Guyton and Hall Physiology Chapter 19 PDF

CHAPTER 19 UNIT IV Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertensio...

CHAPTER 19 UNIT IV Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension: The Integrated System for Arterial Pressure Regulation In addition to the rapidly acting mechanisms for regula- just as sensitive—if not more so—to pressure changes as tion of arterial pressure discussed in Chapter 18, the body in the hagfish. Indeed, an increase in arterial pressure in also has powerful mechanisms for regulating arterial the human of only a few millimeters of Hg can double pressure week after week and month after month. This the renal output of water, a phenomenon called pressure long-term control of arterial pressure is closely inter- diuresis, as well as double the output of salt, called pres- twined with homeostasis of body fluid volume, which is sure natriuresis. determined by the balance between fluid intake and out- In humans, just as in the hagfish, the renal–body put. For long-term survival, fluid intake and output must fluid system for arterial pressure control is a fundamen- be precisely balanced, a task that is performed by multiple tal mechanism for long-term arterial pressure control. nervous and hormonal controls and by local control sys- However, through the stages of evolution, multiple refine- tems in the kidneys that regulate their excretion of salt ments have been added to make this system much more and water. In this chapter, we discuss these renal–body precise in its control. An especially important refinement, fluid systems that play a major role in long-term blood as discussed later, has been the addition of the renin- pressure regulation. angiotensin mechanism. RENAL–BODY FLUID SYSTEM FOR QUANTITATION OF PRESSURE DIURESIS ARTERIAL PRESSURE CONTROL AS A BASIS FOR ARTERIAL PRESSURE CONTROL The renal–body fluid system for arterial pressure control acts slowly but powerfully, as follows. If blood volume Figure 19-1 shows the approximate average effect of dif- increases and vascular capacitance is not altered, arterial ferent arterial pressure levels on the renal output of salt pressure will also increase. The rising pressure, in turn, and water by an isolated kidney, demonstrating mark- causes the kidneys to excrete the excess volume, thus edly increased urine output as the pressure rises. This returning the pressure back toward normal. increased urinary output is the phenomenon of pressure In the phylogenetic history of animal development, this diuresis. The curve in this figure is called a renal urinary renal–body fluid system for pressure control is a primitive output curve or a renal function curve. In humans, at an one. It is fully operative in one of the lowest of vertebrates, arterial pressure of 50 mm Hg, the urine output is essen- the hagfish. This animal has a low arterial pressure, only 8 tially zero. At 100 mm Hg, it is normal and, at 200 mm to 14 mm Hg, and this pressure increases almost directly Hg, it is 4 to 6 times normal. Furthermore, not only does in proportion to its blood volume. The hagfish continually increasing the arterial pressure increase urine volume drinks sea water, which is absorbed into its blood, increas- output, but it also causes an approximately equal increase ing the blood volume and blood pressure. However, when in sodium output, which is the phenomenon of pressure the pressure rises too high, the kidney excretes the excess natriuresis. volume into the urine and relieves the pressure. At low pressure, the kidney excretes less fluid than is ingested. Experiment Demonstrating the Renal–Body Fluid Therefore, because the hagfish continues to drink, extra- System for Arterial Pressure Control. Figure 19-2 cellular fluid volume, blood volume, and pressure all build shows the results of an experiment in dogs in which all up again to the higher levels. the nervous reflex mechanisms for blood pressure con- This primitive mechanism of pressure control has sur- trol were first blocked. Then, the arterial pressure was vived throughout the ages, but with the addition of multi- suddenly elevated by infusing about 400 ml of blood ple nervous system, hormones, and local control systems intravenously. Note the rapid increase in cardiac out- that also contribute to the regulation of salt and water put to about double normal and the increase in mean excretion. In humans, kidney output of water and salt is arterial pressure to 205 mm Hg, 115 mm Hg above its 229 UNIT IV The Circulation 8 Renal output of 4000 Cardiac output water and salt 7 Intake and output (x normal) (ml/min) 3000 6 2000 5 4 1000 B Urinary output 4 3 Equilibrium (ml/min) 3 point 2 Water and 2 salt intake 1 1 A 0 0 225 0 40 80 120 160 200 Arterial pressure 200 Mean arterial pressure (mm Hg) 175 (mm Hg) Figure 19-1. A typical arterial pressure–renal urinary output curve 150 measured in a perfused isolated kidney, showing pressure diuresis 125 when the arterial pressure rises above normal (point A) to approxi- 100 mately 150 mm Hg (point B). The equilibrium point A describes the 75 level to which the arterial pressure will be regulated if intake is not 50 altered. (Note that the small portion of the salt and water intake that Infusion period is lost from the body through nonrenal routes is ignored in this and 0 10 20 30 40 50 60 120 similar figures in this chapter.) Time (minutes) Figure 19-2. Increases in cardiac output, urinary output, and arterial resting level. Shown by the middle curve is the effect of pressure caused by increased blood volume in dogs whose nervous this increased arterial pressure on urine output, which pressure control mechanisms had been blocked. This figure shows increased 12-fold. Along with this tremendous loss of return of arterial pressure to normal after about 1 hour of fluid loss fluid in the urine, both the cardiac output and arterial into the urine. (Courtesy Dr. William Dobbs.) pressure returned to normal during the subsequent hour. output. Therefore, body fluid volume increases, blood Thus, one sees an extreme capability of the kidneys to volume increases, and the arterial pressure rises until eliminate excess fluid volume from the body in response once again it returns to the equilibrium point. This return to high arterial pressure and, in so doing, to return the of the arterial pressure always back to the equilibrium arterial pressure back to normal. point is known as the near-infinite feedback gain principle Renal–Body Fluid Mechanism Provides Nearly Infinite for control of arterial pressure by the renal–body fluid Feedback Gain for Long-term Arterial Pressure Control. mechanism. Figure 19-1 shows the relationship of the following: (1) the renal output curve for water and salt in response to rising ar- Two Key Determinants of Long-Term Arterial Pressure. terial pressure; and (2) the line that represents the net water In Figure 19-1, one can also see that two basic long-term and salt intake. Over a long period, the water and salt output factors determine the long-term arterial pressure level. must equal the intake. Furthermore, the only point on the As long as the two curves representing the renal output graph in Figure 19-1 at which output equals intake is where of salt and water and the intake of salt and water remain the two curves intersect, called the equilibrium point (point exactly as they are shown in Figure 19-1, the mean arte- A). Let us see what happens if the arterial pressure increases rial pressure level will eventually readjust to 100 mm Hg, above or decreases below the equilibrium point. which is the pressure level depicted by the equilibrium First, assume that the arterial pressure rises to 150 mm point of this figure. Furthermore, there are only two ways Hg (point B). At this level, the renal output of water and in which the pressure of this equilibrium point can be salt is