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Erythrocytosis: A key to understanding the hemodynamic changes in hypertension
Medical Hypotheses 0 Longman Group
(19%) 27. 107-I 13 UK Ltd 198X
Erythrocytosis: Hemodynamic
A Key To Understanding Changes in Hypertension
the
KERMIT A. GAAR, Jr. L.S.U. Medical Center, P.O. Box 33932, Shreveport,
LA 71730, U.S.A.
Abstract - Theories that would propose to explain the increased vascular resistance that accompanies hypertension include the presence circulating vasoconstrictor substances (angiotensin II, vasopressin, epinephrine, etc.), a centrally mediated generalized increase in sympathetic tone, increased vascular smooth muscle tone due to increased calcium ion permeability, and perhaps others. While each of these may be valid in some circumstances there exists yet another mechanism, indirect and potent, that could account for much of the change in peripheral vascular resistance that accompanies hypertension. This is the erythrocytosis mechanism that is mainly controlled by the kidneys. This treatise concerns the manner in which the kidneys supposedly react to disturbances in oxygen transport coincident with the development of hypertension and the effect that this might have in modifying peripheral resistance to blood flow.
Introduction Guyton et al (1) used sophisticated computer simulations to show that sustained hypertension will not occur in any individual who has completely normal kidneys. In learning more about how abnormal kidney function can affect blood pressure, computer simulations have helped also to explain some of the clinical observations found in hypertension. Among these are: 1) As hypertension becomes more severe, the systemic vascular resistance increases correspondingly. This observation led to the general belief that an increase in the peripheral vascular resistance was the primary cause of hypertension. Contrary to this notion, computer simulation studies have
suggested that cardiac output may be the first to become elevated, and the resistance increase follows as the tissues attempt to autoregulate their blood flow back toward normal. 2) In some types of hypertension the plasma volume may be lowered. This has been called a “non-volume-dependent” type of hypertension to contrast it with the socalled “volume-loading” type. In any case, it should always be remembered that hypertension is the consequence of too much blood in the cardiovascular system relative to the capacity of the system to hold it. 3) In some cases of hypertension red blood cell volume is elevated. In a recent study (2) both male and female 107
108
essential hypertensive patients differed from their respective normotensive control groups in having an increase in the number of red blood cells (7% in men and 4.4% in women). Moreover, in some renal diseases with concomitant hypertension hematocrits ranging from 55 to 66 or more have been observed.
MEDICAL HYPOTHESES
Lately, I have been studying these phenomena using an improved version of a model (Fig. 1) that originally was developed to study the erythrocytosis mechanism and its relationship to the renal hypertensive disease process (3). From the results of these studies, it was learned that: A. Not only do the kidneys control the level of
Fig 1 This shows the block diagram of the hemodynamic model used to simulate hypertension. the Appendix.
The symbols are defined in
ERYTHROCYTOSIS:
THE HEMODYNAMIC
CHANGES
109
IN HYPERTENSION
arterial pressure, they can also have a powerful indirect effect on the resistance to blood flow throughout the body. This effect, which involves the erythrocytosis mechanism, can be demonstrated even without any vasoactive peptides, hormones or other factors affecting the circulation. B. Following the establishment of hypertension, the amount that the peripheral vascular resistance will have risen is determined not only by the level of blood pressure, but also by the amount of renal hypoxia that was initially present. C. If significant renal tissue hypoxia is coincident with diminished kidney function, then an increased red cell mass and a decreased plasma volume would be expected clinical findings in hypertension. Background
Blood flow to most tissues of the body is geared to preserving a normal level of tissue oxygenation. The way the tissues do this is the following: The smooth muscle in the walls of the smallest blood vessels located in the tissues is either directly or indirectly sensitive to the level of oxygen. If the tissue oxygen level decreases, the smooth muscle relaxes enough to allow increased blood flow. If the oxygen level is higher than is needed at the moment, the smooth muscle constricts the vessel and lowers the blood flow. This is the mechanism of autoregulation and it is highly effective in keeping blood flow to most tissues at an optimum level to meet their needs for oxygen. Furthermore, within physiological limits the arterial pressure can rise well above normal or fall below normal and the tissues will still be able to regulate their blood flow and maintain normal tissue oxygenation. The same cannot be said for the kidneys. Normally, the autoregulation mechanism in the kidneys is committed to maintaining blood flow within narrow limits so that the GFR, the rate of glomerular filtration of fluid, will remain constant. In order for the renal autoregulation mechanism to do this there must always be a sufficient blood pressure to sustain a high rate of blood flow (about one-fifth the resting cardiac output). Therefore, the kidneys will adjust the arterial pressure to whatever level is needed. But, in doing so, they might not be able to maintain a normal level of tissue oxygenation unless there is a special mechanism dedicated to this purpose.
