Salt Balance and Long-Term Blood Pressure Control

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<ul><li><p>Ann. Rev. Med. 1980. 31:15-27 Copyright 1980 by Annual Reviews Inc. All rights reserved </p><p>SALT BALANCE AND LONG-TERM BLOOD PRESSURE CONTROL </p><p>Arthur C Guyton, MD., Thomas G. Coleman, MD., David B. Young, MD., Thomas E Lohmeier, MD., and James W. DeClue, MD. </p><p>Department of Physiology and Biophysics, University of Mississippi Medical School, Jackson, Mississippi 39216 </p><p>.7339 </p><p>Most of us are well aware of the many studies showing that segregated groups of people who live with meager intakes of salt usually maintain entirely normal blood pressures throughout their lives (1-4). At the other extreme, populations in which salt intake is greater than the norm have an especially high incidence of hypertension (5, 6). One of the most graphic examples of relationships between salt intake and blood pressure was recorded by Prior and his colleagues (1, 2): the natives living on the island of Pukapuka and some other Pacific islands have a daily salt intake many times less than that of persons living in the Western culture, and their arterial pressures do not increase as they age. Yet, many of these natives have migrated to New Zealand and have taken up the cultural and dietary habits of the European New Zealanders. Subsequently, these migrants experience an incidence of increasing arterial pressure similar to that in the other new Zealanders of different racial stock. </p><p>SHORT-TERM SALT LOADING AND HYPERTENSION </p><p>It is common experience that a person can eat tremendous amounts of salt for a few days or even a few weeks at a time without experiencing a significant rise in arterial pressure; or he can go for weeks with almost no </p><p>15 0066-4219/80/040 1-00 15$0 1.00 </p><p>Ann</p><p>u. R</p><p>ev. M</p><p>ed. 1</p><p>980.</p><p>31:1</p><p>5-27</p><p>. Dow</p><p>nloa</p><p>ded </p><p>from</p><p> ww</p><p>w.an</p><p>nual</p><p>revi</p><p>ews.o</p><p>rgby</p><p> Uni</p><p>vers</p><p>ity o</p><p>f Abe</p><p>rdee</p><p>n on</p><p> 09/</p><p>20/1</p><p>3. F</p><p>or p</p><p>erso</p><p>nal u</p><p>se o</p><p>nly.</p></li><li><p>16 GUYTON ET AL </p><p>salt intake, also without a significant change in pressure. These effects have been quantitated in the past few years by Langston et al (7), Douglas et al (8), Coleman &amp; Guyton (9), DeClue et al (10), and Manning et al (11). The curve labeled "CHRONIC" in Figure 1 illustrates an average drawn from data in these studies, and shows the relationship of arterial pressure to urinary sodium output when the sodium intake is increased progressively over a period of two weeks from about 0.2 of normal up to 8 times normal. Note that the arterial pressure hardly changes, though the sodium output from the kidneys increases markedly. This curve is called a long-term renal junction curve: It illustrates that, whatever the intake load of sodium within very wide limits, the kidney can excrete the salt load with very slight change in arterial pressure. Similar quantitative studies in human beings (12) show that the arterial pressure in the normal person changes an average of only </p><p>8 </p><p>C'II:II 6 E .... c::I en cu e 4 :.;::: </p><p>....... = ICL.. ....... == 2 = :&amp; = = en 0 </p><p>o </p><p>RENIN = ( </p><p>CHRONIC </p><p>DECREASED RENIN &amp; ALDOSTERONE </p><p>/ I </p><p>ACUTE / </p><p>/ </p><p>, </p><p>RENIN = .25 / </p><p>--_/ ""''''''' I </p><p>,/ ..... </p><p>/ / </p><p>/ / </p><p>/ </p><p>INCREASED RENIN &amp; ALDOSTERONE I I I </p><p>25 50 75 100 125 150 175 200 ARTERIAL PRESSURE (mmHgj </p><p>Figure 1 The normal acute and chronic renal function curves, illustrating the relationship between arterial pressure and urinary sodium output. The dashed arrows illustrate the directional shift of the acute curve toward the chronic curve caused by renin and aldosterone. The renin values are expressed in relative units with 1.0 equal to the normal value. </p><p>Ann</p><p>u. R</p><p>ev. M</p><p>ed. 1</p><p>980.