is not very permeant in this part to excrete them. For example, if 600 milliosmoles of solute of the nephron, resulting in increased urea concentra- must be excreted each day, this requires at least 0.5 liter tion as water is reabsorbed. This process allows most of urine if the maximal urine concentrating ability is 1200 of the urea delivered to the distal tubule and collecting mOsm/L. 373 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys Quantifying Renal Urine Concentration and Dilution: urine-­concentrating ability. No matter how much ADH Free Water and Osmolar Clearances is present, maximal urine concentration is limited by the The process of concentrating or diluting the urine requires degree of hyperosmolarity of the medullary interstitium. the kidneys to excrete water and solutes somewhat inde- 3.  Inability of the distal tubules, collecting tubules, and col- pendently. When the urine is dilute, water is excreted in ex- lecting ducts to respond to ADH. cess of solutes. Conversely, when the urine is concentrated, Failure to Produce ADH: Central Diabetes Insipidus. solutes are excreted in excess of water. An inability to produce or release ADH from the posterior The total clearance of solutes from the blood can be ex- pituitary can be caused by head injuries or infections, or it pressed as the osmolar clearance (Cosm). This is the volume can be congenital. Because the distal tubular segments can- of plasma cleared of solutes each minute, in the same way not reabsorb water in the absence of ADH, this condition, that clearance of a single substance is calculated: called central diabetes insipidus, results in the formation of a Uosm × V̇ large volume of dilute urine, with urine volumes that can ex- Cosm = ceed 15 L/day. The thirst mechanisms, discussed later in this Posm chapter, are activated when excessive water is lost from the where Uosm is the urine osmolarity, V is the urine flow rate, and body; therefore, as long as the person drinks enough water, Posm is plasma osmolarity. For example, if the plasma osmo- large decreases in body fluid water do not occur. The primary larity is 300 mOsm/L, urine osmolarity is 600 mOsm/L, and abnormality observed clinically in people with this condition urine flow rate is 1 ml/min (0.001 L/min), the rate of osmolar is the large volume of dilute urine. However, if water intake is excretion is 0.6 mOsm/min (600 mOsm/L × 0.001 L/min), and restricted, as can occur in a hospital setting when fluid intake osmolar clearance is 0.6 mOsm/min divided by 300 mOsm/L, is restricted or the patient is unconscious (e.g., because of a or 0.002 L/min (2.0 ml/min). This means that 2 milliliters of head injury), severe dehydration can rapidly occur. plasma are being cleared of solute each minute. The treatment for central diabetes insipidus is admin- Free Water Clearance—Relative Rates at Which istration of a synthetic analogue of ADH, desmopressin, Solutes and Water Are Excreted which acts selectively on V2 receptors to increase water permeability in the late distal and collecting tubules. Desm- Free water clearance (CH2O) is calculated as the difference opressin can be given by injection, as a nasal spray, or orally, between water excretion (urine flow rate) and osmolar and it rapidly restores urine output toward normal. clearance: Inability of Kidneys to Respond to ADH: Nephrogenic U osm × V̇ C H2O = V − C osm = V − Diabetes Insipidus. In some circumstances, normal or Posm elevated levels of ADH are present but the renal tubular Thus, the rate of free water clearance represents the segments cannot respond appropriately. This condition is rate at which solute-­free water is excreted by the kidneys. referred to as nephrogenic diabetes insipidus because the When free water clearance is positive, excess water is being abnormality resides in the kidneys. This abnormality can excreted by the kidneys; when free water clearance is nega- be due to failure of the countercurrent mechanism to form tive, excess solutes are being removed from the blood by a hyperosmotic renal medullary interstitium or failure of the kidneys, and water is being conserved. the distal and collecting tubules and collecting ducts to Using the example discussed earlier, if urine flow rate is 1 respond to ADH. In either case, large volumes of dilute ml/min and osmolar clearance is 2 ml/min, free water clear- urine are formed, which causes dehydration unless fluid ance would be –1 ml/min. This means that instead of water intake is increased by the same amount as urine volume being cleared from the kidneys in excess of solutes, the kid- is increased. neys are actually returning water to the systemic circulation, Many types of