Although the kidneys’ own blood flow is among the highest anywhere, oxygen is still the most flow-limited of all the important metabolic substances. Special cells have been found in the kidneys which have been shown to increase their rate of erythropoietin (EPO) production whenever the oxygen level falls below normal (4). EPO enters the circulation and goes to the bone marrow where it stimulates the rate of formation of red blood cells; this is called erythrocytosis. New red cells enter the circulation causing the rate of oxygen delivery to the kidneys to rise. Therefore, the kidneys can use their ability to regulate erythrocytosis to help maintain their own supply of oxygen. Procedure
Figure 2 illustrates the time course of development of hypertension and the accompanying changes in cardiac output, total peripheral resistance and blood hematocrit. Shortly after beginning the simulation the renal arterial resistance was suddenly increased, reducing the renal blood flow below normal. Consequently, a much higher blood pressure is required to restore renal blood flow to the point where normal salt and water excretion will occur. Fluid build-up begins in the circulation, increasing the return of blood back to the heart and elevating the cardiac output. The increased cardiac output raises the blood pressure. Although it is not indicated on the figure, by. the end of the first day the mean arterial pressure has risen to a higher level of
I
0
0
1
2
3
4
5
6
7
8
9
10
Days
Fig 2 A computer simulation of the development of hypertension showing the changes in the important variables. Although not shown. mean arterial pressure increases from a normal value of 100 mm Hg to a new steady state value of 130 mm Hg during the first day.
110 130 mm Hg which is needed for normal kidney function under these conditions. While the elevated arterial pressure may act to increase the renal blood flow, it might not return all the way back to normal. Also, any excess fluid in the circulation dilutes the blood and lowers the hemoglobin concentration. These factors cause a reduction in the amount of oxygen transported by the blood. Because of this, a gradual rise in the blood hematocrit occurs over the next few days. Although this may help to relieve the renal hypoxia, it also causes an excess of oxygen to be delivered to other body tissues. But the intrinsic autoregulation mechanism in these tissues gradually constricts the blood vessels, increasing the total peripheral resistance and lowering the cardiac output, until the amount of oxygen being delivered to the extra-renal tissues is almost back to normal. These changes are indicated in Figure 2. Thirteen simulated experiments in all were run. Nine of these were run in a manner similar to the one above, i.e., by initially increasing the basic renal vascular resistance in increments of 50%, 100% or 150% above normal. In six of the nine experiments, however, some additional reductions in kidney function of varying degree were superimposed; this was done because can hypertension have many different manifestations. Results
There are several important features to be noted in Figure 3 which show the changes in blood volume that occurred when arterial pressure became elevated. First, at the top of the figure is shown that only a small increase (6%) in the total blood volume was responsible for the large increase (50%) in blood pressure. A second important feature to be noted in Figure 3 is that when renal tissue hypoxia was present during the development of hypertension, there was also an increase in the red cell mass. By contrast, when hypertension developed in the absence of renal tissue hypoxia no significant change in the red cell mass occurred. The importance of the above is that the kidneys can adjust the arterial pressure to almost any level within physiological limits and still be able to maintain a normal level of renal tissue oxygenation. This is illustrated by the open symbols in Figure 4 where it can be seen that
MEDICAL HYPOTHESES h
__:+---*A
‘7
_-
A--
,*_-A--
:
+---+ m--m--
_ _ _,
A--A----A_--. ‘--.-_ -
--me_ ----_*
t 100
125
150
175
Mean Arterial Pressure - mmHg
Fig 3 Relationship between mean arterial pressure, total blood volume (top composite curve) and red cell volume (four middle curves). As explained in the text, primary increases in renal resistance to blood flow correspond as follows: circles - none; triangles - 50%; squares - 100%; diamonds - 150%. Plasma volume can be estimated from the area between the two sets of curves.
