Long-term arterial pressure control: an analysis from animal experiments and computer and graphic models.

Long-term arterial pressure control: an analysis from animal experiments and computer and graphic models ARTHUR

C. GUYTON

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216

GUYTON, ARTHUR C. Long-term arterial pressure control: an analysis from animal experiments and computer and graphic models. Am. J. Physiol. 259 (Regulatory Integrative Comp. Physiol. 28): R865-R877, 1990.-Longterm arterial pressure control is very different from acute control, because many of the acute control systems are overridden by a single long-term mechanism that has little to do with short-term control. This is the renal fluid volume mechanism for pressure control. It is based on a simple functional property of the kidney: as the arterial pressure rises, the kidney output of water and electrolytes increases dramatically. When the output rises above the net intake of water and electrolytes, negative body fluid balance occurs, causing both the body fluid volume and the pressure to decrease. This decrease continues until the kidney fluid output exactly balances the net fluid intake. Conversely, if the pressure falls below the exact level for balance, intake becomes greater than output; then fluid builds up in the body and the pressure rises until intake and output again exactly balance each other. This fluid mechanism for pressure control has been known from the beginning of blood pressure research. However, its overpowering importance was not appreciated until a mathematical computer analysis in 1966 demonstrated the renal-fluid feedback mechanism to have infinite feedback gain for long-term pressure control. This is the principal topic of the present review. body fluids; renin; angiotensin; kidney; bl .ood volume; ulation; computer analysis; macula densa; salt

EARLY IN MY STUDY of physiology

I became deeply fascinated with arterial pressure control. The reason was that different ones of my professors emphasized different often without mentioning the control mechanisms, mechanisms taught by others. Also, in still earlier training, I had studied mathematical analysis of electronic circuits and it quickly became clear that the same principles applied equally for integrating the different mechanisms of pressure control. Then, later, as a resident in surgery, I had the opportunity to work with Dr. Reginald Smithwick, who pioneered the sympathectomy operation for treating severe hypertension in an era before the development of adequate drugs for treatment. It was always very dramatic to see the patient’s mean arterial pressure fall from extremely hypertensive levels, sometimes over 200 mmHg, to normal or even subnormal within a fraction of a minute after the last major sympathetic nerve was sectioned. With this background it was hardly possible for me to 0363-6119/90

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blood flow autoreg-

choose any other field of physiological research besides an attempt to unravel the interrelationships among the different pressure control mechanisms. Yet, because my immediately preceding experiences had been with nervous control of blood pressure, I soon found that my initial goal was not really to unravel but instead to prove my preconception that nervous mechanisms dominated all the other pressure control factors. After a series of early experiments to study multiple nervous factors in pressure control, such as the baroreceptor feedback system (18), the central nervous system ischemic pressure control mechanism (13), the feedback gains of all or most of the neurogenic pressure controllers, the oscillating properties of the nervous controllers (15, 16), the damping effects of nervous mechanisms on arterial pressure when the blood volume is changedeven with this broad approach-it soon became clear that all I had been studying was details of specific factors that altered the pressure, not how these operated to-

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gether as an integrated system for daily pressure control. Also, to dash still further my hopes of proving the nervous system to be the all-important controller, follow-up studies on the hypertensive patients treated by sympathectomy operations showed their pressures often, if not usually, to return within months back to high levels, despite removal of either all or almost all of their peripheral sympathetic nerves (31). This was the background of an almost about-face that occurred in the mid-1960s in our approach to arterial pressure control. It also explains why a major share of our subsequent work has emphasized successive generations of graphic and computer models of circulatory control but always linked with parallel animal experiments to test theories and generate necessary data. In the remainder of this paper I will discuss several important steps and findings in this back-and-forth interplay between the quantitative models and the animal experiments. RENAL-FLUID CONTROL: FEEDBACK

VOLUME MECHANISM A DOMINATING ROLE GAIN PROPERTY

FOR

FOR PRESSURE ITS INFINITE

Principles of renal-fluid volume mechanism forpressure control. One of the most basic factors in any mathemat-

ical model of circulatory function is the effect of increased blood volume to increase the arterial pressure. Equally important is the tremendous effect that increased arterial pressure has to increase renal excretion of both fluid volume and electrolytes. This in turn de-

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creases the blood volume and also the arterial pressure back toward lower levels. All of this together constitutes a renal-fluid volume negative-feedback mechanism for pressure control. Figure 1 gives the results from a simple experiment that strongly suggested major importance of the renalfluid volume mechanism for pressure control (22). This experiment was performed in four dogs over a period of -3 mo. At point A in the experiment, the two poles of one kidney were removed. Then, several weeks later, at point B, the other normal kidney was removed, thus leaving the animal with only -30% of its normal renal mass. After recovery from this second operation, at -day 55 in the experiment, the animal’s drinking water was changed from normal tap water to 0.9% sodium chloride solution. Note the marked rise in arterial pressure that occurred within a few days and note also the rapid return of the pressure to normal 2 wk later, when the drinking fluid was returned to tap water instead of sodium chloride solution. Then, several weeks later, the procedure was repeated and again the pressure rose very high when the animal drank the sodium chloride solution instead of normal drinking water. This same basic experiment has been repeated many different times in different ways, but usually by intravenous infusion of the sodium chloride solution instead of simply allowing the animal to drink uncontrolled amounts (4,5,9,24). When the salt intake was increased to about five times its normal level, various experiments demonstrated a 20-40% rise in extracellular fluid volume and blood volume during the early stages of the devel-

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HG. 1. Volume-loading hypertension recorded in 4 dogs. The 2 poles of left kidney were first removed (A) ana later the entire right kidney was removed (ES). After 2 wk of recovery from all surgery, dogs were made to drink 0.9% sodium chloride instead of tap water for a period of 2 wk, followed by tap water for another 2 wk, and finally by sodium chloride solution again for last 2 wk. [From Langston et al. (22).]


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FIG. 2. Diagram of a simple feedback control mechanism for long-term control of arterial pressure by changes in the body fluid volumes. See text for discussion. [From Guyton and Coleman (17).]