renal diseases can impair the concen- as occurs during water deficits. Thus, whenever urine osmo- trating mechanism, especially those that damage the renal larity is greater than plasma osmolarity, free water clear- medulla (see Chapter 32 for further discussion). Also, im- ance is negative, indicating water conservation. pairment of the function of the loop of Henle, as occurs When the kidneys are forming a dilute urine (i.e., urine with diuretics that inhibit electrolyte reabsorption by this osmolarity < plasma osmolarity), free water clearance will segment, such as furosemide, can compromise urine-­ be a positive value, denoting that water is being removed concentrating ability. Furthermore, certain drugs such as from the plasma by the kidneys in excess of solutes. Thus, lithium (used to treat manic-­depressive disorders) and tet- water free of solutes, called free water, is being lost from racyclines (used as antibiotics) can impair the ability of the the body, and the plasma is being concentrated when free distal nephron segments to respond to ADH. water clearance is positive. Nephrogenic diabetes insipidus can be distinguished from central diabetes insipidus by administration of desm- Disorders of Urinary Concentrating Ability opressin, the synthetic analogue of ADH. Lack of a prompt Impairment in the ability of the kidneys to concentrate or decrease in urine volume and an increase in urine osmo- dilute the urine appropriately can occur with one or more larity within 2 hours after injection of desmopressin is of the following abnormalities: strongly suggestive of nephrogenic diabetes insipidus. The 1. Inappropriate secretion of ADH. Either too much or too appropriate treatment for nephrogenic diabetes insipidus little ADH secretion results in abnormal water excre- is to correct, if possible, the underlying renal disorder. The tion by the kidneys. hypernatremia can also be attenuated by a low-­sodium diet 2. Impairment of the countercurrent mechanism. A hyper- and administration of a diuretic that enhances renal sodi- osmotic medullary interstitium is required for maximal um excretion, such as a thiazide diuretic. 374 https://ebook2book.ir/  Chapter 29 Urine Concentration and Dilution − CONTROL OF EXTRACELLULAR Water deficit FLUID OSMOLARITY AND SODIUM CONCENTRATION Regulation of extracellular fluid osmolarity and sodium Extracellular osmolarity concentration are closely linked because sodium is the UNIT V most abundant ion in the extracellular compartment. Osmoreceptors Plasma sodium concentration is normally regulated within close limits of 140 to 145 mEq/L, with an average ADH secretion (posterior pituitary) concentration of about 142 mEq/L. Osmolarity averages about 300 mOsm/L (≈282 mOsm/L when corrected for interionic attraction) and seldom changes more than ±2% to 3%. As discussed in Chapter 25, these variables must Plasma ADH be precisely controlled because they determine the distri- bution of fluid between the intracellular and extracellular compartments. H2O permeability in distal tubules, Estimating Plasma Osmolarity From collecting ducts Plasma Sodium Concentration In most clinical laboratories, plasma osmolarity is not routinely measured. However, because sodium and its H2O reabsorption associated anions account for about 94% of the solute in the extracellular compartment, plasma osmolarity (Posm) can be roughly estimated from the plasma sodium con- centration (PNa+) as follows: H2O excreted Posm = 2.1 × PNa+ (mmol/L) Figure 29-9. Osmoreceptor-­antidiuretic hormone (ADH) feedback mechanism for regulating extracellular fluid osmolarity in response For example, with a plasma sodium concentration of to a water deficit. 142 mEq/L, the plasma osmolarity would be estimated from this formula to be about 298 mOsm/L. To be more OSMORECEPTOR-­ADH FEEDBACK exact, especially in conditions associated with renal dis- SYSTEM ease, the contribution of the plasma concentrations (in units of mmol/L) of two other solutes, glucose and urea, Figure 29-9 shows the basic components of the are usually included: osmoreceptor-­ADH feedback system for control of extra- Posm = 2 × [PNa+ ,mmol/L] + [Pglucose ,mmol/L] + [Purea ,mmol/L] cellular fluid sodium concentration and osmolarity. When osmolarity increases above normal because of water defi- Such estimates of plasma osmolarity are usually accu- cit, for example, this feedback system operates as follows: rate within a few percentage points of those measured 1. An increase in extracellular fluid osmolarity directly. (which in practical terms means an increase in Normally, sodium ions and associated anions (pri- plasma sodium concentration) causes the special marily bicarbonate and