Clin. Cardiol. l4 (Supp\. IV), IV-6-21 (1991)
Control of Blood Pressure by the Renin-Angiotensin-Aldosterone System JOHN
E.
HALL, Ph .D .
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA
Summary: Modification of the renin-angiotensin system, part of a powerful feedback system for long-term control of arterial pressure and volume homeostasis, through use of angiotensin-converting enzyme (ACE) inhibitors, offers a powerful means of reducing blood pressure in many hyperten ive patients . There is considerable evidence to suggest that the chronic renal and blood pressure actions of ACE inhibitors are mediated mainly by blockade of angiotensin II formation , rather than by other effects such as increased levels of kinins or prostaglandins . The loogterm actions of angiotensin U and aldosterone on blood pressure are closely intertwined with their effects on volume homeostasis and the renal pressure natriuresis mechanism. In most instances, changes in angiotensin II and aldosterone act to amplify the effectiveness of pressure natriuresis and minimize changes .in blood pressure needed to maintain sodium balance. When angiotensin II or aldosterone levels are inappropriately elevated, the antinatriuretic effects of these hormones shift pressure natriuresis to higher levels, thereby necessitating increased blood pressure to maintain sodium balance. Control of renal excretory function and modulation of pressure natriuresis by angiotensin II is mediated by intrarenal and extrarenal effects , including stimulation of aldosterone secretion. Current evidence indicates that the intra renal effects of angiotensin II are quantitatively more important than changes in aldosterone in regu lating renal excretion and arterial pressure. The intrarenal actions of angiotensin II include a direct effect on tubular sodium transport as well as a potent constrictor action on efferent arterioles , which increases reabsorption by altering peritubular capillary forces. The constrictor effect of angiotensin II on efferent arterioles also helps to stabilize glomerular filtration
Address for reprints: John E. Hall , Ph .D. Department of Physiology and Biophysics University of Mississippi Medical Center 2500 N. State Street Jackson , MS 39216-4505 , USA
rate and therefore excretion of metabolic waste products, an action that may be particularly important when renal perfusion is impaired (e.g. , in renal artery stenosis or heart failure).
Key words: angiotensin, renin, blood pressure, kidney, sodium excretion , glomerular filtration, converting enzyme inhibition
Introduction Our understanding of the various physiologic functions of the renin-angiotensin system has accelerated rapidly with the development of powerful pharmacologic tools that can be used to block the different components of this system . From experimental and clinical studies, it is now clear that the renin-angiotensin system is one of the body's most powerful regulators of body fluid volumes and arterial pressure. \ - 4 It is not surprising , therefore, that blockade of the formation of angiotensin ll , the primary active component of the renin-angiotensin system, with angiotensinconverting enzyme (ACE) inhibitors has proved very effective therapy for such diseases as hypertension and heart failure. Although considerable effort has been put forth in developing other clinically useful inhibitors of the reninangiotensin system, especially inhibitors of renin and angiotensin II antagonists that are orally active, the ACE inhibitors have been the most widely used and effective blockers, both for the olinical treatment of disease and for unraveling the various physiologic functions of the reninangiotensin system. ACE inhibitors may have additional actions besides blockade of angiotensin II fomlation; however, there is considerable evidence that most of their long-term antihypertensive effects are mediated by this means. Therefore, an understanding of the mechanism of action of these antihypertensive agents requires an understanding of the physiology of the renin-angiotensin system . Angiotensin II participates in short-term and long-term blood pressure regulation through several pathways. A powerful vasoconstrictor, angiotensin IT contributes to the maintenance of blood pressure in circumstances such a
1. E. Hall: Renin-angiotensin-aldosterone system
acute hemorrhage or dehydration. However, hypertension represents a disturbance of long-term blood pressure regulation, and the chronic actions of angiotensin II on blood pressure are closely intertwined with its effects on volume homeostasis, especially those that influence renal excretory capability. 1.2 Therefore, the focus of this brief review is the basic mechanisms that link the renal actions of angiotensin II to long-term blood pressure regulation and why blockade of these actions is an effective means of treating hypertension.
rV -7
til blood pressure returns to normal . Conversely, hypotension causes sodium retention until blood pressure i restored to normal. 6 Chronic
I
'-......