</p><p>31:1</p><p>5-27</p><p>. Dow</p><p>nloa</p><p>ded </p><p>from</p><p> ww</p><p>w.an</p><p>nual</p><p>revi</p><p>ews.o</p><p>rgby</p><p> Uni</p><p>vers</p><p>ity o</p><p>f Abe</p><p>rdee</p><p>n on</p><p> 09/</p><p>20/1</p><p>3. F</p><p>or p</p><p>erso</p><p>nal u</p><p>se o</p><p>nly.</p></li><li><p>SALT:BALANCE AND BLOOD PRESSURE 17 </p><p>17 mm H;g when the salt intake is varied between 0.1 of normal salt intake and 10 times normal intake, a range of lOO-fold </p><p>This relationship between arterial pressure and urinary sodium output is very important in understanding the relationship between salt load and blood pressure. Thus we need to examine the physiological causes for the extremely steep relationship between pressure and sodium output as illustrated by the chronic renal function curve of Figure 1. The curve in Figure 1 that is labeled "ACUTE" will help explain this. This curve shows the relationship between arterial pressure and sodium output found in acute laboratory experiments in which the kidney is perfused with blood and the arterial pressure is changed through a range of values (13-15). One can readily see the marked difference between the two curves. But the conditions of the two experiments also are markedly different. For the acute curve, the arterial pressure was increased over a period of a few minutes to an hour or more. For"the chronic curve, the salt intake was increased progressively over a period of'several weeks; this caused a slight rise in arterial pressure but it also caused other physiological changes. For instance, it is well known that increasing the sodium intake decreases both renin and aldosterone secretion, while decreasing the sodium intake has the opposite effects. DeClue and his associates (10) and Young and his associates (16, 17) demonstrated the effects illustrated by the two dashed arrows in Figure I: the decreased renin and aldosterone secretion at high salt intakes shifts the top of the renal function curve toward the left, and the increased renin and aldosterone secretion at low salt intakes shifts the bottom of the renal function curve toward the right. In support of these findings, note the relative renin values at different levels of the chronic renal function curve as recorded by DeClue et al (10), illustrating marked reduction of renin secretion at high sodium level and marked increase in renin at low sodium level. Quantitatively, these effects of renin and aldosterone can account for almost half of the total change from the sloping acute curve to the very steep chronic renal function curve. Other factors that may also play roles in this effect are long-term intrarenal hemodynamic changes and natriuretic factors, but the quantitative importance of both of these is yet to be established. </p><p>Because of the widely heralded ability of renin to increase the rate of aldosterone secretion, it is tempting to ascribe the steepening of the renal function curve by both renin and aldosterone entirely to changes in aldosterone, with the renin-angiotensin system functioning by changing the rate of aldosterone secretion. However, many different studies in which the aldosterone factor has been controlled show that angiotensin very potently and directly causes the kidneys to retain sodium (18-20); angiotensin blockade causes markedly increased excretion of sodium (21, 22). In fact, the </p><p>Ann</p><p>u. R</p><p>ev. M</p><p>ed. 1</p><p>980.</p><p>31:1</p><p>5-27</p><p>. Dow</p><p>nloa</p><p>ded </p><p>from</p><p> ww</p><p>w.an</p><p>nual</p><p>revi</p><p>ews.o</p><p>rgby</p><p> Uni</p><p>vers</p><p>ity o</p><p>f Abe</p><p>rdee</p><p>n on</p><p> 09/</p><p>20/1</p><p>3. F</p><p>or p</p><p>erso</p><p>nal u</p><p>se o</p><p>nly.