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Irvine H. Page Lecture 1982
A new look at the old mosaic1
J a c q u e s G e n e s t , C. C., M . D . 2 The author pays tribute to Dr. Irvine H. Page, whose life was a
"mosaic" of key scientific contributions in the field of hypertension
and of professional and societal involvement. Important and re-
cent contributions are brought together to confirm the hypothesis,
as expressed by Dr. Page in 1937, that the secretions of some
endocrine glands, in particular, the adrenal cortex, keep the vas-
cular system in a hyper-reactive state. Evidence is presented to
demonstrate that increased peripheral resistance and chronic hy-
pertension are neither due to an increase in cardiac output or
plasma or extracellular fluid volume nor arteriosclerotic lesions,
but are primarily related to increased arterial sensitivity and
responsiveness to pressor agents, such as norepinephrine and
angiotensin II. The sodium balance, which is mainly determined
by the production of aldosterone in the adrenal cortex, is funda-
mentally involved in the increased peripheral resistance of hyper-
tension. Since hypertension is the result of disequilibrium between
the sympathetic nervous system activity and the state of sensitivity
and reactivity of the contractile proteins in the arterial walls,
models are proposed based on increased sympathetic nervous
system activity, increased activity of the renin-angiotensin system,
and a disturbance in aldosterone regulation and sodium transport
1
across cell membranes and which are associated with the increased
Delivered at The Cleveland Clinic Foundation, sensitivity and reactivity of the arterioles.
Mav 18, 1982
Scientific Director, Clinical Research Institute of I n d e x terms: Hypertension • Irvine H. Page Lecture
Montreal, and Director, Multidisciplinary Research
Group on Hypertension of the Medical Research Cleve Clin Q 5 1 : 4 4 9 - 4 6 1 , Summer 1984
Council of Canada. Present address: Institut de Re-
cherches Cliniques de Montréal, 110 avenue des Pins
ouest, Montreal, Quebec, Canada H2W 1R7. lp Tribute to Dr. Page
0009-8787/84/02/0449/13/$4.25/0 In 1 9 4 9 , Dr. Irvine H . P a g e p r o p o s e d w h a t h e called t h e
"Mosaic T h e o r y o f H y p e r t e n s i o n , " b a s e d o n t h e a s s u m p t i o n
Copyright © 1984, The Cleveland Clinic Foun- that "a steady state exists in t h e circulation in w h i c h t h e
dation. i m p o r t a n t r e g u l a t o r y factors are in e q u i l i b r i u m , maintain-
449
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CHEMICAL reninism, renovascular hypertension, malignant
hypertension),
2. T h e adrenal cortex and aldosterone (pri-
mary aldosteronism,* excessive production o f
C o r t i s o l and deoxycorticosterone [Cushing's syn-
drome]),
3. T h e adrenal medulla and catecholamines
(pheochromocy toma),
4. T h e thyroid h o r m o n e (thyrotoxicosis),
5. Increased plasma volume in terminal renal
failure and possibly acute glomerulonephritis,
6. Increased cardiac output in hyperkinetic
patients with labile blood pressure,
VISCOSITY 7. Loss o f elasticity of the large vessel (athero-
Fig. 1. The Mosaic Theory of Hypertension as first proposed arteriosclerotic) type of hypertension in elderly
by Page in 1937
patients,
8. Proximal resistance to cardiac output
ing blood pressure and tissue perfusion at relative (coarctation o f the aorta),
constancy adapted to tissue needs." 1 T h e mosaic 9. Loss o f renal tissue and of the antihyper-
(Fig. 1 ) showed what were considered at that time tensive function o f the kidney (atrophic pyelo-
the most important regulatory factors o f hyper- nephritis, polycystic kidney disease),
tension. In view o f the extraordinary growth of 10. Increase in red cell mass and blood vis-
knowledge o f all aspects of hypertension, Page 2 cosity (polycythemia vera), and
has proposed in a recent commentary that the 11. Excessive sodium intake in genetically
Mosaic T h e o r y might be more appropriately ex- predisposed individuals.
pressed as genetic, environmental (e.g., salt in- H o w do these factors, or a combination o f
take, stress, trace metals), anatomic (e.g., coarc- factors, interact with each other to produce the
tation o f the aorta), adaptive (intracellular N a + condition known as primary or idiopathic or es-
and Ca 2 + ), neural (e.g., baroreceptors, area pos- sential hypertension, which affects approximately
trema, anteroventral region o f the third ventri- 90% of the large hypertensive population, which
cle), endocrine (e.g., catecholamines, aldoster- itself constitutes about 17% of the total popula-
one), humoral (e.g., angiotensin, prostaglandins), tion? T h e Mosaic T h e o r y o f Hypertension, an
or hemodynamic (e.g., blood volume, cardiac attempt to answer this question, is a reflection o f
output, viscosity) (Fig. 2). Each of these factors the life and scientific contributions of Dr. Page.