5
Acute
"
'---...,' I I
4
I I
Renal Excretory Function and Long-Term Blood Pressure Regulation Before discussing the specific mechanisms by which angiotensin II influences renal function and blood pressure regulation, we first must consider a more basic feedback mechanism that links control of body fluid volumes with blood pressure: the renal-body fluid feedback mechanism (Fig. I). A primary component of this feedback is the effect of arterial pressure on sodium and water excretion, often referred to as renal-pressure natriuresis (Fig. 2). S - 7 Normally, this mechanism serves as a powerful means of stabi lizing blood pressure. For instance, disturbances that tend to raise blood pressure without impairing renal excretory function also raise sodium excretion, via pressure natriuresis , thereby reducing extracellular fluid volume un-
I I
Urinary sodium 3 output (x normal)
I I I I I
I I I
I
2
I
I I I I
I
Normal
I
intake
o ~----~~--~~------~----50
100
150
...J
200
Mean arterial pressure (mmHg)
FIG . 2 Acule and chronic relationships between anerial pres ure and sodi um excretion.
Fluid intake
Nonrenal fluid loss
:........... Arterial pressure
Renal excretion
•
•
Rate of change extracellular fluid
Total peripheral resistance
.!.1 Q)
E
co~
~
Extracellular fluid
Blood volume
I
2 0«
.cU)
1~
Cardiac output
Q.U)
Venous return
Mean circulatory filling pressure
E::J
>'0 (/)~ Q)
c:
Heart strength
Vascular capacity
FIG . I Basic components of renal- body fluid feedback system for long-tenn regulation of blood pre•. ure. - - = po itive effects; --- = negative e ffects. ADH = anlidiuretic honnone; All = angiotensin II.
IV-8
Clin . Cardiol. Vol. 14 (Suppl. IV) , August 1991
An important feature of this feedback is that there are multiple neurohumoral factors that can amplify or blunt the basic effect of blood pressure on sodium excretion. In most instances, these neurohumoral systems work in concert with pressure natriuresis to maintain a stable blood pressure and body fluid volume. For example, with chronic increases in sodium intake, suppression of angiotensin II formation helps to raise sodium excretion and minimizes the rise in blood pressure needed to maintain sodium balance via pressure natriuresis . 8 Therefore, the chronic relationship between blood pressure and sodium excretion is much steeper than that observed during acute changes in blood pressure (Fig. 2). However, in certain pathologic conditions (e.g., renin-secreting tumor) , excessive angiotensin II formation may reduce renal excretory capability and shift pressure natriuresis to higher levels, thereby necessitating increased blood pressure to maintain sodium balance, as discussed below . One aspect of this feedback that becomes obvious upon careful inspection is that it continues to operate until blood pressure is restored to the normal set point, thereby providing an "infinite gain " control system. S Thus, an elevation in blood pressure caused by increased total peripheral resistance or enhanced cardiac function could not be sustained without a shift of pressure natriuresis , because the ri se in blood pressure would also increase sodium excretion above intake and reduce extracellular fluid volume until blood pressure returned to normal (Fig. 3) . As long as pressure natriuresis is undisturbed, tbe only point where sodium balance can be maintained is at the normal blood pressure. Chronic changes in blood pressure can occur, however, if pre sure natriuresis is altered. For example, disturbances that impair renal excretory capability (e.g., renal disease or excessive formation of antinatriuretic hormones) could shift pressure natriuresis to higher levels , requiring increased blood pressure to maintain sodium balance (Fig. 4). Initially, a decrease in renal excretory capability would tend to reduce sodium excretion below intake and increase extracellular fluid volume . However, as blood pressure increased, sodium excretion would also increase, via pressure natriuresis . Eventually, arterial pressure would stabi lize, and , under steady-state conditions, intake and ex cretion of sodium would be balanced, but at the expense of hypertension . If the hypertensive stimulus also caused peripheral vasoconstriction and reduced vascular capacitance, only small increases in extracellular fluid volume would be needed to raise blood pressure sufficiently to maintain sodium balance. With very powerful vasoconstrictors, vascular capacity could be reduced markedly and blood pressure might be elevated transiently above the set point for sodium balance; if this occurred , sodium excretion could actually increase via pressure natriuresis in spite of a reduction in renal excretory capability and a shift of pressure natriuresis to higher levels. However, as discussed above, chronic hypertension could not be sustained by changes in peripheral vascular
resistance alone; to sustain the hypertension and stiJI maintain sodium balance, a shift of pressure natriuresis to higher levels must occur. Likewise, a chronic reduction in blood pressure with effective antihypertensive therapy must increase renal excretory capability and shift pressure natriuresis so that sodium balance can be maintained at reduced blood pressures. Therefore, in analyzing the potential mechanism by which the renin-angiotensin system regu lates blood pressure chronically and how ACE inhibitors lower blood pressure in hypertensive patients, particular attention must be paid to the effect of these agents on renal excretory capability and pressure natriuresis.