I

RAP oping hypertension. Yet, as we shall note later, these lular fluid volume to give the momentary level of extravolumes returned within days or weeks almost to normal, cellular fluid volume (ECFV) in the body. although the pressure remained high. Even so, the slight Block 4: approximate normal relationship between exresidual increase in the volume seemed to be crucial in tracellular fluid volume and blood volume (BV). maintaining the continuously high pressure levels. This Block 5: approximate normal effect of blood volume on the mean systemic pressure (MSP). we will try to explain. An important feature of the experiment in Fig. 1 was Block 6: subtraction of right atria1 pressure (RAP) that significant elevation in arterial pressure usually did from mean systemic pressure to give the pressure granot occur in response to sodium chloride loading, unless dient for venous return (MSP-RAP). renal function had been significantly decreased. The Block 7: division of the pressure gradient for venous reason for this was that normal kidneys can excrete return by the resistance to venous return (RVR) to give sodium chloride solution so rapidly that even slight ele- the actual rate of venous return (VR). The venous return vations of pressure plus humoral and neural changes will is also equal to cardiac output (CO), because when the remove the sodium chloride solution almost as rapidly as heart pumps the venous return it becomes cardiac output. it can be infused or drunk by the animal. Therefore, we Block 8: multiplication of cardiac output times total learned to appreciate very early the tremendous overca- peripheral resistance (TPR) to give arterial pressure. pacity of normal kidneys for eliminating excess extracelThus the circulatory loop is closed. It shows the effect lular fluid volume from the body as well as the extreme of arterial pressure on urinary output and how changes rapidity with which this occurs. Nevertheless, when we in pressure have negative effects on the flu id volumes did succeed in maintaining excess fluid volume in the and cardiac output, finally returning around the loop to animals by decreasing kidney excretory capability and cause n.egative- feedback effects on the arterial pressure simultaneously giving extra-large amounts of saline so- as we1.1. lution, even small amounts of sustained excess volume The importance of this circulatory model, as simple as caused marked elevation of pressure. it was, was that it allowed us to visualize in gross quantitative terms the manner in which the major compoA simple computer model of renal-fluid volume mechanism for pressure control. In an attempt to understand nents of circulatory function all operate together for the the quantitative aspects of the renal-fluid volume mechcontrol of arterial pressure. Even more i.mportant, when anism for pressure control, Dr. Thomas Coleman and I we ran the model on the computer, we were in for a started by setting up the simple computer model of this surprise, and we quickly considered ourselves stupid for control system illustrated in Fig. 2 (17). The blocks in not thinking about the surprise in advance. This was the this model are the following. fact that the fluid feedback loop in Fig. 2 has an infinite Block 1: a function curve illustrating the effect of gain feedback property for controlling the long-term increasing arterial pressure (AP) on urinary volume out- arterial pressure level. How many of you readers recognized this infinite gain put (UO). Block 2: subtraction of urinary output from volume property before reading the previous paragraph? And if any of you did recognize it, why is it almost never intake (Intake) to give the rate of change of extracellular fluid volume (dE/dt ). mentioned in th .e vast literature on arterial pressure Block 3: integration of the rate of change of extracelcontrol? In fact, why h.ad it never been mentioned, to


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the best of our knowledge, prior to our chance observation in 1966? Therefore, let me explain. Infinite gain feedback property of renal-fluid volume mechanism for pressure control. While running the model of Fig. 2 on the computer, we changed the total peripheral resistance to different levels and recorded the computer output results until steady-state values were achieved for cardiac output, arterial pressure, and blood volume. The results are illustrated in Fig. 3. Our preconceived notion was that for each given level of total peripheral resistance there would be a different long-term level of arterial pressure. This notion was held because that was the teaching of virtually everyone in the field of circulatory physiology, and it is still the teaching of most. In Fig. 3, the total peripheral resistance was first decreased in steps, then later increased in steps, with each step lasting for a simulated time of -1 wk, enough time to reach steady-state values. Note that the arterial pressure changed from the normal value of 100 mmHg only for approximately the first day after each step change in total peripheral resistance. That is, the pressure always returned exactly back to the 100 mmHg pressure level, regardless of the level of total peripheral resistance. This result stated that the renal-fluid volume mechanism for pressure control has infinite capability for returning the pressure to its original value if nothing else changes in the circulatory system besides the total peripheral resistance. Similar simulations showed that changes in heart pumping capability and changes in vascular capacitance had exactly the same effects on the steady-state level of the arterial pressure as changes in total peripheral resistance, that is, acute changes in pressure but no change in the long-term steady-state level, provided nothing else changed in the circulatory system besides the heart pumping capability or the vascular capacitance. The importance of these results was immediately apparent. Anyone familiar with control system theory understands that a system with infinite feedback gain be-

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comes so dominating that other control systems attempting to control the same variable can do so only by altering some component of the infinite gain system that will change the “set-point” of this system to a new level. Let us explain this further using the diagram in Fig. 4. Figure 4 shows arterial pressure on the abscissa and both the rate of fluid intake and rate of urinary output on the ordinate. The curve in the figure is a renal function curve that depicts the effect of different levels of arterial pressure on the urinary output. The broken line in the figure is the net fluid intake; all of this intake must eventually be excreted by the kidneys (ignoring the additional small amounts of fluid intake that are lost from the body in other ways) . Obvi .ously, in the steadystate condition, the rate of output must exactly equal the rate of intake. This occurs where the line and the curve cross, at the point called the equilibrium pressure. On studying Fig. 4, one can readily see that when the arterial pressure rises to a level greater than that of the equilibrium pressure, the urinary output becomes greater than the intake. Because of this imbalance, the body will continue to lose body fluid volume until the pressure falls back exactly to the equilibrium pressure. Conversely, if the pressure falls below the equilibrium level, the intake becomes greater than the output; therefore, fluid builds up indefinitely in the body until the arterial pressure again returns to the equilibrium pressure. Furthermore, the arterial pressure will never stop changing until it reaches exactly and precisely this equilibrium pressure level. Thus infinite correction of the pressure always occurs back to the equilibrium pressure, which is therefore also the set-point pressure level for control by the infinite feedback gain system. This is the principle of infinite feedback gain of the renal-fluid volume mechanism for control of arterial pressure. There are two ways by which factors outside the basic renal-fluid volume pressure control mechanism can alter the pressure, for there are two components in Fig. 4, each of which can itself be altered. One can see from Fig. 4 that the level to which the renal-fluid volume mechanism

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FIG. 4. Graphic analysis of long-term arterial pressure regulation, illustrating equilibration of urinary output of fluid with net intake of fluid at equilibrium pressure where renal function curve crosses line depicting net intake of fluid. [Adapted from Guyton (14).]