chloride) represent about 94% nerve cells called osmoreceptor cells, located in the of the extracellular osmoles, with glucose and urea con- anterior hypothalamus near the supraoptic nuclei, tributing about 3% to 5% of the total osmoles. However, to shrink. because urea easily permeates most cell membranes, it 2. Shrinkage of the osmoreceptor cells causes them to exerts little effective osmotic pressure under steady-­state fire, sending nerve signals to additional nerve cells conditions. Therefore, the sodium ions in the extracel- in the supraoptic nuclei, which then relay these sig- lular fluid and associated anions are the principal deter- nals down the stalk of the pituitary gland to the pos- minants of fluid movement across the cell membrane. terior pituitary. Consequently, we can discuss the control of osmolarity 3. These action potentials conducted to the posterior and control of sodium ion concentration at the same pituitary stimulate release of ADH, which is stored time. in secretory granules (or vesicles) in the nerve end- Although multiple mechanisms control the amount of ings. sodium and water excretion by the kidneys, two primary 4. ADH enters the blood stream and is transported systems are especially involved in regulating the concen- to the kidneys, where it increases the water perme- tration of sodium and osmolarity of extracellular fluid: ability of the late distal tubules, cortical collecting (1) the osmoreceptor-­ADH system; and (2) the thirst tubules, and medullary collecting ducts. mechanism. 375 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys 5.  The increased water permeability in the distal nephron segments causes increased water reab- sorption and excretion of a small volume of concen- trated urine. Thus, water is conserved while sodium and other sol- Pituitary utes continue to be excreted in the urine. This causes dilution of the solutes in the extracellular fluid, thereby correcting the initial excessively concentrated extracellu- Osmoreceptors lar fluid. Baroreceptors The opposite sequence of events occurs when the Cardiopulmonary extracellular fluid becomes too dilute (hypo-­ osmotic). Supraoptic receptors For example, with excess water ingestion and a decrease neuron in extracellular fluid osmolarity, less ADH is formed, the Paraventricular renal tubules decrease their permeability for water, less Anterior neuron water is reabsorbed, and a large volume of dilute urine lobe is formed. This in turn concentrates the body fluids and Posterior returns plasma osmolarity toward normal. lobe ADH SYNTHESIS IN SUPRAOPTIC ADH AND PARAVENTRICULAR NUCLEI OF HYPOTHALAMUS AND ADH RELEASE FROM POSTERIOR PITUITARY Figure 29-10 shows the neuroanatomy of the hypothala- mus and the pituitary gland, where ADH is synthesized and released. The hypothalamus contains two types of magnocellular (large) neurons that synthesize ADH in the supraoptic and paraventricular nuclei of the hypothala- Urine: mus, about five-sixths in the supraoptic nuclei and about decreased flow one-sixth in the paraventricular nuclei. Both of these and concentrated nuclei have axonal extensions to the posterior pituitary. Figure 29-10. Neuroanatomy of the hypothalamus, where antidiu- Once ADH is synthesized, it is transported down the retic hormone (ADH) is synthesized, and the posterior pituitary gland, axons of the neurons to their tips, terminating in the pos- where ADH is released. terior pituitary gland. When the supraoptic and paraven- tricular nuclei are stimulated by increased osmolarity or region cause multiple deficits in the control of ADH other factors, nerve impulses pass down these nerve end- secretion, thirst, sodium appetite, and blood pressure. ings, changing their membrane permeability and increas- Electrical stimulation of this region or stimulation by ing calcium entry. ADH stored in the secretory granules angiotensin II can increase ADH secretion, thirst, and (also called vesicles) of the nerve endings is released in sodium appetite. response to increased calcium entry. The released ADH In the vicinity of the AV3V region and supraoptic is then carried away in the capillary blood of the poste- nuclei are neuronal cells that are excited by small increases rior pituitary into the systemic circulation. The secretion in extracellular fluid osmolarity—hence, the term osmore- of ADH in response to an osmotic stimulus is rapid, so ceptors has been used to describe these neurons. These plasma ADH levels can increase several-fold within min- cells send nerve signals to the supraoptic nuclei to control utes, thereby providing a rapid means for altering renal their firing and secretion of ADH. It is also likely that they