almost three times as great as intake. Therefore, changed from the 100 mm Hg level. One is by shifting the the body loses fluid, the blood volume decreases, and the pressure level of the renal output curve for salt and water, arterial pressure decreases. Furthermore, this negative and the other is by changing the level of the water and salt balance of fluid will not cease until the pressure falls all intake line. Therefore, expressed simply, the two primary the way back exactly to the equilibrium level. Even when determinants of the long-term arterial pressure level are the arterial pressure is only a few mm Hg greater than the as follows: equilibrium level, there still is slightly more loss of water 1. The degree of pressure shift of the renal output and salt than intake, so the pressure continues to fall that curve for water and salt last few mm Hg until the pressure eventually returns to the 2. The level of the water and salt intake equilibrium point. Operation of these two determinants in the control of If the arterial pressure falls below the equilibrium arterial pressure is demonstrated in Figure 19-3. In Fig- point, the intake of water and salt is greater than the ure 19-3A, some abnormality of the kidneys has caused 230  Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension 8 8 Chronic Acute Intake or output (× normal) 6 High intake 6 B 4 4 UNIT IV Normal Elevated Intake or output (× normal) 2 pressure 2 0 Normal intake A 0 50 100 150 200 250 A 0 0 50 100 150 200 Arterial pressure (mm Hg) 8 Figure 19-4. Acute and chronic renal output curves. Under steady- Elevated state conditions, the renal output of salt and water is equal to intake 6 of salt and water. Points A and B represent the equilibrium points for pressure long-term regulation of arterial pressure when salt intake is normal or 4 six times normal, respectively. Because of the steepness of the chronic renal output curve, increased salt intake normally causes only small Normal changes in arterial pressure. In persons with impaired kidney func- 2 tion, the steepness of the renal output curve may be reduced, similar to the acute curve, resulting in increased sensitivity of arterial pres- 0 sure to changes in salt intake. B 0 50 100 150 200 250 Arterial pressure (mm Hg) much greater effect on the renal output of salt and wa- Figure 19-3. Two ways in which the arterial pressure can be in- ter than that observed during acute changes in pressure creased. A, By shifting the renal output curve in the right-hand direc- (Figure 19-4). Thus, when the kidneys are functioning tion toward a higher pressure level or by increasing the intake level normally, the chronic renal output curve is much steeper of salt and water (B). than the acute curve. the renal output curve to shift 50 mm Hg in the high- The powerful effects of chronic increases in arte- pressure direction (to the right). Note that the equilib- rial pressure on urine output occur because increased rium point has also shifted to 50 mm Hg higher than pressure not only has direct hemodynamic effects on normal. Therefore, one can state that if the renal output the kidney to increase excretion, but also has indirect curve shifts to a new pressure level, the arterial pressure effects mediated by nervous and hormonal changes that will follow to this new pressure level within a few days. occur when blood pressure is increased. For example, Figure 19-3B shows how a change in the level of salt increased arterial pressure decreases activity of the and water intake also can change the arterial pressure. In sympathetic nervous system, partly through the baro- this case, the intake level has increased fourfold, and the receptor reflex mechanisms discussed in Chapter 18, equilibrium point has shifted to a pressure level of 160 and by reducing formation of various hormones such as mm Hg, 60 mm Hg above the normal level. Conversely, angiotensin II and aldosterone that tend to reduce salt a decrease in the intake level would reduce the arterial and water excretion by the kidneys. Reduced activity pressure. of these antinatriuretic systems therefore amplifies the Thus, it is impossible to change the long-term mean arte- effectiveness of pressure natriuresis and diuresis in rais- rial pressure level to a new value without changing one or ing salt and water excretion during chronic increases both of the two basic determinants of long-term arterial in arterial pressure (see Chapters 28 and 30 for further pressure, either (1) the level of salt and water intake or (2) discussion). the degree of shift of the renal function curve along the Conversely, when blood pressure is reduced, the sym- pressure axis. However, if either of these is changed, one pathetic nervous system is activated, and formation of finds the arterial pressure thereafter to be regulated at a antinatriuretic hormones is increased, adding to the new pressure level, the arterial pressure at which the two direct effects of reduced pressure to decrease renal out- new curves intersect. put of salt and water. This combination of direct effects In most people, however, the renal function curve of pressure on the kidneys and indirect effects of pressure is much steeper than that shown in Figure 19-3, and on the sympathetic nervous system and various hormone changes in salt intake have only a modest effect on arterial systems make pressure natriuresis and diuresis extremely pressure, as discussed in the next section. powerful factors for long-term control of arterial pressure and body fluid volumes. Chronic Renal Output Curve Much Steeper Than the The importance of neural and hormonal influences Acute Curve. An important characteristic of pressure on pressure natriuresis is especially evident during natriuresis (and pressure diuresis) is that chronic changes chronic changes in sodium intake. If the kidneys and in arterial pressure, lasting for days or months, have a nervous and hormonal mechanisms are functioning 231 UNIT IV The Circulation Hyperthyroidism normally, chronic increases in intakes of salt and water Beriberi to as high as six times normal are usually associated AV shunts Pulmonary disease with little effect on arterial pressure. Note that the Removal of four limbs Paget's disease Arterial pressure and cardiac output blood pressure equilibrium point B on the curve is 200 nearly the same as point A, the equilibrium point at Hypothyroidism normal salt intake. Conversely, decreases in salt and Ca Normal (percent of normal) rd water intake to as low as one-sixth normal typically 150 ia Anemia c have little effect on arterial pressure. Thus, many per- sons are said to be salt-insensitive because large varia- 100 outp tions in salt intake do not change blood pressure more Arterial pressure ut than a few mm Hg. Persons with kidney injury or excessive secretion of 50 antinatriuretic hormones such as angiotensin II or aldo- sterone, however, may be salt-sensitive, with an attenu- ated renal output curve similar to the acute curve shown 0 in Figure 19-4. In these cases, even moderate increases 40 60 80 100 120 140 160 Total peripheral resistance in salt intake may cause significant increases in arterial (percent of normal) pressure. Figure 19-5. Relationships of total peripheral resistance to the long- Some of the factors that cause blood pressure to be term levels of arterial pressure and cardiac output in different clinical salt-sensitive include loss of functional nephrons due abnormalities. In these conditions, the kidneys were functioning nor- to kidney injury and excessive formation of antinatri- mally. Note that changing the whole-body total peripheral resistance uretic hormones such as angiotensin II or aldosterone. caused equal and opposite changes in cardiac output but, in all cases, For example, surgical reduction of kidney mass or had no effect on arterial pressure. AV, Arteriovenous. (Modified