4
3 Urinary sodium output (x normal)
o ~----~----~----~----~ 50 100 150 Mean arterial pressure (mmHg)
200
Stimulus 150 Mean arterial pressure (mmHg) 100 ~----~
3 Urinary sodium output (x normal)
2
-2
-1
o
2
3
4
Time (days) FIG 3 Chronic effects of hypertensive stimulus, caused by increased total peripheml vascular resistance or increased cardiac out put, with no change in renal -pre sure natriuresis . Blood pressure is initially elevated , but hypertension cannot be su tained because sodium excretion exceeds intake and decreases extmcellular fluid volume until blood pressure returns to normal, where intake and output are in balance.
IV-9
1. E. Hall: Renin-angiotensin-aldosterone system
. - Control • _.. ACE inhibitor 0- ~ Angiotensin :II: 500 400 Urinary sodium output (x normal)
..
Urinary 300 sodium excretion 200 (mEq/day) 100
70 50 Mean arterial pressure (mmHg)
FIG . 5 Steady-state relationships between blood pressure and sodium excretion in control dogs and in dog infused with an ACE inhibitor or angiotensin II . [Adapted with penni sion from Hall JE , Guyton AC, Smith MJ Jr, Coleman TG : Blood pre sure and renal function during chronic changes in sodium intake: Role of angiotensin . Alii J Physio/239, F271 - F280, (1980), Ref. 8.)
Stimulus 150 Mean arterial pressure (mmHg) 100
80 90 100 11 0 120 130 140 150 Mean arterial pressure (mmHg)
I-------!-I
Urinary sodium output IX normal)
-2
-1
o
2
3
4
Time (days) FIG . 4
Chronic effects of an an tinatriuretic stimulus that shifts renal-pressute natriuresis but does not cause a primary change in total peripheral vascular resistance or cardiac function . Blood pressure does not change initially but gradually rises until sodium excretion is returned to nom1al, via pressure natriuresis .
The Renin-Angiotensin System and Pressure Natriuresis Numerous studies indicate that angiotensin II has important acute and chronic effects on pressure natriuresis. 8.9 Figure 5 illustrates the effects of blocking angiotensin II formation with an ACE inhibitor or angiotensin II infusion on the long-term relationship between blood pressure and sodium excretion. In these experiments, sodium intake was increased in step from 5 mEq/day to approximately 80, 240, and 500 mEq/day and maintained at each level for 8 days until balance between intake and output of sod ium was achieved. In normal dogs, with an intact renin-angiotensin sy tem, sodium balance was maintained with only minor changes (5-10 mmHg) in blood pressure over the entire range of sodium intake, indicating a very effective pressure natriuresi mechanism . Thus, when the
renin-angiotensin system is functioning normally, blood pressure is relatively insensitive to sodium intake. One of the most important reasons for the steepness of the normal pressure natriuresi curve is that angiotensin II levels can be suppressed when odium intake is rai ed. When angiotensin II was infused at a low rate throughout the experiment so that circulating level could not decrease as sodium intake was raised , much larger increa es in blood pressure (40-50 mmHg) were required to maintain sodium balance at high intakes. Thus, the inability to suppress angiotensin 11 formation greatly decrease the effectiveness of pressure natriuresis and makes blood pressure very sensitive to sodium intake. After blockade of angiotensin 11 formation with an ACE inhibitor, the renal-pressure natriuresis mechani sm was shifted to lower blood pre sure. Thi indicates increa ed renal excretory capability, ince intake and excretion of sodium were balanced at lower than normal blood pre sures. This effect of ACE inhibitors, a hift of pre sure natriuresis , provides the basis of their effectiveness a chronic antihyperten ive agent. However, the fact that blood pressure is also very sodium sen itive after ACE inhibition indicates that the effectiveness of ACE inhibitors in lowering blood pressure is inversely related to sodium intake.