can produce a specific type o f hypertension be- Figure 3 shows the major aspects of Dr. Page's
cause o f most productive research career, which started
1. The renin-angiotensin system (primary in Munich and continued with Dr. Donald Van
Slyke at the Rockefeller Institute for Medical
Research. After six years with Dr. Van Slyke, Dr.
GENETIC Page began his leadership career in the field o f
hypertensive cardiovascular diseases in Indian-
apolis and later at the Cleveland Clinic. During
this period, he trained many soon-to-be leading
hypertension experts in the world. His numerous,
important contributions in the field o f hyperten-
sion, atherosclerosis, and brain chemistry are
shown in Figure 4. His work dealing with the
renin-angiotensin system (leading to the discov-
ery of angiotonin simultaneously with the Braun-
Menéndez g r o u p in B u e n o s Aires), as well as
HUMORAL
* Excessive intake of licorice can produce a similar syndrome
Fig. 2. The Mosaic Theory of Hypertension as reviewed by due to glycyrrhi/.ic acid—a substance with mineralocorticoid activ-
Page in 1982 ity.
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ment of the Council for High Blood Pressure
CORCORAN Research—probably his most important contri-
MASSON bution. He is an example for all of us and pro-
MoCUBBIN vides a lesson to so many of us too often satisfied
LEWIS
to remain in our ivory tower and not having the
DUSTAN
BUMPUS D.D. VAN courage to enter the broader picture of the socie-
KHAIRALLAH SLYKE tal aspects of biomedical research and its role in
SMEBY modern society.
TARAZI
FRÖHLICH
FERRARIO Confirmation of Dr. Page's hypothesis
(LILLY LAB.)
KOHLSTAEDT
According to Poiseuille's Law, described in
HELMER 1835, three major hypotheses explain the possi-
ble mechanisms of essential hypertension:
Fig. 3. T h e mosaic of Page's life
1. Increased cardiac output, the initial event
leading to elevated blood pressure,
hemodynamics and baroreceptors and the man- 2. Increased blood volume within the arterial
agement of hypertension, had a major impact on system or increased intracellular fluid volume,
the history of hypertension research. and
Dr. Page also went into the field of atheroscle- 3. Increased arteriolar sensitivity and reactiv-
rosis research, studying nonesterified fatty acids, ity, followed by increased wall thickness of the
lipoproteins, strokes, and brain chemistry and small resistance arterioles. Presently, evidence
discovered serotonin. Aside from these tremen- favors the third theory.
dous scientific accomplishments, Dr. Page gave These hypotheses are especially difficult to
us the image of the complete physician by being evaluate because no experimental type of hyper-
deeply involved in professional and societal af- tension is the counterpart of essential hyperten-
fairs, as editor of Modern Medicine with its superb sion in humans. Even spontaneously hypertensive
and far-reaching editorials, 3 as the originator of strains of rats differ in some ways from human
the Coronary Club, as one of the chief instigators essential hypertension. 4 Renal experimental hy-
of the Institute of Medicine, in the International pertension produced by clipping one of the two
Society of Hypertension, and with the establish- main arteries by a "figure-of-eight" procedure,
RENIN-ANGIOTENSIN SYSTEM
(DISCOVERY OF ANGIOTONIN)
HEMODYNAMICS MANAGEMENT
AND BARORECEPTORS AND T R E A T M E N T
DIET
(NONESTERIFIED TRAINING OF
FATTY ACIDS, YOUNG
LIPOPROTEINS) SCIENTISTS
STROKES SEROTONIN
SOCIETAL AND PROFESSIONAL
INVOLVEMENT
COUNCIL FOR HIGH BLOOD PRESSURE RESEARCH
MODERN MEDICINE
CORONARY CLUB
I N S T I T U T E OF MEDICINE
I N T E R N A T I O N A L SOCIETY OF HYPERTENSION
Fig. 4. T h e mosaic of Page's contributions
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cellophane wrapping, or an aortic ligature be- norepinephrine in hypertensive arteries as that
tween the renal arteries in rats has b e e n invalua- of normotensive animals, a hyporesponsiveness
ble for studying the effects o f persistent hyper- o f the individual smooth muscle cell is obviously
tension and its mechanisms, but the only human indicated. 8 Furthermore, an increased flow re-
counterpart is renovascular, not essential, hyper- sistance reported at maximal dilatation could be
tension. Also, experimental hypertension can nei- explained by a decreased number of arterioles
ther be produced nor maintained in the absence per tissue volume as suggested by Hutchins and
of the adrenal cortex and dietary salt. Darnell. 9