tissue oxygen tension varies only slightly from normal over a wide range of blood pressure. In the closed symbols show what comparison, happens under similar conditions if the erythrocytosis feedback control mechanism is completely blocked. Figure 5 shows the relationship that exists between red cell volume and renal blood flow. The rate at which oxygen is being delivered to the kidneys is directly related to these two factors. Therefore, to maintain homeostasis, if renal blood flow changes in one direction then the red cell volume would be expected to change proportionately in the opposite direction. Figure 6 shows the variations in the total peripheral resistance that can occur in hyperten-
ERYTHROCYTOSIS:
THE HEMODYNAMIC
CHANGES
111
IN HYPERTENSION
65
60 -
_____-__o---
-0
Normal
_-A
A_----A--___~__
,o---
-
-0
Q_-
00
/
Cl
A
,
55
.-
.A0
/cO m- -m--,~~
50 100
Mean
Arterial
1.k
D
A’
-.,’
I
1
125
150
Pressure
Total Peripheral
- mmHg
Fig 4 Effect of arterial.pressure and changes in renal resistance to blood flow on renal tissue oxygen tension (estimated from venous blood PO*) both with (open symbols), and without (closed symbols), the feedback effect of erythrocytosis. See Figure 3 for definition of symbols.
40 Resistance
- X Normal
Fig 6 Relationship between mean arterial pressure and total peripheral resistance. By definition, the slope of a line drawn from-the origin to any point on the graph indicates the relative cardiac output. Since the axes are in proportionately equal units the graph is bisected into a shaded area where cardiac output is above normal and a clear area where cardiac output is below normal. An explanation of the labeled curves is given in the text.
present. Cardiac output is below normal, as indicated by the curve’s depressed slope. Dashed curves B, C and D indicate the effects of the superimposed additional reductions in kidney function described previously. The closed circles plotted in Figure 7 show that changes in non-renal resistance to blood 3 E B z
2.0 Erythrocytosir Regulation Functional
:
l
0 Blocked
10 I 0.7
I 0.8
I 0.9
I 1.0
I 1.1
I 1.2
I 1.3
Renal Blood Flow - X Normal
Fig 5 Effect of renal blood flow on erythrocytosis, cated by changes in the red blood cell mass.
as indi-
sion. The dashed curve labeled A represents a pure volume-loading type of hypertension without any renal hypoxic stimulus present. Cardiac output is increased above normal, as indicated by the elevated slope of the curve. Under a different set of conditions the solid curve represents a mainly vasoconstrictor type of hypertension with a renal hypoxic stimulus
1.2
1.4
1.6
1.8
2.0
Renal Vascular Resistance (X Normal) Fig 7 Relationship between renal and non-renal resistance to blood flow. See text for explanation.
112 flow correspond almost exactly to changes in the renal resistance. This seems extraordinary since they are each controlled by different mechanisms. However, by blocking the feedback control of erythrocytosis it is found the correspondence that previously existed disappears, as indicated by the open circles in the figure. This suggests that the large increases in total peripheral resistance that have been observed in some hypertensive patients was a response to the stimulation of erythrocytosis caused by a renal hypoxic stimulus. Discussion
Evidence is now accumulating to support an etiologic relationship between both renovascular and essential types of hypertension and an increased red cell mass. Furthermore, the fact that no change in the hematocrit is observed in a hypertensive patient does not necessarily mean that ‘an increase in the red cell mass has not occurred. This is because the red cell volume could have increased in proportion to the plasma volume; in this case no change in the hematocrit would be found. This is essentially what happened for the hypothetical patient situated at point B in Figure 6. Therefore, it is not unusual that some studies have reported an increase in hematocrit in some hypertensive patients, but not in others. In this study it was shown that whether or not the red cell mass became elevated in hypertension depended entirely on the amount of renal hypoxia that was present, and not on the level of the arterial pressure. It was also shown in this study that, invariably, the total peripheral resistance increase that occurs in hypertension is associated with an increased renal resistance to blood flow. In some cases an elevated cardiac output accompanied the increased peripheral resistance. For example, the curve labeled A in Figure 6 lies within the shaded area where the hypertension is sustained more by an elevated cardiac output than by increased peripheral resistance. In other cases, C and D, the peripheral resistance is much higher and cardiac output is below normal. It is important to point out here, however, that the cardiac output had been elevated at the beginning, and this was the main reason for the hypertension developing in the first place. It is easy to understand how an increase in the total peripheral resistance occurs when there is
MEDICAL HYPOTHESES