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itself controls the pressure can be changed to a new setpoint level by 1) changing the level of the fluid intake line in Fig. 4 or 2) shifting the renal function curve to the right or left. Figure 5 illustrates approximate changes in the renal function curve caused by several physiological factors known to affect the arterial pressure (14). For instance, sympathetic stimulation shifts the curve to the right, that is, toward higher pressure levels. Also, the administration of either angiotensin or aldosterone shifts it to the right. Conversely, most drugs that are used in treating hypertension have the specific property of shifting the curve in the leftward direction, toward lower pressure. To emphasize again the importance of a shifted renal function curve on long-term arterial pressure control, let us trace through the events for one of these curves that lead to a new pressure level. For example, increased angiotensin acts directly on the kidneys to shift the function curve to the right as shown in Fig. 5. When the circulating angiotensin increases three- to fivefold, the curve is generally shifted -20-30 mmHg. Therefore, the new equilibrium pressure where the curve crosses the fluid intake line will be at a pressure level that is also mmHg; this, therefore, becomes the increased -20-30 new set point for pressure control. Thus the renal-fluid mechanism dictates that the pressure thereafter be controlled with infinite gain at this new level. AMOUNT CHANGE

OF FLUID ARTERIAL

VOLUME PRESSURE

CHANGE

REQUIRED

TO

The discussion thus far, as well as the results from the simple circulatory model, suggests that changes in extracellular fluid volume and blood volume play major roles in long-term control of arterial pressure. Yet, most human beings who have hypertension do not have large enough increases in fluid volumes for these to be measured with certainty by present methods. How can such small volume changes in hypertensive patients be reconciled with the concept that fluid volumes are of major importance in long-term pressure control? Is it possible that even very small changes in fluid volumes when

PRESSURE lmmHg1 5. Analysis of long-term arterial pressure level for 2 different as levels of fluid intake and 6 different states of renal function, (14).] represented by changed renal function curves. [ From Guyton FIG.

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persisting for weeks and years are enough to provide long-term control of pressure? At least two circulatory mechanisms help to answer this. One mechanism is the ability of the nervous feedback control systems to oppose an acute increase in pressure when the blood volume is first increased but not to oppose a long-term pressure increase. Within a few days most if not all of these nervous feedbacks “adapt” (or “reset”). After resetting, only much smaller increases in blood volume are then required to cause elevated pressure. The second mechanism is blood flow autoregulation. This, too, causes the pressure to increase many times more over the long term, requiring a few days to weeks for the full effect to occur. Let us discuss each of these in turn. Adaptation of nervous pressure control systems: much greater increase in arterial pressure caused by increased volume after adaptation. Figure 6 illustrates the effect of increasing the blood volume -30% in two different series of dogs (8). In Fig. 6A, the nervous pressure control mechanisms, i.e., the baroreceptor reflexes, the central nervous system ischemic response, and others, were all intact and functioning. In Fig. 6B, these had all been rendered nonfunctional by destroying the central nervous system. Note in Fig. 6A, that when the nervous mechanisms were functioning, the arterial pressure rose only 12-15 mmHg in response to the 30% volume increase. This contrasts starkly with the over 100 mmHg rise when the nervous mechanisms were not functioning, as shown in Fig. 6B. Thus a massive acute blood volume increase normally has little effect on the arterial pressure, whereas in the absence of the nervous pressure control mechanisms the pressure increase is as much as eight times as great. Many other experiments have also suggested that nervous pressure controllers can suppress acute changes in pressure but not long-term changes. For instance, in the experiment illustrated in Fig. 1, note that it took 24 days for the arterial pressure to rise to its new height after the animals began to drink large volumes of saline solution. Yet, in baroreceptor denervated dogs, Cowley and Guyton (5) found the arterial pressure to rise to its full new height within 8 h. The difference in timing of the pressure increases before and after denervation was predictable from Kezdi and Wennemark’s (20) and McCubbin’s (25) measurements of the time for the baroreceptors to adapt (to reset) completely in dogs, a period of a few hours to a few days. Therefore, one would expect relatively small changes in pressure during the first few hours of fluid volume loading because of the nervous feedback blocking effects but then several times as much additional increase in pressure during the next several days, as the nervous pressure controlling mechanisms become adapted. Role of blood flow autoregulation in decreasing fluid volume change required to increase arterial pressure. Figure 7 illustrates the approximate summarized results from multiple experiments of the type illustrated in Fig. 1, but performed by several different investigators, on volume-loading hypertension (4, 9, 22, 24). In each experiment, the functional renal mass was decreased to -30% of normal. Then, beginning on day 0 in Fig. 7, the