</p></li><li><p>18 GUYTON ET AL </p><p>quantitative results of all these studies suggest that the direct effect of angiotensin on the kidneys is several times as potent as the direct effect of aldosterone to cause sodium retention. Therefore, there is accumulating evidence that this direct action of angiotensin on the kidneys is the major mechanism for sodium conservation rather than the effect of the aldosterone. </p><p>In summary, because the kidney can excrete extreme amounts of salt with very little rise in arterial pressure, massive salt loading in normal animals and normal humans does not cause hypertension. </p><p>Hemodynamics By the term "short-term salt-loading hypertension" we mean hypertension that occurs in a matter of days following buildup of excess sodium in the body. Then, when the excess sodium is removed, arterial pressure returns to its normal level within another few days. It is not possible to cause such hypertension in most normal animals by acutely loading them with large excesses of salt, but it can be achieved by a combination of salt loading and almost any maneuver that inhibits the kidney's ability to excrete salt-for instance, removing kidney mass. </p><p>Figure 2 illustrates the circulatory hemodynamic changes that lead to hypertension at the onset of chronic salt loading. It is a composite diagram from experiments by Langston et al (7), Douglas et al (8), Coleman &amp; Guyton (9), and Manning et al (11), in which approximately 70% of the kidney mass was first removed and then the animal's daily salt intake was increased to approximately five times normal. The sequential changes were the following: </p><p>The extracellular fluid volume, blood volume, mean circulatory filling pressure, pressure gradient for venous return, and cardiac output all increased 20-60% during the first few days, but after about two weeks all of these had returned to almost normal, with the exception of the mean circulatory filling pressure, which remained 20% above normal. The "mean circulatory filling pressure" is the pressure measured in the entire circulatory system when the heart stops pumping and the pressures everwhere in the circulation are allowed to equalize. Thus, the mean circulatory filling pressure is a measure of how tightly the circulatory system is filled with blood. And the "pressure gradient for venous return" is the difference between the mean circulatory filling pressure and the right atrial pressure; this difference is a measure of the driving force that causes return of blood from the peripheral circulation to the heart. </p><p>The total peripheral resistance actually decreased during the first few days of salt loading, decreasing to about 20% below normal at the end of the first day but then rising to 38% above normal after about two weeks. </p><p>Ann</p><p>u. R</p><p>ev. M</p><p>ed. 1</p><p>980.</p><p>31:1</p><p>5-27</p><p>. Dow</p><p>nloa</p><p>ded </p><p>from</p><p> ww</p><p>w.an</p><p>nual</p><p>revi</p><p>ews.o</p><p>rgby</p><p> Uni</p><p>vers</p><p>ity o</p><p>f Abe</p><p>rdee</p><p>n on</p><p> 09/</p><p>20/1</p><p>3. F</p><p>or p</p><p>erso</p><p>nal u</p><p>se o</p><p>nly.</p></li><li><p>20 EXTRACELLULAR : FLUID VOLUME 17 (liters) 16 </p><p>33% </p><p>_4_% 15L--..1 BLOOD VOLUME 55 </p><p>6.0f (liters) . 5.0 </p><p>MEAN CIRCULATORY 1 6 </p><p>FILLING 14 PRESSURE 12 </p><p>20% r--- 5% </p><p>-----------------------. </p><p>20% (mmHg) 10L---L-------------------------PRESSURE 13 </p><p>GRADIENT FOR 12 VENOUS RETURN I I </p><p>(mmHg) 1 0L--..J 7.0 CARDIAC 6.5 OUTPUT 6.0 </p><p>(liters/min) 5.5 </p><p>TOTAL PERIPHERAL RESISTANCE </p><p>5.0</p><p>L....-....I 40 35 30 25 </p><p>(mmHg/liter / 201----min) 15 </p><p>____ 4_.4 % </p><p>____ 5% </p><p>38% ----</p><p>ARTERIAL PRESSURE </p><p>(mmHg) </p><p>140 I 130 : 120 I 22.5% 110 I </p><p>45% 150f SET.'-ETEEc:------= .. </p><p>1001 I ---,,----------I-------o 4 8 12 16 </p><p>DAY S Figure 2 Sequential changes in the important cardiovascular hemodynamic variables in the first few weeks following the onset of short-term salt-loading hypertension. Note especially that the arterial pressure rises ahead of the increase in total peripheral resistance. (Preprinted from Guyton, A. C. 1980. Arterial Pressure Control and Hypertension, Philadelphia: Saunders. In press.) </p><p>Ann</p><p>u. R</p><p>ev. M</p><p>ed. 1</p><p>980.</p><p>31:1</p><p>5-27</p><p>. Dow</p><p>nloa</p><p>ded </p><p>from</p><p> ww</p><p>w.an</p><p>nual</p><p>revi</p><p>ews.o</p><p>rgby</p><p> Uni</p><p>vers</p><p>ity o</p><p>f Abe</p><p>rdee</p><p>n on</p><p> 09/</p><p>20/1</p><p>3. F</p><p>or p</p><p>erso</p><p>nal u</p><p>se o</p><p>nly.