Pressure Natriuresis and Renal "Escape" from Angiotensin II The extreme importance of the interrelationship between angiotensin II and pressure natriure i in controlling blood pressure and body fluid volum an be demon trated by preventing renal artery pres ure from increa ing during chronic angioten in II hypertension . 10 rnfu ion of angiotensin II nonnally causes a tran ient decrea e in odium
Clin. Cardiol. Vol. 14 (Suppl. IV), August 1991
IV-IO
excretion, lasting for 1-2 days, followed by a return of excretion to normal, similar to the "escape" seen with mineralocorticoid excess. 10 . 11 However, when renal perfusion pressure was prevented from increasing with an electronic servo-control device, escape from sodium retention did not occur during chronic angiotensin II infusion, and cumulative sodium balance and systemic pressure continued to rise until symptoms of pulmonary edema developed in only a few days (Fig. 6). When the servocontroller was stopped and renal artery pressure was aJlowed to increase to hypertensive levels while angiotensin II infusion was continued, sodium excretion increased markedly and sodium balance was quickly restored. 10 These observations emphasize the essential role of pressure natriuresis in maintaining sodium balance during angiotensin II hypertension. We have also found similar results in other models of hypertension caused by infusion of antinatriuretic or antidiuretic honnones, such as aldo terone, vasopressin, or norepinephrine. 12- 14 Chronic
HS - 7 170 I I I I
150 Arterial pressure 130 (mmHg) 110 90 250
I
I I I
........................... I
Renal
I
I I "
Pulmonary edema symptoms
150 Cumulative 50 Na 0 balance -50 (mEq) 150 450
hypertension appears to be a necessary "trade-off' that allows fluid balance to be maintained in the face of impaired renal function. However, when high levels of anti natriuretic hormones occur as a result of abnormalities that cause circulatory depression (e.g., heart failure, cirrhosis) and are unopposed by pressure natriuresis, sodium retention continues unabated , possibly because blood pressure cannot be raised ufficiently to offset the effects of sodium-retaining hormones.
Pressure Natriuresis in Essential Hypertension: Effects of ACE Inhibition A common misconception about patients with essentiaJ hypertension is that their renal function is normal. In many patients. no obvious abnormality of glomerular filtration rate (GFR), renal blood flow, or sodium excretion can be identified . However, when one considers the steady-state relationships between blood pressure and sodium excretion in these individuals, it is clear that renal function is not normal. In all hypertensive patients, including those with essential hypertension, there is a shift of renalpressure natriuresis to higher blood pressures, indicating an impairment of renal excretory capability (Fig. 7). The exact causes of this shift are still unclear and it seems likely that essential hypertension is a very heterogeneous disease beginning with different abnormalities of renal hemodynamics or tubular reabsorption in different patients. Unfortunately, measurements of various indices of renal function after hypertension is established, or even during the development of hypertension , may not provide a great deal of in ight into the pathophysiologic processes that initiate the hypertension, because such measurements represent the summation of compensatory mechanisms and
5
I
4
400
Sodium intake 3 and output (x normal) 2
Urinary 150 Na excretion 100 (mEq/day)
_~["--- _____ l ,_ eIL _____ _ : intake
_ ~
Normal ------- intake
50 0 -4
-2
o
246
8
10
12
Time (days) FIG 6 Effects of angiotensin U infusion when renal perfusion pressure was servo-controlled at the normal level. After four days. severe hypertension and sodium retention caused pulmonary edema . LAdapted with permission from Hall JE. Granger JP, Hester RL. Coleman TG. Smith MJ Jr. Cross RB : Mechanisms of e cape from sodium retention during angiotensin ]J hypertension . Am J Physiol 246. F627- F634 (1984). Ref. 10.]