excessive secretion of a vasoconstrictor by one of the endocrine glands. But, how can it be possible to have a greatly increased peripheral resistance if none of the usual vasoconstrictor mechanisms can be demonstrated? This can be easily explained as follows: In those cases where the increase in renal resistance to blood flow is greater than the increase in arterial pressure renal blood flow is below normal. Initially, this causes diminished oxygen delivery to the kidneys, but the subsequent stimulation of erythrocytosis raises the blood oxygen transport capacity. Because of this, the autoregulation mechanism in the peripheral tissues will have to increase the peripheral resistance by a greater amount than would normally be needed to fully offset the increased blood pressure. The net result is that both the renal and peripheral resistances become increased, and by an amount that is proportionately greater than the increase in the mean arterial pressure. Therefore, cardiac output is below normal. In general, the model predicts that in established long-term hypertension, the cardiac output will be below normal if renal blood flow is below normal (and vice versa). If overactivity of the circulatory renin-angiotensin system cannot be demonstrated in a hypertensive patient, then how are the kidneys involved? It has been hypothesized that some tissues might regulate their vascular resistance via an intrinsic renin-angiotensin system (5, 6). Overactivity of such a system operating within the kidneys is one mechanism that could explain the changes observed in this study. Over 90% of all hypertension cases - the socalled “essential hypertension” type - have no known cause and often have to be treated empirically. It is interesting to note the many similarities between the results of this study and the clinical findings in human essential hypertension; thus, in both we might find: a) elevated mean arterial pressure b) normal-to-decreased cardiac output c) both increased renal and peripheral resistance to blood flow d) normal-to-decreased renal blood flow e) normal-to-increased blood hematocrit In view of all of the above, it is not surprising that antihypertensive drugs that act by inhibiting the renin-angiotensin system are often very effective even when this system cannot be directly implicated in the hypertension.
ERYTHROCYTOSIS:
THE HEMODYNAMIC
CHANGES
IN HYPERTENSION
Conclusions
The “non-volume-dependent” type of hypertension can probably best be explained as a condition whereby the plasma volume contracts, thereby offsetting an increase in the red cell volume. However, as demonstrated in this study, blood volume is slightly increased overall. Considering the fact that only a very small blood volume increase is ever needed to sustain a high level of blood pressure, it is not surprising that this might easily go undetected. Perhaps the term “non-volume-dependent” should be reserved for those situations in which no change in the blood volume can be clearly documented. More important, however, this study has shown how it is possible for a significant component of the increased peripheral resistance that occurs in hypertension to be solely due to the excess oxygen-carrying capacity of the blood, induced by a renal hypoxic stimulus.
113
KTC, kidney autoregulation time constant. minutes LAG, long-term autoregulatory feedback gain LTC, long-term autoregulation time constant, minutes NI, normal fluid intake, ml/minute NRF, non-renal fraction of total blood flow. dl/minute NRQv, non-renal venous blood volume. dl NRTPR, non-renal total peripheral resistance. mm Hg/dl per minute PaO,, arterial blood oxygen tension, torr PV, plasma volume. ml PvOz, venous blood oxygen tension, torr RCV, red blood cell volume, ml RF, renal fraction of total blood flow, dl/minute RTPR. renal total peripheral resistance. mm Hg/dl per minute SAG, short-term autoregulatory feedback gain SFP. mean systemic filling pressure. mm Hg STC, short-term autoregulation time constant, minutes UO, rate of urine output, ml/minute VaO,. rate of arterial blood oxygen delivery. ml O?/minute VcO,, rate of tissue oxygen uptake, ml Odminute VvO?, venous blood oxygen volume. ml O2 VvOz. rate of venous blood oxygen return. ml Oz/minute
References Appendix Definition of symbols AP, mean arterial pressure. mm Hg BV. total blood volume. ml CaO,, arterial blood oxygen concentration, ml 03/d] CAP-Hb, blood oxygen transport capacity (hemoglobin), Ojdl per torr CvOZ. venous blood oxygen concentration, ml Oz/dl E, extracellular fluid volume, ml EG. erythrocytosis feedback gain ETC, erythrocytosis time constant, minutes KAG. kidney autoregulatory feedback gain KF. kidney function. UO per mm Hg
ml
1. Guyton A C. Circulatory Physiology III: Arterial Pressure and Hypertension. 1980. WB Saunders Co., Pub. 2. Bruschi G et al. Similarities of essential and spontaneous hypertension: Volume and number of blood cells. Hypertension 8(11): 983. 1986. Gaar Jr. K A. Renal disease and hypertension: The erythrocytosis factor. Medical Hypotheses 19: 359. 1986. Bauer C and Kurtz A. Erythropoietin production in the kidney. News in Physiological Sciences 2169, 1987. Dzau V J. Significance of vascular renin-angiotensin pathways. Hypertension 8: 553, 1986. Kifor I and Dzau V J. Endothelial renin-angiotensin pathway: Evidence for intracellular synthesis and secretion of angiotensin. Circulation Research 60: 422, 19R7.