excretion of water. induce thirst in response to increased extracellular fluid A second neuronal area important in control- osmolarity. ling osmolarity and ADH secretion is located along Both the subfornical organ and organum vasculosum the anteroventral region of the third ventricle, called of the lamina terminalis have vascular supplies that lack the AV3V region. At the upper part of this region is a the typical blood–­brain barrier that impedes the diffusion structure called the subfornical organ and, at the infe- of most ions from the blood into brain tissue. This char- rior part, is another structure called the organum vas- acteristic makes it possible for ions and other solutes to culosum of the lamina terminalis. Between these two cross between the blood and local interstitial fluid in this organs is the median preoptic nucleus, which has mul- region. As a result, the osmoreceptors rapidly respond tiple nerve connections with the two organs, as well as to changes in osmolarity of the extracellular fluid, exert- with the supraoptic nuclei and blood pressure control ing powerful control over the secretion of ADH and over centers in the medulla of the brain. Lesions of the AV3V thirst, as discussed later. 376 https://ebook2book.ir/  Chapter 29 Urine Concentration and Dilution Table 29-­2  Control of Antidiuretic Hormone Secretion Isotonic volume depletion Isovolemic osmotic increase Increase ADH Decrease ADH ↑ Plasma osmolarity ↓ Plasma osmolarity PAVP = 1.3 e−0.17 vol. 50 ↓ Blood volume ↑ Blood volume 45 ↓ Blood pressure ↑ Blood pressure UNIT V 40 Nausea Plasma ADH (pg/ml) 35 Hypoxia 30 Drugs Drugs 25 Morphine Alcohol PAVP = 2.5 Osm + 2.0 20 Nicotine Clonidine (antihypertensive) Cyclophosphamide Haloperidol (dopamine blocker) 15 10 5 more sensitive to small changes in osmolarity than to simi- 0 lar percentage changes in blood volume. For example, a change in plasma osmolarity of only 1% is sufficient to 0 5 10 15 20 increase ADH levels. By contrast, after blood loss, plasma Percent change ADH levels do not change appreciably until blood volume Figure 29-11. Effect of increased plasma osmolarity or decreased is reduced by about 10%. With further decreases in blood blood volume on the level of plasma (P) antidiuretic hormone (ADH), also called arginine vasopressin (AVP). (Modified from Dunn FL, Bren- volume, ADH levels rapidly increase. Thus, with severe nan TJ, Nelson AE, et al: The role of blood osmolality and volume in decreases in blood volume, the cardiovascular reflexes regulating vasopressin secretion in the rat. J Clin Invest 52:3212, play a major role in stimulating ADH secretion. The usual 1973.) daily regulation of ADH secretion during simple dehydra- tion is effected mainly by changes in plasma osmolarity. Decreases in blood volume and blood pressure, however, STIMULATION OF ADH RELEASE BY greatly enhance the ADH response to increased osmolarity. DECREASED ARTERIAL PRESSURE AND/ OR DECREASED BLOOD VOLUME OTHER STIMULI FOR ADH SECRETION ADH release is also controlled by cardiovascular reflexes that respond to decreases in blood pressure and/or blood ADH secretion can also be increased or decreased by volume, including the following: (1) the arterial barorecep- other stimuli to the central nervous system, as well as by tor reflexes; and (2) the cardiopulmonary reflexes, both of various drugs and hormones, as shown in Table 29-­2. For which are discussed in Chapter 18. These reflex pathways example, nausea is a potent stimulus for ADH release, originate in high-­pressure regions of the circulation, such which may increase to as much as 100 times normal after as the aortic arch and carotid sinus, and in low-­pressure vomiting. Also, drugs such as nicotine and morphine stim- regions, especially in the cardiac atria. Afferent stimuli are ulate ADH release, whereas some drugs, such as alcohol, carried by the vagus and glossopharyngeal nerves, with inhibit ADH release. The marked diuresis that occurs synapses in the nuclei of the tractus solitarius. Projections after ingestion of alcohol is due in part to the inhibition from these nuclei relay signals to the hypothalamic nuclei of ADH release. that control ADH synthesis and secretion. Thus, in addition to increased osmolarity, two other IMPORTANCE OF THIRST IN stimuli increase ADH secretion: (1) decreased arterial CONTROLLING EXTRACELLULAR pressure; and (2) decreased blood volume. Whenever FLUID OSMOLARITY AND SODIUM blood pressure and blood volume are reduced, such as CONCENTRATION during hemorrhage, increased ADH secretion causes increased fluid reabsorption by the kidneys, helping The kidneys minimize fluid loss during water deficits restore blood pressure and blood volume toward normal. through the osmoreceptor-­ADH feedback system. Ade- quate fluid intake, however, is necessary to counterbal- Quantitative Importance of Osmolarity ance whatever fluid loss does occur through sweating and Cardiovascular Reflexes in and breathing and through the gastrointestinal tract. Stimulating ADH Secretion Fluid intake is regulated by the thirst mechanism, which, As shown in Figure 29-11, a decrease in effective blood together with the osmoreceptor-­ADH mechanism, main- volume or an increase in extracellular fluid osmolarity tains precise control of extracellular fluid osmolarity and stimulates ADH secretion. However, ADH is considerably sodium concentration. 