.S? ~ ~
o
z
50
-
UJ.c
~ -
- - _ .
Control of Blood Pressure by the Renin-Angiotensin-Aldosterone System JOHN
E.
HALL, Ph .D .
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA
Summary: Modification of the renin-angiotensin system, part of a powerful feedback system for long-term control of arterial pressure and volume homeostasis, through use of angiotensin-converting enzyme (ACE) inhibitors, offers a powerful means of reducing blood pressure in many hyperten ive patients . There is considerable evidence to suggest that the chronic renal and blood pressure actions of ACE inhibitors are mediated mainly by blockade of angiotensin II formation , rather than by other effects such as increased levels of kinins or prostaglandins . The loogterm actions of angiotensin U and aldosterone on blood pressure are closely intertwined with their effects on volume homeostasis and the renal pressure natriuresis mechanism. In most instances, changes in angiotensin II and aldosterone act to amplify the effectiveness of pressure natriuresis and minimize changes .in blood pressure needed to maintain sodium balance. When angiotensin II or aldosterone levels are inappropriately elevated, the antinatriuretic effects of these hormones shift pressure natriuresis to higher levels, thereby necessitating increased blood pressure to maintain sodium balance. Control of renal excretory function and modulation of pressure natriuresis by angiotensin II is mediated by intrarenal and extrarenal effects , including stimulation of aldosterone secretion. Current evidence indicates that the intra renal effects of angiotensin II are quantitatively more important than changes in aldosterone in regu lating renal excretion and arterial pressure. The intrarenal actions of angiotensin II include a direct effect on tubular sodium transport as well as a potent constrictor action on efferent arterioles , which increases reabsorption by altering peritubular capillary forces. The constrictor effect of angiotensin II on efferent arterioles also helps to stabilize glomerular filtration
Address for reprints: John E. Hall , Ph .D. Department of Physiology and Biophysics University of Mississippi Medical Center 2500 N. State Street Jackson , MS 39216-4505 , USA
rate and therefore excretion of metabolic waste products, an action that may be particularly important when renal perfusion is impaired (e.g. , in renal artery stenosis or heart failure).
Key words: angiotensin, renin, blood pressure, kidney, sodium excretion , glomerular filtration, converting enzyme inhibition
Introduction Our understanding of the various physiologic functions of the renin-angiotensin system has accelerated rapidly with the development of powerful pharmacologic tools that can be used to block the different components of this system . From experimental and clinical studies, it is now clear that the renin-angiotensin system is one of the body's most powerful regulators of body fluid volumes and arterial pressure. \ - 4 It is not surprising , therefore, that blockade of the formation of angiotensin ll , the primary active component of the renin-angiotensin system, with angiotensinconverting enzyme (ACE) inhibitors has proved very effective therapy for such diseases as hypertension and heart failure. Although considerable effort has been put forth in developing other clinically useful inhibitors of the reninangiotensin system, especially inhibitors of renin and angiotensin II antagonists that are orally active, the ACE inhibitors have been the most widely used and effective blockers, both for the olinical treatment of disease and for unraveling the various physiologic functions of the reninangiotensin system. ACE inhibitors may have additional actions besides blockade of angiotensin II fomlation; however, there is considerable evidence that most of their long-term antihypertensive effects are mediated by this means. Therefore, an understanding of the mechanism of action of these antihypertensive agents requires an understanding of the physiology of the renin-angiotensin system . Angiotensin II participates in short-term and long-term blood pressure regulation through several pathways. A powerful vasoconstrictor, angiotensin IT contributes to the maintenance of blood pressure in circumstances such a
1. E. Hall: Renin-angiotensin-aldosterone system
acute hemorrhage or dehydration. However, hypertension represents a disturbance of long-term blood pressure regulation, and the chronic actions of angiotensin II on blood pressure are closely intertwined with its effects on volume homeostasis, especially those that influence renal excretory capability. 1.2 Therefore, the focus of this brief review is the basic mechanisms that link the renal actions of angiotensin II to long-term blood pressure regulation and why blockade of these actions is an effective means of treating hypertension.
rV -7
til blood pressure returns to normal . Conversely, hypotension causes sodium retention until blood pressure i restored to normal. 6 Chronic
I
'-......