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salt intake was increased to about five times normal and continued at this rate for the remainder of the experimental period. Note that despite the continued high salt intake both the extracellular fluid volume and blood volume, after increasing markedly for the first few days, fell almost back to normal within 7-14 days. In addition, the cardiac output rose at first to -40% above normal but then it also returned to within a few percent of normal by the end of 2 wk. By contrast, the arterial pressure was slower to rise, requiring several days to reach high elevation. Yet, once at its new high level, it remained there infinitely, so long as the high salt intake was maintained. Finally, note the changes in total peripheral resistance. During the first few days, this resistance actually fell below normal. This fall appeared to be associated with the pressure feedback control effects of the baroreceptor system, because in a separate series of baroreceptordenervated dogs, Cowley and Guyton (5) found that the initial decrease in total peripheral resistance did not occur; instead, the arterial pressure rose approximately as rapidly as the rise in cardiac output, without being delayed by the feedback effect of the baroreceptors. Furthermore, even in the dogs with normal baroreceptor systems, the decrease in resistance lasted only 3-4 days, which was also the approximate time required for all the baroreceptors to adapt. After these 3-4 days, the resistance then rose above normal; by the end of 2 wk it had increased almost as much as the increase in arterial pressure. At the same time, the early excess in cardiac output mostly disappeared while the total peripheral

resistance was rising an opposite amount, thus keeping the pressure at its elevated level. Similar changes in blood flow and resistance have been observed in numerous experiments on isolated tissues after the tissue arterial pressure has been increased. That is, excess blood flow occurs instantly along with the increase in pressure, but the excess flow then causes a secondary increase in resistance; the increased resistance in turn causes the blood flow to return back toward normal. This is the phenomenon of blood flow autoregulation. Part of the autoregulatory process usually occurs within minutes, but still much more occurs during the following hours to days and weeks. Let us give examples of some of the more prolonged types of blood flow autoregulation, for these appear to be especially potent in controlling the blood flow. First, Granger and Guyton (11) studied autoregulation in the whole body of dogs whose nervous systems had been destroyed. They increased or decreased the arterial pressure by increasing or decreasing the blood volume, which caused an initial increase or decrease in cardiac output as well. Then, during the next 0.5-l h, while the pressure was kept constant at its new level, the cardiac output returned most of the way back toward normal. Second, in prolonged experiments lasting weeks to months, Folkow et al. (10) increased or decreased blood flow by changing the arterial pressure in individual limbs of animals for several weeks at a time. The result was that the structure of the blood vasculature actually changed in response to the changed blood flow, i.e., excess flow caused a progressive increase in vascular


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resistance, as well as return of the flow toward normal, because of structural vascular changes that diminished flow capacity through the tissue vessels. Conversely, decreased flow caused opposite effects. Another interesting observation that supports the concept of long-term, total-body autoregulation comes from studies in human patients with coarctation of the aorta, in whom the thoracic descending aorta had become constricted prior to birth. When data from many patients are combined, the pressure in the arteries above the coarctation averaged 55% greater than the pressure in the arteries below the coarctation (29,33). Yet, the blood flow per unit mass of tissue was so nearly normal both above and below the coarctation that statistical analysis could not detect a difference. Therefore, long-term blood flow autoregulation appeared to have been almost perfect in these patients, with the vasculature having changed over years of time to provide almost exactly normal blood flow to the different tissues, regardless of differences in regional arterial pressure levels. Therefore, it is difficult to come to any other conclusion in relation to Fig. 7 except one: excess blood flow through tissues is an abnormal condition. In the whole body, this causes a progressive increase in total peripheral resistance until whole body blood flow (cardiac output) returns to normal or nearly to normal. This is the principle of long-term whole body autoregulation. Also, another important effect of whole body autoregulation in volume-loading hypertension is that the amount of excess fluid volume required to cause a high

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arterial pressure becomes progressively less as the autoregulation takes place. This, too, is illustrated in Fig. 7. During the first day or so of the volume-loading hypertension, the blood volume rose to -20% above normal, the extracellular fluid volume increased to -33% above normal, and cardiac output increased to -40% above normal, all this occurring while the arterial pressure was rising to its full height. Then, during the next 2 wk, the blood volume, extracellular fluid volume, and cardiac output all decreased back so nearly to normal that their differences from normal were no longer statistically significant. Predictions of role of autoregulation in volume-loading hypertension from a computer model. Early in our studies on arterial pressure regulation, we began developing a much more complex computer model of the circulation \ than that illustrated in Fig. 2, mainly for the purpose of studying the complex circulatory regulatory mechanisms and to understand the quantitative roles of each of these (19). This model has -500 equations that are updated periodically as new data become available. Without going into the details (the model can be requested for use on appropriate computers), let us use the model here to help quantify the role of autoregulation in volume-loading hypertension. Use of the computer for this purpose has much more physiological importance than one might suspect at first, because there is no present experimental method that allows one to perform hypertension experiments in animals without a functioning autoregulation system. Yet, by using a mathematical procedure such as this, one has the possibility at least of understanding the quantitative importance of whole body autoregulation during the course of arterial pressure regulation. Figure 8 gives the computer predictions for the changes in cardiac output, arterial pressure, and total, peripheral resistance as volume-loading hypertension develops in a theoretical human being, first, without a functioning autoregulation system and, second, with normal autoregulation. In both instances, the pressure rose from an initial value of 100 up to 150 mmHg in 3 wk. Some of the differences with and without autoregulation are as follows. First, observe from the abscissathe difference in blood volume required to cause the 50-mmHg rise in pressure, more than four times as much increase required in the absence of an autoregulation system. Second, in the absence of autoregulation (as seen in the left-hand simulation), the total peripheral resistance did not increase at all but instead decreased 33%. Why? Very simple: the increasing arterial pressure stretches the peripheral blood vessels (12), thus decreasing the resistance in all these vessels. Without autoregulation the resistance remains decreased indefinitely. Third, without autoregulation, the cardiac output must rise greatly to increase the pressure. In fact, a 50% increase in pressure required 116% increase in cardiac output, 50% of this to cause the direct increase in pressure and another 66% to make up for the decreased total peripheral resistance. Finally, study the changes in resistance and cardiac output that occur when the autoregulation system is functioning. The autoregulation keeps the blood flow in


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FIG. 8. Computer-analyzed effects of increased blood volume on arterial pressure (AP), cardiac output (CO), andtotal peripheral resistance (TPR) under 2 different conditions: without any autoregulation of blood flow in the body (left), and with approximately normal shortterm and long-term autoregulation (right). (F rom the teaching slides of Department of Physiology and Biophysics, University of Mississippi Medical Center.)