According to proponents of the first hypothe- 2. Hypertrophy of the vascular smooth mus-
sis, the initial event leading to essential hyperten- cle in the media of arterioles is not necessarily
sion is increased cardiac output secondary to the result o f adaptation to an increase in pressure
excessive neural activity, presumably o f hypotha- since myocardial hypertrophy can occur without
lamic origin 5 or to a hyperkinetic heart leading hypertension in sympathectomized sponta-
to an increase in arterial wall thickness with a neously hypertensive rats 10 and before the onset
decreased wall-lumen ratio and subsequent in- of hypertension in deoxycorticosterone acetate
crease in peripheral resistance. T h e hypothesis ( D O C A ) salt- and aldosterone-treated rats. 11
o f thickened arterial walls encroaching on the 3. If the increased thickness o f the arterial
lumen is based on measurements o f the pressure- wall was the initial event leading to hypertension,
flow relationship at maximal arterial dilatation. a progressive increase in mean internal or exter-
In these experiments, threshold responsiveness nal diameter a n d / o r in mean wall-lumen ratio o f
to norepinephrine was the same for hypertensive the arterioles would be expected to occur in aged
as for normotensive arteries, and hyper-reactivity patients with prolonged and severe hypertension,
to norepinephrine was a simple consequence of as compared with younger patients or those with
the increase in the wall mass relative to the lu- milder hypertension. Nevertheless, this does not
men. appear to be so since n o significant difference in
Objections to the first hypothesis are: the parameters o f hypertensive patients more
1. T h e conclusions were mostly based o n than 4 5 years old were noted when compared to
studies of flow resistance of the arterial vascula- younger patients. 1 2 According to Friedman, 8 the
ture in the isolated hind quarters o f eviscerated data o f Furuyafna, 1 3 used to support the hypoth-
rats perfused with Tyrode's solution and with a esis of a primary thickening of the walls o f the
repeated bolus administration o f papaverine (1 small arterioles, are based on histologic exami-
mg) to achieve maximal dilatation. Perfusion of nations o f arteries larger than 3 0 0 /¿m—vessels
hind legs with artificial solutions is frequently that contribute little to the total resistance o f the
accompanied by increased capillary permeability vascular beds. N o wall hypertrophy in the resis-
with e d e m a and swelling. This can be corrected tance arteries o f less than 100 /im was present.
by adding a dextran type o f colloid polymer to 4. Many normotensive patients show the
increase osmotic pressure of the perfusate and to same degree of arteriosclerosis, especially in the
prevent edema. T h e increased permeability is splanchnic area, as patients who die from hyper-
o n e of the major consequences o f bilateral adren- tension, although the lesions are more frequent
alectomy and is probably related to the absence and m o r e severe in the latter. 12
of adrenocortical h o r m o n e s in the perfusates. 6 In 5. T h e fact that many clinical and experimen-
addition, the large amounts of administered pa- tal hypertensive states revert to a normal blood
paverine may produce toxic effects in the tonicity pressure within minutes or hours after removal
and responsiveness o f the arterioles. Lais and of the causal factor is a strong argument against
Brody, 7 w h o could not confirm the findings of the proposition that arterial structural changes
Folkow et al, 5 demonstrated, by perfusion o f the are primarily responsible for increased blood
hind quarters o f spontaneously hypertensive rats pressure. Clinically, frequent and immediate cure
with blood instead of Tyrode's solution, a signif- of hypertension is possible within minutes or
icant reduction in the threshold concentration o f hours after the removal of a pheochromocytoma
norepinephrine n e e d e d to elicit a pressor re- or an adrenal a d e n o m a in patients with primary
sponse (less than o n e third o f that required for aldosteronism, despite prolonged periods (often
controls). If there is an increased thickness o f the for several years) of high cardiac output. Resec-
media due to hyperplasia of the resistance arter- tion o f a coarctation o f the aorta is often followed
ies with the same threshold responsiveness to immediately by normal blood pressure, despite