from Guyton AC: Arterial Pressure and Hypertension. Philadelphia: WB injury to the kidney due to hypertension, diabetes, or Saunders, 1980.) various kidney diseases all cause blood pressure to be more sensitive to changes in salt intake. In these cases, greater than normal increases in arterial pressure are amounts of salt and water are lost from the body; this pro- required to raise renal output sufficiently to maintain cess continues until the arterial pressure returns to the a balance between the intake and output of salt and equilibrium pressure level. At this point, blood pressure water. is normalized, and extracellular fluid volume and blood There is evidence that long-term high salt intake, last- volume are decreased to levels below normal. ing for several years, may actually damage the kidneys and Figure 19-5 shows the approximate cardiac outputs eventually makes blood pressure more salt-sensitive. We and arterial pressures in different clinical conditions in will discuss salt sensitivity of blood pressure in patients which the long-term total peripheral resistance is much with hypertension later in this chapter. less than or much greater than normal, but kidney excre- tion of salt and water is normal. Note in all these differ- Failure of Increased Total Peripheral ent clinical conditions that the arterial pressure is also Resistance to Elevate Long-Term Level of normal. Arterial Pressure if Fluid Intake and Renal A word of caution is necessary at this point in our Function Do Not Change discussion. Often, when the total peripheral resistance Recalling the basic equation for arterial pressure—arte- increases, this also increases the intrarenal vascular rial pressure equals cardiac output times total peripheral resistance at the same time, which alters the function of resistance—it is clear that an increase in total peripheral the kidney and can cause hypertension by shifting the resistance should elevate the arterial pressure. Indeed, renal function curve to a higher pressure level, as shown when the total peripheral resistance is acutely increased, in Figure 19-3A. We will see an example of this mecha- the arterial pressure does rise immediately. Yet, if the nism later in this chapter when we discuss hypertension kidneys continue to function normally, the acute rise in caused by vasoconstrictor mechanisms. However, it is arterial pressure usually is not maintained. Instead, the the increase in renal resistance that is the culprit, not arterial pressure returns all the way to normal within the increased total peripheral resistance—an important about 1 or 2 days. Why? distinction. The reason for this phenomenon is that increasing vas- cular resistance everywhere else in the body besides in the Increased Fluid Volume Can Elevate kidneys does not change the equilibrium point for blood Arterial Pressure by Increasing Cardiac pressure control as dictated by the kidneys (see Figures Output or Total Peripheral Resistance 19-1 and 19-3). Instead, the kidneys immediately begin The overall mechanism whereby increased extracellular fluid to respond to the high arterial pressure, causing pres- volume may elevate arterial pressure, if vascular capacity is sure diuresis and pressure natriuresis. Within hours, large not simultaneously increased, is shown in Figure 19-6. The 232  Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension − Increased extracellular fluid volume Finally, because arterial pressure is equal to cardiac output times total peripheral resistance, the secondary increase in total peripheral resistance that results from the autoregulation mechanism helps increase the arte- Increased blood volume rial pressure. For example, only a 5% to 10% increase in UNIT IV cardiac output can increase the arterial pressure from Increased mean circulatory filling pressure the normal mean arterial pressure of 100 mm Hg up to 150 mm Hg when accompanied by an increase in total peripheral resistance due to tissue blood flow autoregu- Increased venous return of blood to the heart lation or other factors that cause vasoconstriction. The slight increase in cardiac output is often not measurable. Increased cardiac output Importance of Salt (NaCl) in the Renal– Body Fluid Schema for Arterial Pressure Regulation Autoregulation Although the discussions thus far have emphasized the importance of volume in regulation of arterial pressure, Increased total experimental studies have shown that an increase in peripheral resistance salt intake is far more likely to elevate the arterial pres- sure, especially in people who are salt-sensitive, than is Increased arterial pressure an increase in water intake. The reason for this finding is that pure water is normally excreted by the kidneys almost as rapidly as it is ingested, but salt is not excreted Increased urine output so easily. As salt accumulates in the body, it also indi- rectly increases the extracellular fluid volume for two basic reasons: Figure 19-6. Sequential steps whereby increased extracellular fluid volume increases the arterial pressure. Note especially that increased 1. Although some additional sodium may be stored in cardiac output has both a direct effect to increase arterial pressure and the tissues when salt accumulates in the body, ex- an indirect effect by first increasing the total peripheral resistance. cess salt in the extracellular fluid increases the fluid osmolality. The increased osmolarity stimulates the sequential events are as follows: (1) increased extracellular thirst center in the brain, making the person drink fluid volume, which (2) increases the blood volume, which extra amounts of water to return the extracellular (3) increases the mean circulatory filling pressure, which salt concentration to normal and increasing the ex- (4) increases venous return of blood to the heart, which (5) tracellular fluid volume. increases cardiac output, which (6) increases arterial pres- 2. The increase in osmolality caused by the excess salt sure. The increased arterial pressure, in turn, increases the in the extracellular fluid also stimulates the hypo- renal excretion of salt and water and may return extracellular thalamic–posterior pituitary gland secretory mech- fluid volume to nearly normal if kidney function is normal anism to secrete increased quantities of antidiuretic and vascular capacity is unaltered. hormone (discussed in Chapter 29). The antidiu- Note especially in this case the two ways in which an retic hormone then causes the kidneys to reabsorb increase in cardiac output can increase the arterial pres- greatly increased quantities of water from the renal sure. One of these is the direct effect of increased car- tubular fluid, thereby diminishing the excreted vol- diac output to increase the pressure, and the other is an ume of urine but increasing the extracellular fluid indirect effect to raise total peripheral vascular resistance volume. through autoregulation of blood flow. The second effect Thus, the amount of salt that accumulates in the can be explained as follows. body is an important determinant of the extracellular Referring to Chapter 17, let us recall that whenever an fluid volume. Relatively small increases in extracellular excess amount of blood flows through a tissue, the local fluid and blood volume can often increase the arterial tissue vasculature constricts and decreases the blood flow pressure substantially. This is true, however, only if the back toward normal. This phenomenon is called autoreg- excess salt accumulation leads to an increase in blood ulation, which simply means regulation of blood flow by volume and if vascular capacity is not simultaneously the tissue itself. When increased blood volume raises the increased. As discussed previously, increasing salt intake cardiac output, blood flow tends to increase in all tissues in the absence of impaired kidney function or excessive of the body; if the increased blood flow exceeds the meta- formation of antinatriuretic hormones usually does not bolic needs of the tissues, the autoregulation mechanisms increase arterial pressure much because the kidneys rap- constricts blood vessels all over the body, which in turn idly eliminate the excess salt, and blood volume is hardly increases the total peripheral resistance. altered. 