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virtually all tissues of the body near to normal. It does this by increasing the resistance in almost all the respective tissue arterioles. Therefore, the resulting increased total peripheral resistance that this causes in the whole body becomes by far the principal factor that increases the arterial pressure, whereas increased cardiac output has only a minimal direct effect in increasing the pressure. These results are the same findings that we have also observed in all of ou r experiments on volume-loading hypertension, as already explained. An added dividend of the autoregulation mechanism in hypertension is that, in the absence of autoregulation, both the cardiac output and the pressure become greatly elevated as the hypertension develops, while with autoregulation the pressure stil .l increases but the cardiac output increases very little. Because work output of the heart is proportional to pressure times cardiac output, one can see-that the lessened cardiac output caused by the autoregulation greatly reduces the increase in cardiac work required to cause the hypertension. This effect fortunately acts as a partial deterrent to the development of congestive heart failure that so often accompanies severe hypertension. Combined quantitative effects of adaptation of the nervous pressure-control mechanisms plus whole body autoregulation. In the experiment of Fig. 6, the results showed

about eight times as much increase in arterial pressure in response to increased blood volume in the absence of nervous feedback control of pressure as in its presence. In addition, one can observe from Fig. 7 that long-term autoregulation probably enhan .ces the effect of small volume increases on pressure at least fivefold. Multiplying the eightfold effect from adaptation of the nervous reflexes times a probable minimum fivefold ef-

feet resulting from autoregulation, one calculates about 40 times as much increase in pressure caused by a longterm increase in blood volume vs. the acute increase in pressure occurring only a few minutes after a similar volume increase. IN SALT-LOADING INCREASE OR THE THE HYPERTENSION?

HYPERTENSION, IS VOLUME INCREASE

IT THE THAT

SALT CAUSES

Almost from the beginning of hypertension research, it has been known that hypertension is usually made much worse by increased salt intake. The increase in salt intake almost always is accompanied by a comparable increase in water intake, because the thirst mechanism drives the drinking process enough to maintain the extrace11 ular sodium concentration almost exactly constant. On the other hand, if water intak :e is forced to the same amount but without increased salt intake, thi .s does not have a significant effect on pressure in most hypertensive patients. Can we explain this difference? -Virtually all mathematical models of pressure control, whether simple models as illustrated in Fig. 2 or the very complex ones (19), have suggested that, following saltloading, it is the resultant increase in extracellular fluid volume and its accompanying increase in blood volume that increase the pressure, not the direct effect of increased salt itself on the circulation. Based on these predictions from models, several different experiments have been performed to determine the relative effects on the pressure of the volume increases vs. possible direct effects of the increased salt itself. Figure 9 illustrates the results from one of these experiments in which Norman et al. (27) used a combina-


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and certainly did not fall with th .e decrease in sodium ion concentration. In two other experimen ts, one by Young et al. (35) and another by Smith et al. (30), the extracellular sodium concentration was manipulated down or up, and the arterial pressure failed to follow either the upward or downward changes in sodium concentration IN ANIMALS ANGIOTENSIN CHANGES TREMENDOUS

IN

WITH NORMAL KIDNEYS, RENINSYSTEM PREVENTS SIGNIFICANT ARTERIAL PRESSURE DESPITE CHANGES IN SALT INTAKE

Both animals and human beings that have normal kidneys can withstand tremendous changes in salt intake without significant changes in arterial pressure. For instance, Murray and his colleagues (26) increased the salt I 80-i I 60 40 50 intake of human volunteers from 10 meq/day up to 1,500 EXCHANGEABLE SODIUM (mEq/kg) meq/day, a l&000% increase, and the arterial pressure increased only lo-20 mmHg (26). Similarly, Norman et FIG. 9. Effect on arterial pressure of -20% increase in exchangeable sodium chloride in sheep under 2 different conditions: 1) with compaal. (28) increased the salt intake in rats -l,OOO%, and rable increase in water along with sodium chloride, so that extracellular DeClue et al. (7) in dogs as much as 5,000%, with no fluid volume increased -20% without significant change in sodium more than 4- to 6-mmHg change in pressure. chloride concentration; and 2) without any increase in water in extraHowever, in DeClue et al. study, they kept the circucellular fluid, so that sodium chloride concentration rose -20% without lating angiotensin approximately constant in an addisignificant change in volume. [From Norman et al. (27).] tional group of dogs while increasing the salt intake. The tion of renal and body fluid manipulations to increase by increases in salt intake then caused 10 times as much -20% the total quantity of exchangeable sodium in two increase in arterial pressure as under normal conditions. groups of sheep. In one group, the extra sodium was The experimental data suggested the following explanagiven along with enough water to keep the extracellular tion for this difference: when the circulating angiotensin sodium concentration always normal, while the extracelwas not fixed at a constant level, a high salt intake lular volume increased -20%. In the second group of caused the renin secretion by the kidneys to fall almost sheep, the exchangeable sodium was increased the same to zero. Therefore, in the salt-loaded condition, one amount, -2O%, but without giving extra water to go with factor, the increased blood volume caused by the extra the sodium; therefore, the extracellular fluid sodium con- salt intake, tended to elevate the arterial pressure, while centration rose to 170 meq/l, a very high sodium hypera second factor, decreased renin secretion, tended to concentration, while the extracellular volume remained lower the pressure and blocked most of the pressure normal. Figure 9 illustrates the results from this experichange. Thus the renin-angiotensin feedback system ment, in one instance with high volume but normal mainly compensated for the pressure effects caused by sodium, and in the other instance with high sodium but the salt-induced volume changes. Let us explain this normal volume. Note that in the animals with volume more fully using Fig. 10, which depicts quantitative data increase the arterial pressure increased an average of from the experiments by DeClue et al. (7) and additional 46%. On the other hand, in the other animals with almost experiments by J. E. Hall and colleagues (unpublished exactly the same increase in sodium but without meas- observations). urable increase in volume the pressure rose only 6-7%, In Fig. 10, the urinary sodium output was changed in an increase that was not statistically significant. Thus three separate groups of dogs from a very low level to a these experiments demonstrated that extracellular volvery high level in four steps by giving different dietary ume changes are exceedingly important in pressure con- salt intakes over many days. The middle curve (solid trol but that changes in salt concentration without ac- line) represents normal dogs. The curve to the right companying changes in volume probably have little effect represents dogs in which sufficient angiotensin II was on the arterial pressure. infused to maintain a plasma concentration of angiotensin calculated to be -2.5 times the normal value. The Also, in several other experiments, extracellular fluid sodium concentration and extracellular fluid volume curve to the left was recorded from dogs that had been were changed independently of each other. In all of these, given the drug captopril (SQ 14225) in sufficient quantity to keep the angiotensin II in the plasma at very near the arterial pressure responded to the changes in volume but not to the changes in sodium concentration. For zero. Now note from the angiotensin curve that the arterial instance, Manning infused vasopressin and hypotonic saline into seven dogs with reduced kidney mass, decreas- pressure increased -40 mmHg between the lowest level ing the extracellular sodium ion concentration from 143 of sodium intake and the highest level. Similarly, the curve from the animals given the captopril shows the to 128 meq/l (23), but increasing the extracellular fluid volume (sodium space) 30%. The arterial pressure rose arterial pressure also to increase -40 mmHg from the 40%. Thus the pressure rose with the volume increase lowest level of sodium intake to the highest level. How-