5
Acute
"
'---...,' I I
4
I I
Renal Excretory Function and Long-Term Blood Pressure Regulation Before discussing the specific mechanisms by which angiotensin II influences renal function and blood pressure regulation, we first must consider a more basic feedback mechanism that links control of body fluid volumes with blood pressure: the renal-body fluid feedback mechanism (Fig. I). A primary component of this feedback is the effect of arterial pressure on sodium and water excretion, often referred to as renal-pressure natriuresis (Fig. 2). S - 7 Normally, this mechanism serves as a powerful means of stabi lizing blood pressure. For instance, disturbances that tend to raise blood pressure without impairing renal excretory function also raise sodium excretion, via pressure natriuresis , thereby reducing extracellular fluid volume un-
I I
Urinary sodium 3 output (x normal)
I I I I I
I I I
I
2
I
I I I I
I
Normal
I
intake
o ~----~~--~~------~----50
100
150
...J
200
Mean arterial pressure (mmHg)
FIG . 2 Acule and chronic relationships between anerial pres ure and sodi um excretion.
Fluid intake
Nonrenal fluid loss
:........... Arterial pressure
Renal excretion
•
•
Rate of change extracellular fluid
Total peripheral resistance
.!.1 Q)
E
co~
~
Extracellular fluid
Blood volume
I
2 0«
.cU)
1~
Cardiac output
Q.U)
Venous return
Mean circulatory filling pressure
E::J
>'0 (/)~ Q)
c:
Heart strength
Vascular capacity
FIG . I Basic components of renal- body fluid feedback system for long-tenn regulation of blood pre•. ure. - - = po itive effects; --- = negative e ffects. ADH = anlidiuretic honnone; All = angiotensin II.
IV-8
Clin . Cardiol. Vol. 14 (Suppl. IV) , August 1991
An important feature of this feedback is that there are multiple neurohumoral factors that can amplify or blunt the basic effect of blood pressure on sodium excretion. In most instances, these neurohumoral systems work in concert with pressure natriuresis to maintain a stable blood pressure and body fluid volume. For example, with chronic increases in sodium intake, suppression of angiotensin II formation helps to raise sodium excretion and minimizes the rise in blood pressure needed to maintain sodium balance via pressure natriuresis . 8 Therefore, the chronic relationship between blood pressure and sodium excretion is much steeper than that observed during acute changes in blood pressure (Fig. 2). However, in certain pathologic conditions (e.g., renin-secreting tumor) , excessive angiotensin II formation may reduce renal excretory capability and shift pressure natriuresis to higher levels, thereby necessitating increased blood pressure to maintain sodium balance, as discussed below . One aspect of this feedback that becomes obvious upon careful inspection is that it continues to operate until blood pressure is restored to the normal set point, thereby providing an "infinite gain " control system. S Thus, an elevation in blood pressure caused by increased total peripheral resistance or enhanced cardiac function could not be sustained without a shift of pressure natriuresis , because the ri se in blood pressure would also increase sodium excretion above intake and reduce extracellular fluid volume until blood pressure returned to normal (Fig. 3) . As long as pressure natriuresis is undisturbed, tbe only point where sodium balance can be maintained is at the normal blood pressure. Chronic changes in blood pressure can occur, however, if pre sure natriuresis is altered. For example, disturbances that impair renal excretory capability (e.g., renal disease or excessive formation of antinatriuretic hormones) could shift pressure natriuresis to higher levels , requiring increased blood pressure to maintain sodium balance (Fig. 4). Initially, a decrease in renal excretory capability would tend to reduce sodium excretion below intake and increase extracellular fluid volume . However, as blood pressure increased, sodium excretion would also increase, via pressure natriuresis . Eventually, arterial pressure would stabi lize, and , under steady-state conditions, intake and ex cretion of sodium would be balanced, but at the expense of hypertension . If the hypertensive stimulus also caused peripheral vasoconstriction and reduced vascular capacitance, only small increases in extracellular fluid volume would be needed to raise blood pressure sufficiently to maintain sodium balance. With very powerful vasoconstrictors, vascular capacity could be reduced markedly and blood pressure might be elevated transiently above the set point for sodium balance; if this occurred , sodium excretion could actually increase via pressure natriuresis in spite of a reduction in renal excretory capability and a shift of pressure natriuresis to higher levels. However, as discussed above, chronic hypertension could not be sustained by changes in peripheral vascular
resistance alone; to sustain the hypertension and stiJI maintain sodium balance, a shift of pressure natriuresis to higher levels must occur. Likewise, a chronic reduction in blood pressure with effective antihypertensive therapy must increase renal excretory capability and shift pressure natriuresis so that sodium balance can be maintained at reduced blood pressures. Therefore, in analyzing the potential mechanism by which the renin-angiotensin system regu lates blood pressure chronically and how ACE inhibitors lower blood pressure in hypertensive patients, particular attention must be paid to the effect of these agents on renal excretory capability and pressure natriuresis.