(19%) 27. 107-I 13 UK Ltd 198X
Erythrocytosis: Hemodynamic
A Key To Understanding Changes in Hypertension
the
KERMIT A. GAAR, Jr. L.S.U. Medical Center, P.O. Box 33932, Shreveport,
LA 71730, U.S.A.
Abstract - Theories that would propose to explain the increased vascular resistance that accompanies hypertension include the presence circulating vasoconstrictor substances (angiotensin II, vasopressin, epinephrine, etc.), a centrally mediated generalized increase in sympathetic tone, increased vascular smooth muscle tone due to increased calcium ion permeability, and perhaps others. While each of these may be valid in some circumstances there exists yet another mechanism, indirect and potent, that could account for much of the change in peripheral vascular resistance that accompanies hypertension. This is the erythrocytosis mechanism that is mainly controlled by the kidneys. This treatise concerns the manner in which the kidneys supposedly react to disturbances in oxygen transport coincident with the development of hypertension and the effect that this might have in modifying peripheral resistance to blood flow.
Introduction Guyton et al (1) used sophisticated computer simulations to show that sustained hypertension will not occur in any individual who has completely normal kidneys. In learning more about how abnormal kidney function can affect blood pressure, computer simulations have helped also to explain some of the clinical observations found in hypertension. Among these are: 1) As hypertension becomes more severe, the systemic vascular resistance increases correspondingly. This observation led to the general belief that an increase in the peripheral vascular resistance was the primary cause of hypertension. Contrary to this notion, computer simulation studies have
suggested that cardiac output may be the first to become elevated, and the resistance increase follows as the tissues attempt to autoregulate their blood flow back toward normal. 2) In some types of hypertension the plasma volume may be lowered. This has been called a “non-volume-dependent” type of hypertension to contrast it with the socalled “volume-loading” type. In any case, it should always be remembered that hypertension is the consequence of too much blood in the cardiovascular system relative to the capacity of the system to hold it. 3) In some cases of hypertension red blood cell volume is elevated. In a recent study (2) both male and female 107
108
essential hypertensive patients differed from their respective normotensive control groups in having an increase in the number of red blood cells (7% in men and 4.4% in women). Moreover, in some renal diseases with concomitant hypertension hematocrits ranging from 55 to 66 or more have been observed.
MEDICAL HYPOTHESES
Lately, I have been studying these phenomena using an improved version of a model (Fig. 1) that originally was developed to study the erythrocytosis mechanism and its relationship to the renal hypertensive disease process (3). From the results of these studies, it was learned that: A. Not only do the kidneys control the level of
Fig 1 This shows the block diagram of the hemodynamic model used to simulate hypertension. the Appendix.
The symbols are defined in
ERYTHROCYTOSIS:
THE HEMODYNAMIC
CHANGES
109
IN HYPERTENSION
arterial pressure, they can also have a powerful indirect effect on the resistance to blood flow throughout the body. This effect, which involves the erythrocytosis mechanism, can be demonstrated even without any vasoactive peptides, hormones or other factors affecting the circulation. B. Following the establishment of hypertension, the amount that the peripheral vascular resistance will have risen is determined not only by the level of blood pressure, but also by the amount of renal hypoxia that was initially present. C. If significant renal tissue hypoxia is coincident with diminished kidney function, then an increased red cell mass and a decreased plasma volume would be expected clinical findings in hypertension. Background
Blood flow to most tissues of the body is geared to preserving a normal level of tissue oxygenation. The way the tissues do this is the following: The smooth muscle in the walls of the smallest blood vessels located in the tissues is either directly or indirectly sensitive to the level of oxygen. If the tissue oxygen level decreases, the smooth muscle relaxes enough to allow increased blood flow. If the oxygen level is higher than is needed at the moment, the smooth muscle constricts the vessel and lowers the blood flow. This is the mechanism of autoregulation and it is highly effective in keeping blood flow to most tissues at an optimum level to meet their needs for oxygen. Furthermore, within physiological limits the arterial pressure can rise well above normal or fall below normal and the tissues will still be able to regulate their blood flow and maintain normal tissue oxygenation. The same cannot be said for the kidneys. Normally, the autoregulation mechanism in the kidneys is committed to maintaining blood flow within narrow limits so that the GFR, the rate of glomerular filtration of fluid, will remain constant. In order for the renal autoregulation mechanism to do this there must always be a sufficient blood pressure to sustain a high rate of blood flow (about one-fifth the resting cardiac output). Therefore, the kidneys will adjust the arterial pressure to whatever level is needed. But, in doing so, they might not be able to maintain a normal level of tissue oxygenation unless there is a special mechanism dedicated to this purpose.