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60

70

MEAN

80

SO 100 HO

ARTERIAL

120 130 140

I50

160 170 180

PRESSURE (% of Control)

WC;. 10. Renal function curves depicting urinary sodium output at different levels of’ arterial pressure under 3 different experimental conditions: middle curve: normal conditions; left curve: when ANG II formation was blocked by converting-enzyme inhibitor captopril (SQ 142%); and right curve: when circulating level of ANG II was increased to -2.5 times normal by continuous angiotensin infusion. Nos. in parentheses are the calculated ANG II concentrations in blood, with normal level considered to be 1.0. [From Guyton (14) and based on data from Ref. 7 and ,J. E. Hall (unpublished observations).]

ever, the captopril curve was shifted 40-55 mmHg to the left of the angiotensin curve. Next, contrast the angiotensin and the captopril curves with the middle curve, which represents the normal dogs in which the circulating angiotensin II was allowed to rise or fall as the salt intake changed. At the lowest sodium intake in the normal dogs, the calculated level of circulating angiotensin was high and very nearly matched that in the animals in which angiotensin was infused. Furthermore, the lower end of the normal curve lies very near to the lower end of the angiotensin curve. At the other extreme, at the upper end of the normal curve, the circulating angiotensin was essentially zero, and this end of the curve lies almost exactly on the upper end of the captopril curve representing zero circulating angiotensin. In other words, when on a low-salt diet, the normal animals were effectively operating on the lower end of the angiotensin curve. In the high-salt state, these same dogs were effectively operating on the upper end of the captopril zeroangiotensin curve. Finally, note in the normal dogs that the change in salt intake between the lowest intake and the highest intake was GO-fold. Yet, the pressure change was only 4 mmHg. Therefore, in the normal animal (or human being), the change in angiotensin production that occurs in response to different levels of salt intake almost completely nullifies the pressure effects that otherwise would occur in response to changes in salt loading. ROLE TERM

OF RENIN-ANGIOTENSIN ARTERIAL PRESSURE

SYSTEM CONTROL

IN

LONG-

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and the fluid volume system ? The answer to this question was evident from the renal function curves labeled “angiotensin” in Figs. 5 and 10. Note in each instance the rightward shift when the blood level of angiotensin was above normal. As already discussed, rightward shift will increase the pressure set-point level of the kidney-fluid volume mechanism for pressure control, thus causing persistent hypertension. Therefore, our problem is not to understand how the renin-angiotensin system causes elevated pressure but instead to understand the different conditions that will cause persistent increase in renin secretion. Some of these conditions are well understood, such as persistently low renal blood flow and the rare renin-secreting tumors. However, less well understood is another entire class of stimuli, namely, factors that affect renal tubular reabsorption of electrolytes and fluid. For two different reasons, I would like to discuss this class of renin control factors: first, evidence is beginning to accumulate that only changes in reabsorption in the post-macula densa tubules, not in the pre-macula densa tubules, will cause long-term changes in renin secretion. Second, this principle that post-macula densa tubular reabsorption specifically affects long-term renin secretion was first seen by us while studying a computer model of renin control; this illustrates again the importance of mathematical models as a fundamental tool in understanding and perhaps even discovering new physiological concepts. Special role of sodium reabsorption in post-macula densa tubules for controlling renin secretion. In recent years, it has become clear that one of the principal factors controlling renin secretion by the kidneys is the rate of delivery of sodium and its associated anions such as chloride ions to the initial segment of the distal tubules where the macula densa lies adjacent to the juxtaglomerular apparatus (32). That is, if all else be equal, the greater the delivery of sodium (and/or anions) to this tubular area, the less becomes the rate of renin secretion by the juxtaglomerular cells. The following general equation expresses this mathematically renin secretion = -function

(sodium delivery to macula densa)

(1)

Next comes the question, What effect does reabsorption of sodium in the different segments of the renal tubules have on the rate of sodium delivery to the macula densa? If we assume that the body is in a steady-state condition and that sodium is not lost from the body by any other means except in the urine (which is mostly true under normal conditions except for very small amounts lost in the feces), then the following three equations apply urinary sodium output = sodium delivery to macula densa

(2)

Thus far we have spoken only briefly about the role of - sodium reabsorption in post-macula densa tubules the renin-angiotensin system in determining the longIn the long-term steady-state condition, after the arterm arterial pressure level. Yet, it is widely known that sustained elevation of renin is almost always associated terial pressure has reached its steady level, the urinary with long-term pressure elevation as well. How does this sodium output from the body must exactly equal the fit with the nrincinles of nressure control bv the kidnevs sodium intake. Therefore. substituting sodium intake for


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urinary sodium output, Eq. 2 can be changed (for the steady-state condition) to the following sodium intake = sodium delivery to macula densa - sodium reabsorption by post-macula