233 UNIT IV The Circulation understanding the role of the renal–body fluid volume CHRONIC HYPERTENSION (HIGH BLOOD mechanism for arterial pressure regulation. Volume- PRESSURE) CAUSED BY IMPAIRED RENAL loading hypertension means hypertension caused by FUNCTION excess accumulation of extracellular fluid in the body, When a person is said to have chronic hypertension (or some examples of which follow. high blood pressure), this means that his or her mean arterial pressure is greater than the upper range of the Experimental Volume-Loading Hypertension accepted normal measure. A mean arterial pressure Caused by Reduced Kidney Mass and Increased Salt greater than 110 mm Hg (normal is ≈90 mm Hg) is con- Intake. Figure 19-7 shows a typical experiment dem- sidered to be hypertensive. (This level of mean pressure onstrating volume-loading hypertension in a group of occurs when the diastolic blood pressure is greater than dogs with 70% of their kidney mass removed. At the first ≈90 mm Hg and the systolic pressure is greater than ≈135 circled point on the curve, the two poles of one of the mm Hg.) In persons with severe hypertension, the mean kidneys were removed, and at the second circled point, arterial pressure can rise to 150 to 170 mm Hg, with dia- the entire opposite kidney was removed, leaving the an- stolic pressure as high as 130 mm Hg and systolic pressure imals with only 30% of their normal renal mass. Note occasionally as high as 250 mm Hg. that removal of this amount of kidney mass increased Even moderate elevation of arterial pressure leads to the arterial pressure by an average of only 6 mm Hg. shortened life expectancy. At severely high pressures— Then, the dogs were given salt solution to drink instead that is, mean arterial pressures 50% or more above nor- of water. Because salt solution fails to quench the thirst, mal—a person can expect to live no more than a few more the dogs drank two to four times the normal amounts years unless appropriately treated. The lethal effects of of volume, and within a few days, their average arterial hypertension are caused mainly in three ways: pressure rose to about 40 mm Hg above normal. After 1. Excess workload on the heart leads to early heart 2 weeks, the dogs were given tap water again instead of failure and coronary heart disease, often causing salt solution; the pressure returned to normal within 2 death as a result of a heart attack. days. Finally, at the end of the experiment, the dogs were 2. The high pressure frequently damages a major given salt solution again, and this time the pressure rose blood vessel in the brain, followed by death of major much more rapidly to a high level, again demonstrating portions of the brain; this occurrence is a cerebral volume-loading hypertension. infarct. Clinically, it is called a stroke. Depending If one considers again the basic determinants of long- on which part of the brain is involved, a stroke can term arterial pressure regulation, it is apparent why be fatal or cause paralysis, dementia, blindness, or hypertension occurred in the volume-loading experiment multiple other serious brain disorders. illustrated in Figure 19-7. First, reduction of the kidney 3. High pressure almost always causes injury in the mass to 30% of normal greatly reduced the ability of the kidneys, producing many areas of renal destruction kidneys to excrete salt and water. Therefore, salt and water and, eventually, kidney failure, uremia, and death. accumulated in the body and, in a few days, raised the Lessons learned from the type of hypertension arterial pressure high enough to excrete the excess salt called volume-loading hypertension have been crucial in and water intake. 0.9% NaCl Tap water 0.9% NaCl 150 140 Mean arterial pressure (percent of control) 130 120 Figure 19-7. The average effect on ar- 35-45% of left Entire right terial pressure of drinking 0.9% saline kidney removed kidney removed 110 solution (0.9% NaCl) instead of water in dogs with 70% of their renal tissue removed. (Modified from Langston JB, 100 Guyton AC, Douglas BH, et al: Effect of changes in salt intake on arterial pressure and renal function in partially 0 nephrectomized dogs. Circ Res 12:508, 0 20 40 60 80 100 1963.) Days 234  Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension Sequential Changes in Circulatory Function During After these early acute changes in the circulatory vari- Development of Volume-Loading Hypertension. It is ables had occurred, more prolonged secondary changes especially instructive to study the sequential changes in occurred during the next few weeks. Especially important circulatory function during progressive development of was a progressive increase in total peripheral resistance, volume-loading hypertension (Figure 19-8). A week or while at the same time the cardiac output decreased back UNIT IV so before the point labeled “0” days, the kidney mass had toward normal, at least partly as a result of the long-term already been decreased to only 30% of normal. Then, at blood flow autoregulation mechanism discussed in Chap- this point, the intake of salt and water was increased to ter 17 and earlier in this chapter. That is, after the car- about six times normal and kept at this high intake there- diac output had risen to a high level and had initiated the after. The acute effect was to increase extracellular fluid hypertension, the excess blood flow through the tissues volume, blood volume, and cardiac output to 20% to 40% then caused progressive constriction of the local arteri- above normal. Simultaneously, the arterial pressure began oles, thus returning the local blood flow in the body tis- to rise but not nearly so much at first as the fluid volumes sues and also the cardiac output toward normal while and cardiac output. The reason for this slower rise in pres- simultaneously causing a secondary increase in total sure can be discerned by studying the total peripheral peripheral resistance. resistance curve, which shows an initial decrease in total Note that the extracellular fluid volume and blood vol- peripheral resistance. This decrease was caused by the ume also returned toward normal along with the decrease baroreceptor mechanism discussed in Chapter 18, which in cardiac output. This outcome resulted from two fac- transiently attenuated the rise in pressure. However, after tors. First, the increase in arteriolar resistance decreased 2 to 4 days, the baroreceptors adapted (reset) and were no the capillary pressure, which allowed the fluid in the tis- longer able to prevent the rise in pressure. At this time, the sue spaces to be absorbed back into the blood. Second, arterial pressure had risen almost to its full height because the elevated arterial pressure now caused the kidneys to of the increase in cardiac output, even though the total excrete the excess volume of fluid that had initially accu- peripheral resistance was still almost at the normal level. mulated in the body. Several weeks after the initial onset of volume loading, 20 the following effects were found: Extracellular fluid volume 19 33% 1. Hypertension (liters) 18 17 4% 2. Marked increase in total peripheral resistance 16 3. Almost complete return of the extracellular fluid 15 volume, blood volume, and cardiac output back to normal volume 6.0 (liters) Blood 5.5 20% 5% Therefore, we can divide volume-loading hypertension 5.0 into two sequential stages. The first stage results from 40% increased fluid volume causing increased cardiac output. resistance Cardiac output 7.0 6.5 This increase in cardiac output mediates the hyperten- (L/min) 6.0 sion. The second stage in volume-loading hypertension 5.5 5% is characterized by high blood pressure and high total 5.0 peripheral resistance but return of the cardiac output so close to normal that the usual measuring techniques (mm Hg/L/min) peripheral 28 frequently cannot detect an abnormally elevated cardiac 26 Total 33% 24 output. 