4
3 Urinary sodium output (x normal)
o ~----~----~----~----~ 50 100 150 Mean arterial pressure (mmHg)
200
Stimulus 150 Mean arterial pressure (mmHg) 100 ~----~
3 Urinary sodium output (x normal)
2
-2
-1
o
2
3
4
Time (days) FIG 3 Chronic effects of hypertensive stimulus, caused by increased total peripheml vascular resistance or increased cardiac out put, with no change in renal -pre sure natriuresis . Blood pressure is initially elevated , but hypertension cannot be su tained because sodium excretion exceeds intake and decreases extmcellular fluid volume until blood pressure returns to normal, where intake and output are in balance.
IV-9
1. E. Hall: Renin-angiotensin-aldosterone system
. - Control • _.. ACE inhibitor 0- ~ Angiotensin :II: 500 400 Urinary sodium output (x normal)
..
Urinary 300 sodium excretion 200 (mEq/day) 100
70 50 Mean arterial pressure (mmHg)
FIG . 5 Steady-state relationships between blood pressure and sodium excretion in control dogs and in dog infused with an ACE inhibitor or angiotensin II . [Adapted with penni sion from Hall JE , Guyton AC, Smith MJ Jr, Coleman TG : Blood pre sure and renal function during chronic changes in sodium intake: Role of angiotensin . Alii J Physio/239, F271 - F280, (1980), Ref. 8.)
Stimulus 150 Mean arterial pressure (mmHg) 100
80 90 100 11 0 120 130 140 150 Mean arterial pressure (mmHg)
I-------!-I
Urinary sodium output IX normal)
-2
-1
o
2
3
4
Time (days) FIG . 4
Chronic effects of an an tinatriuretic stimulus that shifts renal-pressute natriuresis but does not cause a primary change in total peripheral vascular resistance or cardiac function . Blood pressure does not change initially but gradually rises until sodium excretion is returned to nom1al, via pressure natriuresis .
The Renin-Angiotensin System and Pressure Natriuresis Numerous studies indicate that angiotensin II has important acute and chronic effects on pressure natriuresis. 8.9 Figure 5 illustrates the effects of blocking angiotensin II formation with an ACE inhibitor or angiotensin II infusion on the long-term relationship between blood pressure and sodium excretion. In these experiments, sodium intake was increased in step from 5 mEq/day to approximately 80, 240, and 500 mEq/day and maintained at each level for 8 days until balance between intake and output of sod ium was achieved. In normal dogs, with an intact renin-angiotensin sy tem, sodium balance was maintained with only minor changes (5-10 mmHg) in blood pressure over the entire range of sodium intake, indicating a very effective pressure natriuresi mechanism . Thus, when the
renin-angiotensin system is functioning normally, blood pressure is relatively insensitive to sodium intake. One of the most important reasons for the steepness of the normal pressure natriuresi curve is that angiotensin II levels can be suppressed when odium intake is rai ed. When angiotensin II was infused at a low rate throughout the experiment so that circulating level could not decrease as sodium intake was raised , much larger increa es in blood pressure (40-50 mmHg) were required to maintain sodium balance at high intakes. Thus, the inability to suppress angiotensin 11 formation greatly decrease the effectiveness of pressure natriuresis and makes blood pressure very sensitive to sodium intake. After blockade of angiotensin 11 formation with an ACE inhibitor, the renal-pressure natriuresis mechani sm was shifted to lower blood pre sure. Thi indicates increa ed renal excretory capability, ince intake and excretion of sodium were balanced at lower than normal blood pre sures. This effect of ACE inhibitors, a hift of pre sure natriuresis , provides the basis of their effectiveness a chronic antihyperten ive agent. However, the fact that blood pressure is also very sodium sen itive after ACE inhibition indicates that the effectiveness of ACE inhibitors in lowering blood pressure is inversely related to sodium intake.