(3)

densa tubules

And Eq. 3 can be rearranged to give sodium delivery to macula densa - sodium intake + sodium reabsorption by post-macula Finally,

combining

(4)

densa tubules

Eq. 4 with Eq. 1 gives

renin secretion = -function reabsorption

(sodium intake by post-macula

+ sodium

(5)

densa tubules)

This Eq. 5 predicts that three fundamental factors are especially potent in controlling renin secretion: 1) sodium intake; 2) post-macula densa tubular sodium reabsorption; and 3) the nature of the negative function (-function) that determines the quantitative effect of the combined factors 1 and 2 on the rate of renin secretion. Let us see whether these predictions fit with what is known experimentally about long-term renin secretion control. First, the effect of sodium intake on long-term renin secretion is so well established that it needs no further elaboration. That is, increased sodium intake leads to decreased renin secretion, or decreased intake leads to increased secretion. Therefore, this fits completely with the prediction. Second, many factors known to affect post-macula densa tubular reabsorption of sodium are also known to affect renin secretion in the inverse direction. For instance, excess aldosterone in the circulating blood increases sodium reabsorption by the post-macula densa tubules, and the renin secretion often decreases almost to the vanishing point (6), as predicted by Eq. 5. Conversely, those tubular effects that decrease post-macula densa sodium reabsorption are predicted by Eq. 5 to have a positive effect on renin secretion. Again, this has been the experience in multiple experiments and in clinical conditions such as 1) when sodium absorption in the distal tubules, collecting tubules, and/or collecting ducts is decreased by any one of a multitude of natriuretic drugs used to treat hypertension (2); 2) in experimental dogs in which the renal medulla has been severely damaged by the renal poison bromoethylamine, which decreases reabsorption of sodium by the collecting duct system (unpublished observations, J. W. Balfe and J. E. Hall); 3) after administering a converting-enzyme inhibitor such as captopril or enalopril, thus blocking the formation of angiotensin II and therefore reducing sodium reabsorption (34). In addition, several other conditions that are not yet fully understood might also increase renin secretion because of depressed sodium reabsorption by the postmacula densa tubular system. One of these is Bartter’s

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syndrome in which renin secretion is very great; in this disease, the post-macula densa tubular system cannot reabsorb the large amounts of sodium that are presented to these tubules, thus causing sodium wasting from the body (1). Also, a patient with congenital analbuminemia was studied in great detail and found to have markedly increased renin secretion (21). This possibly resulted from the greatly reduced plasma colloid osmotic pressure (only one-quarter normal, -6-8 mmHg) that occurs in this condition, which theoretically reduces reabsorption of fluid and sodium all through the tubular system. Finally, let us discuss the other factor in Eq. 5 that helps to determine the rate of renin secretion, the negative function (-function). This function determines both 1) the background rate of renin secretion and 2) the sensitivity of renin secretion to changes in sodium at the level of the macula densa in the distal tubules. The most important data supporting the importance of -function for control of renin secretion are multiple demonstrations that sympathetic nervous stimulation of the juxtaglomerular apparatus increases renin secretion (3). In addition, there have been suggestions that different hormones also affect the sensitivity level of -function. Are there still other controllers of -function? For instance, concentrations of other ions in the plasma besides sodium ions? Thus Eq. 5 provides a fertile area for research. Are changes in pre-macula densa reabsorption of sodium also a primary factor in controlling renin-angiotensin system? Now, let us ask whether pre-macula densa

tubular reabsorption, like post-macula densa reabsorption, might also be a primary controller of renin secretion. On first thought one would say that increased premacula densa reabsorption would decrease the delivery of sodium to the macula densa, which in turn would increase renin secretion. However, Eq. 4 showed that in the long-term steady-state sodium delivery to the macula densa equals sodium intake plus sodium reabsorption by the post-macula densa tubules, but not including premacula densa reabsorption. Instead, over the long term, increased pre-macula densa absorption of sodium should lead to the following sequence: 1) increased total body sodium, 2) increased blood volume, 3) increased cardiac output, 4) increased arterial pressure, 5) increased glomerular filtration of sodium until sodium delivery to the macula densa returns to normal, and 6) finally, steadystate renin secretion also returned to normal. Because all these long-term factors have never been measured at the same time in animal experiments, we again resorted to computer modeling to try to understand the role of pre-macula densa reabsorption, using the same computer model of the circulation as used in calculating the results shown in Fig. 8 (19). Figure 11 gives the significant predictions from these computer studies, showing two separate computer simulation runs. In the first run, pre-macula densa tubular reabsorption of sodium was increased to reduce sodium delivery initially at the macula densa to one-half normal. The results showed within minutes a large increase in blood angiotensin because of the reduced delivery of sodium to the macula densa. However, during the next few days, progressive sodium buildup in the extracellular fluid increased the blood volume, arterial pressure, glomerular filtration,


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FIG. 11. Computer predictions, using a complex computer model of circulation (14), of changes in arterial pressure, angiotensin concentration in plasma, and volume in 2 conditions: increased proximal tubular reabsorption of sodium and decreased distal reabsorption of sodium. Note return of angiotensin concentration to normal when proximal tubular reabsorption was changed but continued elevation of angiotensin when distal reabsorption was changed. (From the teaching slides of Department of Physiology and Biophysics, University of Mississippi Medical Center.)