22 20 Thus, the increased total peripheral resistance in 18 −13% volume-loading hypertension occurs after the hyper- 150 40% tension has developed and, therefore, is secondary to 30% pressure (mm Hg) 140 the hypertension rather than being the cause of the Arterial 130 hypertension. 120 110 Volume-Loading Hypertension in Patients 0 0 2 4 6 8 10 12 14 Who Have No Kidneys but Are Being Days Maintained With an Artificial Kidney Figure 19-8. Progressive changes in important circulatory system When a patient is maintained with an artificial kidney, variables during the first few weeks of volume-loading hypertension. it is especially important to keep the patient’s body fluid Note especially the initial increase in cardiac output as the basic cause volume at a normal level by removing the appropriate of the hypertension. Subsequently, the autoregulation mechanism amount of water and salt each time the patient undergoes returns the cardiac output almost to normal while simultaneously causing a secondary increase in total peripheral resistance. (Modified dialysis. If this step is not performed, and extracellular from Guyton AC: Arterial Pressure and Hypertension. Philadelphia: fluid volume is allowed to increase, hypertension almost WB Saunders, 1980.) invariably develops in exactly the same way as shown 235 UNIT IV The Circulation in Figure 19-8. That is, the cardiac output increases at sympathetic nervous system, various hormones, and local first and causes hypertension. Then, the autoregulation autacoids such as prostaglandins, nitric oxide, and endo- mechanism returns the cardiac output back toward nor- thelin. When the arterial pressure falls, the JG cells release mal while causing a secondary increase in total peripheral renin by at least three major mechanisms: resistance. Therefore, in the end, the hypertension appears 1. Pressure-sensitive baroreceptors in the JG cells re- to be a high peripheral resistance type of hypertension, spond to decreased arterial pressure with increased although the initial cause is excess volume accumulation. release of renin. 2. Decreased sodium chloride delivery to the macula Hypertension Caused by Excess densa cells in the early distal tubule stimulates renin Aldosterone release (discussed further in Chapter 27) Another type of volume-loading hypertension is caused 3. Increased sympathetic nervous system activity stim- by excess aldosterone in the body or, occasionally, by ulates renin release by activating beta-adrenergic excesses of other types of steroids. A small tumor in one receptors in the JG cells. Sympathetic stimulation of the adrenal glands occasionally secretes large quanti- also activates alpha-adrenergic receptors, which ties of aldosterone, which is the condition called primary can increase renal sodium chloride reabsorption aldosteronism. As discussed in Chapters 28 and 30, aldo- and reduce the glomerular filtration rate in cases sterone increases the rate of salt and water reabsorption of strong sympathetic activation. Increased renal by the tubules of the kidneys, thereby increasing blood sympathetic activity also enhances the sensitivity of volume, extracellular fluid volume, and arterial pressure. renal baroreceptor and macula densa mechanisms If salt intake is increased at the same time, the hyperten- for renin release. sion becomes even greater. Furthermore, if the condition Most of the renin enters the renal blood and then persists for months or years, the excess arterial pressure passes out of the kidneys to circulate throughout the often causes pathological changes in the kidneys that entire body. However, small amounts of the renin do make the kidneys retain even more salt and water in addi- remain in the local fluids of the kidney and initiate several tion to that caused directly by the aldosterone. Therefore, intrarenal functions. the hypertension often finally becomes severe to the point Renin itself is an enzyme, not a vasoactive substance. of being lethal. As shown in Figure 19-9, renin acts enzymatically on Here again, in the early stages of this type of hyperten- another plasma protein, a globulin called renin substrate sion, cardiac output is often increased but, in later stages, (or angiotensinogen), to release a 10–amino acid peptide, the cardiac output generally returns almost to normal angiotensin I. Angiotensin I has mild vasoconstrictor while total peripheral resistance becomes secondarily elevated, as explained earlier in the chapter for primary Decreased volume-loading hypertension. arterial pressure ROLE OF THE RENIN-ANGIOTENSIN Renin (kidney) SYSTEM IN ARTERIAL PRESSURE CONTROL Renin substrate Aside from the capability of the kidneys to control arterial (angiotensinogen) pressure through changes in extracellular fluid volume, Angiotensin I the kidneys also have another powerful mechanism for controlling pressure, the renin-angiotensin system. Converting Renin is a protein enzyme released by the kidneys enzyme when the arterial pressure falls too low. In turn, it raises (lung) the arterial pressure in several ways, thus helping correct Angiotensin II the initial fall in pressure. Angiotensinase COMPONENTS OF THE RENIN- (Inactivated) ANGIOTENSIN SYSTEM Renal retention Vasoconstriction of salt and water Figure 19-9 shows the main functional steps whereby the renin-angiotensin system helps regulate arterial pressure. Renin is synthesized and stored in the juxtaglomerular cells (JG cells) of the kidneys. The JG cells are modified Increased arterial pressure smooth muscle cells located mainly in the walls of the afferent arterioles immediately proximal to the glomeruli. Figure 19-9. The renin-angiotensin vasoconstrictor mechanism for Multiple factors control renin secretion, including the arterial pressure control. 236  Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension properties but not enough to cause significant changes in 100 Arterial pressure (mm Hg) With circulatory function. The renin persists in the blood for renin-angiotensin system 30 to 60 minutes and continues to cause formation of still 75 more angiotensin I during this entire time. Within a few seconds to minutes after the formation 50 Without UNIT IV of angiotensin I, two additional amino acids are split renin-angiotensin system from the angiotensin I to form the 8–amino acid peptide 25 Hemorrhage angiotensin II. This conversion occurs to a great extent in the lungs while the blood flows through the small vessels 0 of the lungs, catalyzed by an enzyme called angiotensin- 0 10 20 30 40 converting enzyme (ACE) that is present in the endothe- Minutes lium of the lung vessels. Other tissues such as the kidneys Figure 19-10. The pressure-compensating effect of the renin- and blood vessels also contain ACE and therefore form angiotensin vasoconstrictor system after severe hemorrhage. (Drawn from experiments by Dr. Royce Brough.) angiotensin II locally. Angiotensin II is an extremely powerful vasocon- strictor, and it affects circulatory function in other ways this system can be of lifesaving service to the body, espe- as well. However, it persists in the blood only for 1 or 2 cially in circulatory shock. minutes because it is rapidly inactivated by multiple blood Note also that the renin-angiotensin vasoconstric- and tissue enzymes collectively called angiotensinases. tor system requires about 20 minutes to become fully Angiotensin II has two principal effects that can ele- active. Therefore, it is somewhat slower for blood pres- vate arterial pressure. The first of these, vasoconstriction sure control than the nervous reflexes and sympathetic in many areas of the body, occurs rapidly. Vasoconstric- norepinephrine-epinephrine system. tion occurs intensely in the arterioles and less so in the veins. Constriction of the arterioles increases the total Angiotensin II Causes Renal Retention of peripheral resistance, thereby raising the arterial pressure, Salt and Water—An Important Means for as demonstrated at the bottom of Figure 19-9. Also, the Long-Term Control of Arterial Pressure mild constriction of the veins promotes increased venous Angiotensin II causes the kidneys to retain both salt and return of blood to the heart, thereby helping the heart water in two major ways: pump against the increasing pressure. 