</p></li><li><p>20 GUYTON ET AL </p><p>The arterial pressure rose progressively for the first several days and at the end of a week or so leveled out at a new plateau level about 45% above normal. </p><p>Now, let us examine these hemodynamic changes. Five of the factors were all related to the increased fluid volume of the body-the extracellular fluid volume, the blood volume, the mean circulatory filling pressure, the pressure gradient for venous return, and the cardiac output. These were transiently but very significantly increased during the first few days of excess salt. It was during these same first few days that the arterial pressure rose most rapidly. However, by the time the arterial pressure had established its steady-state elevated level, all of the factors related to increased volume had' returned almost to normal. In fact, none of the factors, with the possible exception of the mean circulatory filling pressure, could reliably be measured as abnormal by that time. Thus, here is an instance of true volume-loading hypertension, and yet once the steady state had been reached it was almost impossible to demonstrate that the volume itself, or other factors directly related to it, had actually increased. </p><p>Note that the total peripheral resistance decreased during the first few days of excess salt intake. It was during this time that most of the arterial pressure increase occurred. Therefore, the total peripheral resistance not only did not contribute to the rise in arterial pressure, it actually inhibited the pressure rise. Once the arterial pressure had reached its hypertensive level, the total peripheral resistance, almost as an afterthought, then increased progressiVely nearly as much as the arterial pressure had increased. During the course of this increase in total peripheral resistance, all of the volume factors returned nearly to normal. </p><p>There are many reasons to believe that the changes in total peripheral resistance recorded in Figure 2 were caused, in the following manner: The initial decrease in total peripheral resistance was almost certainly caused by the baroreceptor reflex that caused peripheral vasodilatation. But the secondary increase in total peripheral resistance is attributed to the autoregulation mechanism (23, 34). This is the effect of excess blood flow through tissues to cause a progressive increase in local vascular resistance until the flow returns nearly to normal. The increase in resistance in all parts of the body in tum decreases the cardiac output baCK toward normal. But it also increases the total peripheral resistance. As shown in Figure 2, this increase in resistance is very marked, increasing almost as much as the increase in arterial pressure-but the increase in resistance follows the increase in pressure; it does not precede it. </p><p>Therefore, by the time short-term salHoading hypertension reaches sieady state (in only a few weeks), it is a high resistance hypertension, not a high cardiac output hypertension, even though its initiating cause was high volume and high cardiac output. </p><p>Ann</p><p>u. R</p><p>ev. M</p><p>ed. 1</p><p>980.</p><p>31:1</p><p>5-27</p><p>. Dow</p><p>nloa</p><p>ded </p><p>from</p><p> ww</p><p>w.an</p><p>nual</p><p>revi</p><p>ews.o</p><p>rgby</p><p> Uni</p><p>vers</p><p>ity o</p><p>f Abe</p><p>rdee</p><p>n on</p><p> 09/</p><p>20/1</p><p>3. F</p><p>or p</p><p>erso</p><p>nal u</p><p>se o</p><p>nly.</p></li><li><p>SALT BALANCE AND BLOOD PRESSURE 21 </p><p>The Volume Factor We have already alluded to the very small increases in extracellular fluid volume and blood volume found during the steady-state stage of short-term salt-loading hypertension. Because of this finding, confirmed by many others, it has often been argued that the hypertension in salt-loading states could not be caused by an increase in volume. However, there are several reasons for believing this is not a reasonable conclusion. First, as illustrated in Figure 2, the hypertension initially developed when there were definite increases in both extracellular fluid volume and blood volume, and also increases in all the other hemodynamic factors related to excess volume. Thus, the hypertension became established even before the total peripheral resistance rose. Second, if...</p></li></ul>