377 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys Table 29-­3  Control of Thirst Studies in animals have shown that angiotensin II acts Increase Thirst Decrease Thirst on the subfornical organ and on the organum vasculosum of the lamina terminalis. These regions are outside the ↑ Plasma osmolarity ↓ Plasma osmolarity blood–brain barrier, and peptides such as angiotensin II ↓ Blood volume ↑ Blood volume diffuse into the tissues. Because angiotensin II is also stimu- lated by factors associated with hypovolemia and low blood ↓ Blood pressure ↑ Blood pressure pressure, its effect on thirst helps restore blood volume and ↑ Angiotensin II ↓ Angiotensin II blood pressure toward normal along with the other actions Dry mouth Gastric distention of angiotensin II on the kidneys to decrease fluid excretion. 4. Dryness of the mouth and mucous membranes of the esophagus can elicit the sensation of thirst. Many of the same factors that stimulate ADH secre- As a result, a thirsty person may receive relief from tion also increase thirst, which is defined as the conscious thirst almost immediately after drinking water, even desire for water. though the water has not been absorbed from the gastro- intestinal tract and has not yet had an effect on extracel- lular fluid osmolarity. CENTRAL NERVOUS SYSTEM CENTERS 5. Gastrointestinal and pharyngeal stimuli influence FOR THIRST thirst. Referring again to Figure 29-10, the same area along the In animals that have an esophageal opening to the anteroventral wall of the third ventricle that promotes exterior so that water is never absorbed into the blood, ADH release also stimulates thirst. Located anterolat- partial relief of thirst occurs after drinking, although the erally in the preoptic nucleus is another small area that relief is only temporary. Also, gastrointestinal distention when stimulated electrically, causes immediate drinking may partially alleviate thirst; For example, simple inflation that continues as long as the stimulation lasts. All these of a balloon in the stomach can relieve thirst. However, areas together are called the thirst center. relief of thirst sensations through gastrointestinal or pha- The neurons of the thirst center respond to injec- ryngeal mechanisms is short-­lived; the desire to drink is tions of hypertonic salt solutions by stimulating drinking completely satisfied only when plasma osmolarity and/or behavior. These cells almost certainly function as osmore- blood volume returns to normal. ceptors to activate the thirst mechanism in the same way The ability of animals and humans to “meter” fluid that the osmoreceptors stimulate ADH release. intake is important because it prevents overhydration. Increased osmolarity of the cerebrospinal fluid in the After a person drinks water, 30 to 60 minutes may be third ventricle has essentially the same effect to promote required for the water to be reabsorbed and distributed drinking. It is likely that the organum vasculosum of the throughout the body. If the thirst sensation were not tem- lamina terminalis, which lies immediately beneath the porarily relieved after drinking water, the person would ventricular surface at the inferior end of the AV3V region, continue to drink more and more, eventually leading is intimately involved in mediating this response. to overhydration and excess dilution of the body fluids. Experimental studies have repeatedly shown that ani- mals drink almost exactly the amount necessary to return STIMULI FOR THIRST plasma osmolarity and volume to normal. Table 29-­3 summarizes some of the known stimuli for thirst. 1. One of the most important is increased extracellular THRESHOLD FOR OSMOLAR STIMULUS fluid osmolarity, which causes intracellular dehydra- OF DRINKING tion in the thirst centers, thereby stimulating the sensa- The kidneys must continually excrete an obligatory tion of thirst. amount of water, even in a dehydrated person, to rid the The value of this response is obvious: it helps dilute