1. Angiotensin II acts directly on the kidneys to cause The second principal means whereby angiotensin II salt and water retention. increases the arterial pressure is decreased excretion of salt 2. Angiotensin II stimulates the adrenal glands to secrete and water by the kidneys due to stimulation of aldoste- aldosterone, and the aldosterone in turn increases salt rone secretion, as well as direct effects on the kidneys. The and water reabsorption by the kidney tubules. salt and water retention by the kidneys slowly increases Thus, whenever excess amounts of angiotensin II the extracellular fluid volume, which then increases the circulate in the blood, the entire long-term renal–body arterial pressure during subsequent hours and days. This fluid mechanism for arterial pressure control automati- long-term effect, through the direct and indirect actions cally becomes set to a higher arterial pressure level than of angiotensin II on the kidneys, is even more powerful normal. than the acute vasoconstrictor mechanism in eventually Mechanisms of the Direct Renal Effects of Angiotensin raising the arterial pressure. II to Cause Renal Retention of Salt and Water. Angio- Rapidity and Intensity of the tensin has several direct renal effects that make the kid- Vasoconstrictor Pressure Response to the neys retain salt and water. One major effect is to constrict Renin-Angiotensin System the renal arterioles, especially the glomerular efferent ar- terioles, thereby diminishing blood flow through the kid- Figure 19-10 shows an experiment demonstrating the neys. The slow flow of blood reduces the pressure in the effect of hemorrhage on the arterial pressure under two peritubular capillaries, which increases reabsorption of separate conditions: (1) with the renin-angiotensin sys- fluid from the tubules. Angiotensin II also has important tem functioning; and (2) after blocking the system with direct actions on the tubular cells to increase tubular re- a renin-blocking antibody. Note that after hemorrhage— absorption of sodium and water, as discussed in Chapter enough to cause acute decrease of the arterial pressure 28. The combined effects of angiotensin II can sometimes to 50 mm Hg—the arterial pressure rose back to 83 mm decrease urine output to less than one-fifth normal. Hg when the renin-angiotensin system was functional. Conversely, it rose to only 60 mm Hg when the renin- Angiotensin II Increases Kidney Salt and Water angiotensin system was blocked. This phenomenon shows Retention by Stimulating Aldosterone. Angiotensin that the renin-angiotensin system is powerful enough to II is also one of the most powerful stimulators of aldos- return the arterial pressure at least halfway back to normal terone secretion by the adrenal glands, as we shall dis- within a few minutes after severe hemorrhage. Therefore, cuss in relation to body fluid regulation in Chapter 30 237 UNIT IV The Circulation and in relation to adrenal gland function in Chapter 78. Role of the Renin-Angiotensin System in Therefore, when the renin-angiotensin system becomes Maintaining a Normal Arterial Pressure activated, the rate of aldosterone secretion usually also Despite Large Variations in Salt Intake increases; an important subsequent function of aldoster- One of the most important functions of the renin- one is to cause marked increase in sodium reabsorption angiotensin system is to allow a person to ingest very by the kidney tubules, thus increasing the total body ex- small or very large amounts of salt without causing major tracellular fluid sodium and, as already explained, extra- changes in extracellular fluid volume or arterial pressure. cellular fluid volume. Thus, both the direct effect of an- This function is explained by Figure 19-12, which shows giotensin II on the kidneys and its effect acting through that the initial effect of increased salt intake is to elevate aldosterone are important in long-term arterial pressure the extracellular fluid volume, which tends to elevate the control. arterial pressure. Multiple effects of increased salt intake, including small increases in arterial pressure and pressure- Quantitative Analysis of Arterial Pressure Changes independent effects, reduce the rate of renin secretion and Caused by Angiotensin II. Figure 19-11 shows a quanti- angiotensin II formation, which then helps eliminate the tative analysis of the effect of angiotensin in arterial pres- sure control. This figure shows two renal function curves, additional salt with minimal increases in extracellular fluid as well as a line depicting a normal level of sodium intake. volume or arterial pressure. Thus, the renin-angiotensin The left-hand renal function curve is that measured in dogs system is an automatic feedback mechanism that helps whose renin-angiotensin system had been blocked by an maintain the arterial pressure at or near the normal level, ACE inhibitor drug that blocks the conversion of angioten- even when salt intake is increased. When salt intake is sin I to angiotensin II. The right-hand curve was measured decreased below normal, exactly opposite effects take place. in dogs infused continuously with angiotensin II at a level To emphasize the efficacy of the renin-angiotensin about 2.5 times the normal rate of angiotensin formation in system in controlling arterial pressure, when the system the blood. Note the shift of the renal output curve toward functions normally, the pressure usually rises no more higher pressure levels under the influence of angiotensin II. than 4 to 6 mm Hg in response to as much as a 100-fold This shift is caused by the direct effects of angiotensin II on increase in salt intake (Figure 19-13). Conversely, when the kidney and the indirect effect acting through aldoster- one secretion, as explained earlier. the usual suppression of angiotensin formation is pre- Finally, note the two equilibrium points, one for zero vented due to continuous infusion of small amounts of angiotensin showing an arterial pressure level of 75 mm angiotensin II so that blood levels cannot decrease, the Hg, and one for elevated angiotensin showing a pressure same increase in salt intake may cause the pressure to level of 115 mm Hg. Therefore, the effect of angiotensin to rise by 40 mm Hg or more (see Figure 19-13). When salt cause renal retention of salt and water can have a powerful intake is reduced to as low as one-tenth normal, arterial effect in promoting chronic elevation of the arterial pres- pressure barely changes as long as the renin-angiotensin sure. system functions normally. However, when angiotensin II Angiotensin levels in the blood Increased salt intake (× normal) 0 2.5 10 Increased extracellular volume Sodium intake and output (× normal) 8 Increased arterial pressure 6 Decreased renin and angiotensin 4 Equilibrium Decreased renal retention of salt and water points 2 Normal Intake Return of extracellular volume almost to normal 0 0 60 80 100 120 140 160 Return of arterial pressure almost to normal Arterial pressure (mm Hg) Figure 19-11. The effect of two angiotensin II levels in the blood on Figure 19-12. Sequential events whereby increased salt intake in- the renal output curve showing regulation of the arterial pressure at creases the arterial pressure, but feedback decrease in activity of the an equilibrium point of 75 mm Hg, when the angiotensin II level is renin angiotensin system returns the arterial pressure almost to the low, and at 115 mm Hg, when the angiotensin II level is high. normal level. 