Although the kidneys’ own blood flow is among the highest anywhere, oxygen is still the most flow-limited of all the important metabolic substances. Special cells have been found in the kidneys which have been shown to increase their rate of erythropoietin (EPO) production whenever the oxygen level falls below normal (4). EPO enters the circulation and goes to the bone marrow where it stimulates the rate of formation of red blood cells; this is called erythrocytosis. New red cells enter the circulation causing the rate of oxygen delivery to the kidneys to rise. Therefore, the kidneys can use their ability to regulate erythrocytosis to help maintain their own supply of oxygen. Procedure
Figure 2 illustrates the time course of development of hypertension and the accompanying changes in cardiac output, total peripheral resistance and blood hematocrit. Shortly after beginning the simulation the renal arterial resistance was suddenly increased, reducing the renal blood flow below normal. Consequently, a much higher blood pressure is required to restore renal blood flow to the point where normal salt and water excretion will occur. Fluid build-up begins in the circulation, increasing the return of blood back to the heart and elevating the cardiac output. The increased cardiac output raises the blood pressure. Although it is not indicated on the figure, by. the end of the first day the mean arterial pressure has risen to a higher level of
I
0
0
1
2
3
4
5
6
7
8
9
10
Days
Fig 2 A computer simulation of the development of hypertension showing the changes in the important variables. Although not shown. mean arterial pressure increases from a normal value of 100 mm Hg to a new steady state value of 130 mm Hg during the first day.
110 130 mm Hg which is needed for normal kidney function under these conditions. While the elevated arterial pressure may act to increase the renal blood flow, it might not return all the way back to normal. Also, any excess fluid in the circulation dilutes the blood and lowers the hemoglobin concentration. These factors cause a reduction in the amount of oxygen transported by the blood. Because of this, a gradual rise in the blood hematocrit occurs over the next few days. Although this may help to relieve the renal hypoxia, it also causes an excess of oxygen to be delivered to other body tissues. But the intrinsic autoregulation mechanism in these tissues gradually constricts the blood vessels, increasing the total peripheral resistance and lowering the cardiac output, until the amount of oxygen being delivered to the extra-renal tissues is almost back to normal. These changes are indicated in Figure 2. Thirteen simulated experiments in all were run. Nine of these were run in a manner similar to the one above, i.e., by initially increasing the basic renal vascular resistance in increments of 50%, 100% or 150% above normal. In six of the nine experiments, however, some additional reductions in kidney function of varying degree were superimposed; this was done because can hypertension have many different manifestations. Results
There are several important features to be noted in Figure 3 which show the changes in blood volume that occurred when arterial pressure became elevated. First, at the top of the figure is shown that only a small increase (6%) in the total blood volume was responsible for the large increase (50%) in blood pressure. A second important feature to be noted in Figure 3 is that when renal tissue hypoxia was present during the development of hypertension, there was also an increase in the red cell mass. By contrast, when hypertension developed in the absence of renal tissue hypoxia no significant change in the red cell mass occurred. The importance of the above is that the kidneys can adjust the arterial pressure to almost any level within physiological limits and still be able to maintain a normal level of renal tissue oxygenation. This is illustrated by the open symbols in Figure 4 where it can be seen that
MEDICAL HYPOTHESES h
__:+---*A
‘7
_-
A--
,*_-A--
:
+---+ m--m--
_ _ _,
A--A----A_--. ‘--.-_ -
--me_ ----_*
t 100
125
150
175
Mean Arterial Pressure - mmHg
Fig 3 Relationship between mean arterial pressure, total blood volume (top composite curve) and red cell volume (four middle curves). As explained in the text, primary increases in renal resistance to blood flow correspond as follows: circles - none; triangles - 50%; squares - 100%; diamonds - 150%. Plasma volume can be estimated from the area between the two sets of curves.