Decreased distal tubular reabsorption

0

2

4

I 0

I

1 4

1

I

a

I

1 12

I

I 1S

DAYS and sodium delivery to the macula aensa until angiotensin, in the steady state, returned exactly back to normal. Thus, in the steady state, it is predicted that increased pre-macula densa reabsorption of sodium should cause a significant increase in arterial pressure, but only a transient activation of the renin-angiotensin system. By contrast, the simulation run to the right in Fig. 11 shows the effects of decreased reabsorption of sodium by the post-macula densa tubules, as occurs when a distal tubular diuretic drug is administered. This time the simulated results showed a long-term continuing alteration of blood angiotensin concentration when post-macula densa reabsorption was changed from normal, as predicted by the principle that altered post-macula densa absorption causes long-term effects. The reason for presenting this analysis has been to demonstrate how a few fundamental factors theoretically could explain most of the abnormal rates of renin secretion in experimental and clinical conditions. Also, the analysis can help in designing new experiments for this area of research. SUMMARY

The main goal of this paper has been to explore the interplay among the kidneys, body fluid volumes, nervous reflexes, blood flow autoregulation, and the renin-angiotensin system in providing long-term stability of the arterial pressure. Over twenty years ago, while using a computer model of the circulation to study arterial pressure regulation, we first recognized that the renal-body fluid volume mechanism for pressure control has a feedback gain that is infinite, so long as the functional properties of the kidneys for excreting fluid volume do not change and so long as salt and water intake remain constant. Because

or tnis inrnnte gain property, the model suggested that those factors that affect the arterial pressure level in steady-state conditions would have to do so by altering either 1) the renal output response to arterial pressure (that is, altering the renal function curve) or 2) the intake level of salt and water. During the subsequent two decades since observing this principle in the computer model, we have not been able to find an experimental exception to the prediction. However, studies in both animals and human beings have shown that the increase in body fluid volumes required to change the arterial pressure acutely is very large. This is in contrast to only a small increase required for a long-term pressure change. The difference has been difficult to reconcile with the principle that body fluid volumes play a major role in long-term arterial pressure control. Part of the explanation is that the circulatory reflexes greatly ameliorate most short-term pressure changes; then most of these reflexes “reset” within a few days, so that much less volume is needed thereafter. In addition, blood flow autoregulation occurring in the whole body causes a large increase in the total peripheral resistance in a few days to weeks. Combining this with resetting of the reflexes, one can calculate for a given volume increase possibly 40 times as much long-term pressure increase as acute increase. Finally, an analysis of the important factors that control long-term renin secretion has been presented. This analysis predicts that one of the most important of all factors determining long-term renin secretion is the rate of sodium reabsorption in the post-macula densa tubules of the nephron. This prediction fits with what is presently known about renin control, but even more important the analysis suggests many new experiments aimed at understanding better the fundamental mechanisms of renin control.


INVITED This study was supported by National Heart, Lung, and Blood Institute Grant HL-11678. Address for reprint requests: Dept. of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216. REFERENCES 1. BARTTER, F. C., P. PRONOVE, J. R. GILL, JR., AND R. C. MACCARIILE. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. Am. J. Med. 33: 811828, 1962. 2. BROWN, T. C., J. 0. DAVIS, AND C. I. JOHNSON. Acute response in plasma renin and aldosterone secretion to diuretics. Am. J. Physiol. 2 11: 437-44 1, 1966. 3. BUHLER, F. R., J. H. LARAGH, L. BAER, E. D. VAUGHAM, JR., AND H. R. BRUNNER. Propranolol inhibition of renin secretion: a specific approach to diagnosis and treatment of renin dependent hypertensive disease. N. Engl. J. Med. 287: 1209-1214, 1972. 4. COLEMAN, T. G., AND A. C. GUYTON. Hypertension caused by salt loading in the dog. III. Onset transients of cardiac output and other circulatory variables. Circ. Res. 25: 152-160, 1969. rcl. COWLEY, A. W., JK., AND A. C. GUYTON. Baroreceptor reflex effects on transient and steady-state hemodynamics of salt-loading hypertension in dogs. Circ. Res. 36: 536-546, 1975. 6. DAVIS, J. 0. The renin-angiotensin system in the control of aldosterone secretion. In: Angiotensin, edited by I. H. Page and F. M. Bumpus. New York: Springer-Verlag, 1974, p. 322-336. 7. DECLUE, J. W., A. C. GUYTON, A. W. COWLEY, JR., T. G. COLEMAN, R. A. NORMAN, JR., AND R. E. MCCAA. Subpressor angiotensin infusion, renal sodium handling, and salt-induced hypertension in the dog. Circ. Res. 43: 503-512, 1978. 8. DOBBS, W. A., JR., J. W. PRATHER, AND A. C. GUYTON. Relative importance of nervous control of cardiac output and arterial pressure. Am. J. Cardiol. 25: 507-512, 1971. 9. DOUGLAS, B. H., A. C. GUYTON, J. B. LANGSTON, AND V. S. BISHOY. Hypertension caused by salt loading. II. Fluid volume and tissue pressure changes. Am. J. Physiol. 207: 669-671, 1964. 10. FOLKOW, B., M. HALLBACK, Y. LUNDGREN, B. SIVERTSSON, AND L. WEISS. Importance of adaptive changes in vascular design for establishment of primary hypertension, studied in man and in spontaneously hypertensive rats. Circ. Res. 32/33, Suppl. 1: 12-138, 1973. 11. GRANGER, H. J., AND A. C. GUYTON. Autoregulation of the total systemic circulation following destruction of the central nervous system in the dog. Circ. Res. 25: 379-388, 1969. 12. GREEN, H. D. Circulation: physical principles. In: Medical Physics, edited by 0. Glasser. Chicago, IL: Year Book Medical Publishers, 1944, p. 208-232. 13. GUYTON, A. C. Acute hypertension in dogs with cerebral ischemia. Am. J. Physiol. 154: 45-54, 1948. Pressure and Hypertension. Philadelphia, 14. GUYTON, A. C. Arterial PA: Saunders, 1980. 15. GUYTON, A. C., AND J. H. SATTERFIELD. Vasomotor waves possibly resulting from CNS ischemic reflex oscillation. Am. J. Physiol. 170: 601-605, 1952. A. C., AND J. W. HARRIS. Pressoreceptor-autonomic 16. GUYTON, oscillation: a probable cause of vasomotor waves. Am. J. Physiol. 165: 158-166, 1951. Long-term regulation of the 17. GUYTON, A. C., AND T. G. COLEMAN. circulation; interrelationships with body fluid volumes. In: Physical Bases of Circulatory Transport Regulation and Exchange, edited by

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