238  Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension 500 Sodium intake 500 (mEq/day) 400 300 240 200 100 80 5 UNIT IV 150 140 Ang II Mean arterial pressure 130 120 (mm Hg) 110 Normal Renal artery constricted Constriction released control 100 Systemic arterial 90 pressure ACE 200 80 inhibition 70 Pressure (mm Hg) 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 150 Time (days) Figure 19-13. Changes in mean arterial pressure during chronic Distal renal arterial changes in sodium intake in normal control dogs and in dogs treated 100 pressure with an angiotensin-converting enzyme (ACE) inhibitor to block an- giotensin II (Ang II) formation or infused with Ang II to prevent Ang II from being suppressed. Sodium intake was raised in steps from a low 50 level of 5 mmol/day to 80, 240, and 500 mmol/day for 8 days at each level. (Modified from Hall JE, Guyton AC, Smith MJ Jr, et al: Blood pressure and renal function during chronic changes in sodium intake: 7 role of angiotensin. Am J Physiol 239:F271, 1980.) X Normal Renin secretion formation is blocked with an ACE inhibitor, blood pres- sure decreases markedly as salt intake is reduced (see 1 Figure 19-13). Thus, the renin-angiotensin system is per- 0 haps the body’s most powerful system for accommodat- 0 4 8 12 Days ing wide variations in salt intake with minimal changes in arterial pressure. Figure 19-14. Effect of placing a constricting clamp on the renal artery of one kidney after the other kidney has been removed. Note the changes in systemic arterial pressure, renal artery pressure distal HYPERTENSION CAUSED BY RENIN- to the clamp, and rate of renin secretion. The resulting hypertension is called one-kidney Goldblatt hypertension. SECRETING TUMOR OR RENAL ISCHEMIA Occasionally, a tumor of the renin-secreting JG cells One-Kidney Goldblatt Hypertension. When one kid- occurs and secretes large quantities of renin, caus- ney is removed, and a constrictor is placed on the renal ing formation of large amounts of angiotensin II. In all artery of the remaining kidney, as shown in Figure 19- patients in whom this phenomenon has occurred, severe 14, the immediate effect is greatly reduced pressure in the hypertension has developed. Also, when large amounts renal artery beyond the constrictor, as demonstrated by of angiotensin II are infused continuously for days or the dashed curve in the figure Then, within seconds or weeks into animals, similar severe long-term hyperten- minutes, the systemic arterial pressure begins to rise and sion develops. continues to rise for several days. The pressure usually We have already noted that angiotensin II can increase rises rapidly for the first hour or so, and this effect is fol- the arterial pressure in two ways: lowed by a slower additional rise during the next several 1. By constricting the arterioles throughout the entire days. When the systemic arterial pressure reaches its new body, thereby increasing the total peripheral resist- stable pressure level, the renal arterial pressure distal to ance and arterial pressure; this effect occurs within the constriction (the dashed curve in the figure) will have seconds after one begins to infuse large amounts of returned almost all the way back to normal. The hyper- angiotensin II. tension produced in this way is called one-kidney Gold- 2. By causing the kidneys to retain salt and water; over blatt hypertension in honor of Harry Goldblatt, who first a period of days, even moderate amounts of angio- studied the important quantitative features of hyperten- tensin II can cause causes hypertension through its sion caused by renal artery constriction. renal actions, the principal cause of the long-term The early rise in arterial pressure in Goldblatt hyper- elevation of arterial pressure. tension is caused by the renin-angiotensin vasoconstrictor 239 UNIT IV The Circulation mechanism. That is, because of poor blood flow through the remaining kidney mass also to retain salt and water. the kidney after acute constriction of the renal artery, One of the most common causes of renal hypertension, large quantities of renin are secreted by the kidney, as especially in older persons, is this patchy ischemic kidney demonstrated by the lowermost curve in Figure 19-14, disease. and this action increases angiotensin II and aldosterone levels in the blood. The angiotensin II, in turn, raises the Other Types of Hypertension Caused by Combinations arterial pressure acutely. The secretion of renin rises to a of Volume Loading and Vasoconstriction peak in about 1 or 2 hours but returns nearly to normal in Hypertension in the Upper Part of the Body Caused by 5 to 7 days because the renal arterial pressure by that time Coarctation of the Aorta. One out of every few thousand has also risen back to normal, so the kidney is no longer babies is born with pathological constriction or blockage ischemic. of the aorta at a point beyond the aortic arterial branches The second rise in arterial pressure is caused by reten- to the head and arms but proximal to the renal arteries, tion of salt and water by the constricted kidney, which is a condition called coarctation of the aorta. When this oc- curs, blood flow to the lower body is carried by multiple also stimulated by angiotensin II and aldosterone. In 5 to 7 small collateral arteries in the body wall, with much vascu- days, the body fluid volume increases enough to raise the lar resistance between the upper aorta and lower aorta. As arterial pressure to its new sustained level. The quantita- a consequence, the arterial pressure in the upper part of the tive value of this sustained pressure level is determined body may be 40% to 50% higher than that in the lower body. by the degree of constriction of the renal artery. That is, The mechanism of this upper body hypertension is al- the aortic pressure must rise enough so that renal arterial most identical to that of one-kidney Goldblatt hyperten- pressure distal to the constrictor is high enough to cause sion. That is, when a constrictor is placed on the aorta normal urine output. above the renal arteries, the blood pressure in both kidneys A similar scenario occurs in patients with stenosis of falls at first, renin is secreted, angiotensin and aldosterone the renal artery of a single remaining kidney, as some- are formed, and hypertension occurs in the upper body. times occurs after a person receives a kidney transplant. The arterial pressure in the lower body at the level of the kidneys rises approximately to normal, but high pressure Also, functional or pathological increases in resistance persists in the upper body. The kidneys are no longer is- of the renal arterioles, due to atherosclerosis or exces- chemic, and thus secretion of renin and formation of angi- sive levels of vasoconstrictors, can cause hypertension otensin and aldosterone return to nearly normal. Likewise, through the same mechanisms as constriction of the main in coarctation of the aorta, the arterial pressure in the lower renal artery. body is usually almost normal, whereas the pressure in the upper body is far higher than normal. Two-Kidney Goldblatt Hypertension. Hypertension also Role of Autoregulation in Hypertension Caused by can result when the artery to only one kidney is con- Aortic Coarctation. A significant feature of hypertension stricted