tissue oxygen tension varies only slightly from normal over a wide range of blood pressure. In the closed symbols show what comparison, happens under similar conditions if the erythrocytosis feedback control mechanism is completely blocked. Figure 5 shows the relationship that exists between red cell volume and renal blood flow. The rate at which oxygen is being delivered to the kidneys is directly related to these two factors. Therefore, to maintain homeostasis, if renal blood flow changes in one direction then the red cell volume would be expected to change proportionately in the opposite direction. Figure 6 shows the variations in the total peripheral resistance that can occur in hyperten-
ERYTHROCYTOSIS:
THE HEMODYNAMIC
CHANGES
111
IN HYPERTENSION
65
60 -
_____-__o---
-0
Normal
_-A
A_----A--___~__
,o---
-
-0
Q_-
00
/
Cl
A
,
55
.-
.A0
/cO m- -m--,~~
50 100
Mean
Arterial
1.k
D
A’
-.,’
I
1
125
150
Pressure
Total Peripheral
- mmHg
Fig 4 Effect of arterial.pressure and changes in renal resistance to blood flow on renal tissue oxygen tension (estimated from venous blood PO*) both with (open symbols), and without (closed symbols), the feedback effect of erythrocytosis. See Figure 3 for definition of symbols.
40 Resistance
- X Normal
Fig 6 Relationship between mean arterial pressure and total peripheral resistance. By definition, the slope of a line drawn from-the origin to any point on the graph indicates the relative cardiac output. Since the axes are in proportionately equal units the graph is bisected into a shaded area where cardiac output is above normal and a clear area where cardiac output is below normal. An explanation of the labeled curves is given in the text.
present. Cardiac output is below normal, as indicated by the curve’s depressed slope. Dashed curves B, C and D indicate the effects of the superimposed additional reductions in kidney function described previously. The closed circles plotted in Figure 7 show that changes in non-renal resistance to blood 3 E B z
2.0 Erythrocytosir Regulation Functional
:
l
0 Blocked
10 I 0.7
I 0.8
I 0.9
I 1.0
I 1.1
I 1.2
I 1.3
Renal Blood Flow - X Normal
Fig 5 Effect of renal blood flow on erythrocytosis, cated by changes in the red blood cell mass.
as indi-
sion. The dashed curve labeled A represents a pure volume-loading type of hypertension without any renal hypoxic stimulus present. Cardiac output is increased above normal, as indicated by the elevated slope of the curve. Under a different set of conditions the solid curve represents a mainly vasoconstrictor type of hypertension with a renal hypoxic stimulus
1.2
1.4
1.6
1.8
2.0
Renal Vascular Resistance (X Normal) Fig 7 Relationship between renal and non-renal resistance to blood flow. See text for explanation.
112 flow correspond almost exactly to changes in the renal resistance. This seems extraordinary since they are each controlled by different mechanisms. However, by blocking the feedback control of erythrocytosis it is found the correspondence that previously existed disappears, as indicated by the open circles in the figure. This suggests that the large increases in total peripheral resistance that have been observed in some hypertensive patients was a response to the stimulation of erythrocytosis caused by a renal hypoxic stimulus. Discussion
Evidence is now accumulating to support an etiologic relationship between both renovascular and essential types of hypertension and an increased red cell mass. Furthermore, the fact that no change in the hematocrit is observed in a hypertensive patient does not necessarily mean that ‘an increase in the red cell mass has not occurred. This is because the red cell volume could have increased in proportion to the plasma volume; in this case no change in the hematocrit would be found. This is essentially what happened for the hypothetical patient situated at point B in Figure 6. Therefore, it is not unusual that some studies have reported an increase in hematocrit in some hypertensive patients, but not in others. In this study it was shown that whether or not the red cell mass became elevated in hypertension depended entirely on the amount of renal hypoxia that was present, and not on the level of the arterial pressure. It was also shown in this study that, invariably, the total peripheral resistance increase that occurs in hypertension is associated with an increased renal resistance to blood flow. In some cases an elevated cardiac output accompanied the increased peripheral resistance. For example, the curve labeled A in Figure 6 lies within the shaded area where the hypertension is sustained more by an elevated cardiac output than by increased peripheral resistance. In other cases, C and D, the peripheral resistance is much higher and cardiac output is below normal. It is important to point out here, however, that the cardiac output had been elevated at the beginning, and this was the main reason for the hypertension developing in the first place. It is easy to understand how an increase in the total peripheral resistance occurs when there is
MEDICAL HYPOTHESES
excessive secretion of a vasoconstrictor by one of the endocrine glands. But, how can it be possible to have a greatly increased peripheral resistance if none of the usual vasoconstrictor mechanisms can be demonstrated? This can be easily explained as follows: In those cases where the increase in renal resistance to blood flow is greater than the increase in arterial pressure renal blood flow is below normal. Initially, this causes diminished oxygen delivery to the kidneys, but the subsequent stimulation of erythrocytosis raises the blood oxygen transport capacity. Because of this, the autoregulation mechanism in the peripheral tissues will have to increase the peripheral resistance by a greater amount than would normally be needed to fully offset the increased blood pressure. The net result is that both the renal and peripheral resistances become increased, and by an amount that is proportionately greater than the increase in the mean arterial pressure. Therefore, cardiac output is below normal. In general, the model predicts that in established long-term hypertension, the cardiac output will be below normal if renal blood flow is below normal (and vice versa). If overactivity of the circulatory renin-angiotensin system cannot be demonstrated in a hypertensive patient, then how are the kidneys involved? It has been hypothesized that some tissues might regulate their vascular resistance via an intrinsic renin-angiotensin system (5, 6). Overactivity of such a system operating within the kidneys is one mechanism that could explain the changes observed in this study. Over 90% of all hypertension cases - the socalled “essential hypertension” type - have no known cause and often have to be treated empirically. It is interesting to note the many similarities between the results of this study and the clinical findings in human essential hypertension; thus, in both we might find: a) elevated mean arterial pressure b) normal-to-decreased cardiac output c) both increased renal and peripheral resistance to blood flow d) normal-to-decreased renal blood flow e) normal-to-increased blood hematocrit In view of all of the above, it is not surprising that antihypertensive drugs that act by inhibiting the renin-angiotensin system are often very effective even when this system cannot be directly implicated in the hypertension.