Pressure Natriuresis and Renal "Escape" from Angiotensin II The extreme importance of the interrelationship between angiotensin II and pressure natriure i in controlling blood pressure and body fluid volum an be demon trated by preventing renal artery pres ure from increa ing during chronic angioten in II hypertension . 10 rnfu ion of angiotensin II nonnally causes a tran ient decrea e in odium
Clin. Cardiol. Vol. 14 (Suppl. IV), August 1991
IV-IO
excretion, lasting for 1-2 days, followed by a return of excretion to normal, similar to the "escape" seen with mineralocorticoid excess. 10 . 11 However, when renal perfusion pressure was prevented from increasing with an electronic servo-control device, escape from sodium retention did not occur during chronic angiotensin II infusion, and cumulative sodium balance and systemic pressure continued to rise until symptoms of pulmonary edema developed in only a few days (Fig. 6). When the servocontroller was stopped and renal artery pressure was aJlowed to increase to hypertensive levels while angiotensin II infusion was continued, sodium excretion increased markedly and sodium balance was quickly restored. 10 These observations emphasize the essential role of pressure natriuresis in maintaining sodium balance during angiotensin II hypertension. We have also found similar results in other models of hypertension caused by infusion of antinatriuretic or antidiuretic honnones, such as aldo terone, vasopressin, or norepinephrine. 12- 14 Chronic
HS - 7 170 I I I I
150 Arterial pressure 130 (mmHg) 110 90 250
I
I I I
........................... I
Renal
I
I I "
Pulmonary edema symptoms
150 Cumulative 50 Na 0 balance -50 (mEq) 150 450
hypertension appears to be a necessary "trade-off' that allows fluid balance to be maintained in the face of impaired renal function. However, when high levels of anti natriuretic hormones occur as a result of abnormalities that cause circulatory depression (e.g., heart failure, cirrhosis) and are unopposed by pressure natriuresis, sodium retention continues unabated , possibly because blood pressure cannot be raised ufficiently to offset the effects of sodium-retaining hormones.
Pressure Natriuresis in Essential Hypertension: Effects of ACE Inhibition A common misconception about patients with essentiaJ hypertension is that their renal function is normal. In many patients. no obvious abnormality of glomerular filtration rate (GFR), renal blood flow, or sodium excretion can be identified . However, when one considers the steady-state relationships between blood pressure and sodium excretion in these individuals, it is clear that renal function is not normal. In all hypertensive patients, including those with essential hypertension, there is a shift of renalpressure natriuresis to higher blood pressures, indicating an impairment of renal excretory capability (Fig. 7). The exact causes of this shift are still unclear and it seems likely that essential hypertension is a very heterogeneous disease beginning with different abnormalities of renal hemodynamics or tubular reabsorption in different patients. Unfortunately, measurements of various indices of renal function after hypertension is established, or even during the development of hypertension , may not provide a great deal of in ight into the pathophysiologic processes that initiate the hypertension, because such measurements represent the summation of compensatory mechanisms and
5
I
4
400
Sodium intake 3 and output (x normal) 2
Urinary 150 Na excretion 100 (mEq/day)
_~["--- _____ l ,_ eIL _____ _ : intake
_ ~
Normal ------- intake
50 0 -4
-2
o
246
8
10
12
Time (days) FIG 6 Effects of angiotensin U infusion when renal perfusion pressure was servo-controlled at the normal level. After four days. severe hypertension and sodium retention caused pulmonary edema . LAdapted with permission from Hall JE. Granger JP, Hester RL. Coleman TG. Smith MJ Jr. Cross RB : Mechanisms of e cape from sodium retention during angiotensin ]J hypertension . Am J Physiol 246. F627- F634 (1984). Ref. 10.]
.S? ~ ~
o
z
50
-
UJ.c
~ -
- - _ .