while the artery to the other kidney is normal. caused by aortic coarctation is that blood flow in the arms, The constricted kidney secretes renin and also retains salt where the pressure may be 40% to 60% above normal, is and water because of decreased renal arterial pressure in almost exactly normal. Also, blood flow in the legs, where this kidney. Then, the “normal” opposite kidney retains the pressure is not elevated, is almost exactly normal. How could this be, with the pressure in the upper body 40% to salt and water because of the renin produced by the is- 60% greater than in the lower body? There are no differ- chemic kidney. This renin causes increased formation of ences in vasoconstrictor substances in the blood of the up- angiotensin II and aldosterone, both of which circulate to per and lower body because the same blood flows to both the opposite kidney and cause it also to retain salt and areas. Likewise, the nervous system innervates both areas water. Thus, both kidneys—but for different reasons—be- of the circulation similarly, so there is no reason to believe come salt and water retainers. Consequently, hyperten- that there is a difference in nervous control of the blood sion develops. vessels. The main reason is that long-term autoregulation The clinical counterpart of two-kidney Goldblatt develops so nearly completely that the local blood flow con- hypertension occurs when there is stenosis of a single trol mechanisms have compensated almost 100% for the renal artery—for example, caused by atherosclerosis—in differences in pressure. The result is that in both the high- a person who has two kidneys. pressure area and low-pressure area, the local blood flow is controlled by local autoregulatory mechanisms almost exactly in accord with the needs of the tissue and not in Hypertension Caused by Diseased Kidneys That accord with the level of the pressure. Secrete Renin Chronically. Often, patchy areas of one or Hypertension in Preeclampsia (Toxemia of Pregnancy). both kidneys are diseased and become ischemic because A syndrome called preeclampsia (also called toxemia of of local vascular constrictions or infarctions, whereas pregnancy) develops in approximately 5% to 10% of expect- other areas of the kidneys are normal. When this situa- ant mothers. One of the manifestations of preeclampsia tion occurs, almost identical effects occur as in the two- is hypertension that usually subsides after delivery of the kidney type of Goldblatt hypertension. That is, the patchy baby. Although the precise causes of preeclampsia are not ischemic kidney tissue secretes renin, which, in turn—by completely understood, ischemia of the placenta and sub- acting through the formation of angiotensin II—causes sequent release by the placenta of toxic factors are believed 240  Chapter 19 Role of the Kidneys in Long-Term Control of Arterial Pressure and in Hypertension to play a role in causing many of the manifestations of this ment of the hypertension, the sympathetic nervous system disorder, including hypertension in the mother. Substances is considerably more active than in normal rats. In the later released by the ischemic placenta, in turn, cause dysfunc- stages of this type of hypertension, structural changes have tion of vascular endothelial cells throughout the body, in- been observed in the nephrons of the kidneys: (1) increased cluding the blood vessels of the kidneys. This endothelial preglomerular renal arterial resistance; and (2) decreased dysfunction decreases release of nitric oxide and other vaso- permeability of the glomerular membranes. These struc- UNIT IV dilator substances, causing vasoconstriction, decreased tural changes could also contribute to the long-term con- rate of fluid filtration from the glomeruli into the renal tu- tinuance of the hypertension. In other strains of hyperten- bules, impaired renal pressure natriuresis, and the develop- sive rats, impaired renal function also has been observed. ment of hypertension. In humans, several different gene mutations have been Another pathological abnormality that may contribute identified that can cause hypertension. These forms of hy- to hypertension in preeclampsia is thickening of the kid- pertension are called monogenic hypertension because they ney glomerular membranes (perhaps caused by an auto- are caused by mutation of a single gene. An interesting fea- immune process), which also reduces the glomerular fluid ture of these genetic disorders is that they all cause impaired filtration rate. For obvious reasons, the arterial pressure kidney function, either by increased resistance of the renal level required to cause normal formation of urine becomes arterioles or by excessive salt and water reabsorption by the elevated, and the long-term level of arterial pressure be- renal tubules. In some cases, the increased reabsorption is comes correspondingly elevated. These patients are espe- due to gene mutations that directly increase the transport cially prone to extra degrees of hypertension when they of sodium or chloride in the renal tubular epithelial cells. In have excess salt intake. other cases, the gene mutations cause increased synthesis Neurogenic Hypertension. Acute neurogenic hyperten- or activity of hormones that stimulate renal tubular salt and sion can be caused by strong stimulation of the sympathetic water reabsorption. Thus, in all monogenic hypertensive nervous system. For example, when a person becomes ex- disorders discovered thus far, the final common pathway to cited for any reason or during states of anxiety, the sym- hypertension appears to be impaired kidney function. Mo- pathetic system becomes excessively stimulated, peripheral nogenic hypertension, however, is rare, and all the known vasoconstriction occurs everywhere in the body, and acute forms together account for less than 1% of cases of human hypertension ensues. hypertension. Another type of acute neurogenic hypertension occurs when the nerves leading from the baroreceptors are cut or when the tractus solitarius is destroyed in each side of the PRIMARY (ESSENTIAL) HYPERTENSION medulla oblongata. These are the areas where the nerves About 90% to 95% of all people who have hypertension from the carotid and aortic baroreceptors connect in the are said to have primary hypertension, also referred to as brain stem. The sudden cessation of normal nerve signals from the baroreceptors has the same effect on the nervous essential hypertension by many clinicians. These terms pressure control mechanisms as a sudden reduction of the simply mean that the hypertension is of unknown origin, in arterial pressure in the aorta and carotid arteries. That is, contrast to the forms of hypertension that are secondary loss of the normal inhibitory effect on the vasomotor center to known causes, such as renal artery stenosis or mono- caused by normal baroreceptor nervous signals allows the genic forms of hypertension. vasomotor center suddenly to become extremely active and In most patients, excess weight gain and a sedentary life- the mean arterial pressure to increase from 100 mm Hg to style appear to play a major role in causing primary hyper- as high as 160 mm Hg. The pressure returns to nearly nor- tension. Most patients with hypertension are overweight, mal within about 2 days because the response of the vaso- and studies of different populations have suggested that motor center to the absent baroreceptor signal fades away, excess adiposity may account for as much as 65% to 75% which is called central resetting of the baroreceptor pressure of the risk for developing primary hypertension. Clinical control mechanism. Therefore, the neurogenic hyperten- sion caused by sectioning the baroreceptor nerves is mainly studies have clearly shown the value of weight loss for an acute type of hypertension, not a chronic type. reducing