ERYTHROCYTOSIS:
THE HEMODYNAMIC
CHANGES
IN HYPERTENSION
Conclusions
The “non-volume-dependent” type of hypertension can probably best be explained as a condition whereby the plasma volume contracts, thereby offsetting an increase in the red cell volume. However, as demonstrated in this study, blood volume is slightly increased overall. Considering the fact that only a very small blood volume increase is ever needed to sustain a high level of blood pressure, it is not surprising that this might easily go undetected. Perhaps the term “non-volume-dependent” should be reserved for those situations in which no change in the blood volume can be clearly documented. More important, however, this study has shown how it is possible for a significant component of the increased peripheral resistance that occurs in hypertension to be solely due to the excess oxygen-carrying capacity of the blood, induced by a renal hypoxic stimulus.
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KTC, kidney autoregulation time constant. minutes LAG, long-term autoregulatory feedback gain LTC, long-term autoregulation time constant, minutes NI, normal fluid intake, ml/minute NRF, non-renal fraction of total blood flow. dl/minute NRQv, non-renal venous blood volume. dl NRTPR, non-renal total peripheral resistance. mm Hg/dl per minute PaO,, arterial blood oxygen tension, torr PV, plasma volume. ml PvOz, venous blood oxygen tension, torr RCV, red blood cell volume, ml RF, renal fraction of total blood flow, dl/minute RTPR. renal total peripheral resistance. mm Hg/dl per minute SAG, short-term autoregulatory feedback gain SFP. mean systemic filling pressure. mm Hg STC, short-term autoregulation time constant, minutes UO, rate of urine output, ml/minute VaO,. rate of arterial blood oxygen delivery. ml O?/minute VcO,, rate of tissue oxygen uptake, ml Odminute VvO?, venous blood oxygen volume. ml O2 VvOz. rate of venous blood oxygen return. ml Oz/minute
References Appendix Definition of symbols AP, mean arterial pressure. mm Hg BV. total blood volume. ml CaO,, arterial blood oxygen concentration, ml 03/d] CAP-Hb, blood oxygen transport capacity (hemoglobin), Ojdl per torr CvOZ. venous blood oxygen concentration, ml Oz/dl E, extracellular fluid volume, ml EG. erythrocytosis feedback gain ETC, erythrocytosis time constant, minutes KAG. kidney autoregulatory feedback gain KF. kidney function. UO per mm Hg
ml
1. Guyton A C. Circulatory Physiology III: Arterial Pressure and Hypertension. 1980. WB Saunders Co., Pub. 2. Bruschi G et al. Similarities of essential and spontaneous hypertension: Volume and number of blood cells. Hypertension 8(11): 983. 1986. Gaar Jr. K A. Renal disease and hypertension: The erythrocytosis factor. Medical Hypotheses 19: 359. 1986. Bauer C and Kurtz A. Erythropoietin production in the kidney. News in Physiological Sciences 2169, 1987. Dzau V J. Significance of vascular renin-angiotensin pathways. Hypertension 8: 553, 1986. Kifor I and Dzau V J. Endothelial renin-angiotensin pathway: Evidence for intracellular synthesis and secretion of angiotensin. Circulation Research 60: 422, 19R7.