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the presence of severe arteriosclerotic lesions in ance, which is elevated in those with elevated
the hypertensive region. pressures and low in those with normal pres-
6. T h e two-kidney-one-clip (2K-1C) hyper- sure." 22
tension in dogs is characterized by an initial in- 11. O n e of the most important studies o f the
crease in cardiac output in the first two t o four hemodynamic factors in patients with early essen-
days after clipping. This is followed by an in- tial hypertension was reported by Safar et al. 24
crease in peripheral resistance. T h e rise in car- O n e hundred and o n e patients with essential
diac output can be prevented by occlusion o f the hypertension (mean age, 29 yrs old) were com-
inferior vena cava; however, the increase in pe- pared to 101 normotensive subjects (mean age,
ripheral resistance and hypertension devel- 28 yrs old). T h e stroke volume and cardiac index
ops. 1 4 , 1 5 Cardiac output can be increased in ani- were similar in both groups. Blood volume was
mals by a variety o f procedures, but n o n e has significantly decreased, but the key finding was
succeeded in producing chronic hypertension. 1 6 the striking increase in total peripheral resistance
7. Nishiyama et al 1 7 a d m i n i s t e r e d t w o in the group o f y o u n g and early essential hyper-
beta-blockers (propranolol and timolol) at the tensive patients when compared with the g r o u p
rate of 0.5 m g / m L each in drinking water to o f normotensive subjects. Frohlich et al 25 have
control Wistar-Kyoto and spontaneously hyper- reported essentially similar results from studies
tensive rats from birth to death. Neither o f these of patients with essential hypertension and a nor-
beta-blockers, which reduced cardiac output by mal-size heart.
30%, had any effect o n the course o f the devel- Although these data appear to invalidate the
opment and maintenance of arterial hypertension first hypothesis, o n e should still remain receptive
in the treated, as compared to the untreated, to studies seeming to support this theory, espe-
spontaneously hypertensive rats. In addition, n o cially in view o f the recent finding of H a m e t et
difference in cardiac output in the untreated al 26 of a significant increase in weight and deoxy-
spontaneously hypertensive rats was noted when ribonucleic acid ( D N A ) content o f the hearts o f
compared to the normotensive Wistar-Kyoto newly born spontaneously hypertensive rats when
rats. T h e s e findings indicate that cardiac output compared with Wistar-Kyoto rats, whether in
has little importance in the development o f hy- absolute terms or as a ratio to body weight (Table
pertension in spontaneously hypertensive rats.
8. In the early stages o f experimental or clin- N o significant evidence for the second hypoth-
ical hypertension, n o structural changes have esis (increased plasma or extracellular fluid vol-
been detected in small arteries either by light or u m e as a primary event in patients with essential
by electron microscopy. 1 8 hypertension) was demonstrated by Ibsen and
9. O f the patients with hyperkinetic hearts Leth, 2 7 Schalekamp et al, 28 and Tarazi et al. 2 9 - 3 1
and high cardiac output as studied by Gorlin, 1 9 Also, most heavy salt eaters have normal blood
50% had labile hypertension; the others were pressure. Furthermore, Tarazi 3 0 demonstrated
normotensive. Evelyn 2 0 , 2 1 has demonstrated in a an inverse correlation between blood volume and
30- to 35-year follow-up that patients with labile blood pressure or total peripheral resistance.
or borderline hypertension may live more than
30 years without stable "true" hypertension or its Table 1. Heart in newborn spontaneously
severe cardiovascular complications developing. hypertensive rats*
10. Many pathologic states characterized by Spontaneously
Wistar •Kyoto hypertensive
high cardiac output (beriberi, thyrotoxicosis, rats rats
Paget's disease, severe anemia, anxiety states, and Weight (mg) 24.2 ± 0.5 25.0±0.3t
even normal pregnancy) are not accompanied by Heart weight/body weight 4.6 ± 0.1 5.5 ± 0 . 1 $
systolodiastolic hypertension. As emphasized by Total protein (mg) 2.6 ± 0.1 3.0 ± 0.1$
Dustan and Tarazi 2 2 and N e f f et al, 2 3 high Protein/100 mg tissue 10.6 ± 0.4 11.3 ± 0.4
Total DNA 81.0 ±6 113.0 ± 6$
cardiac output in advanced renal failure and sec-
DNA/100 mg tissue 334.0 ± 18 425.0 ± 20$
ondary to severe anemia seems to have little
relationship to hypertension since normotensive * Data adapted from Hamet et al26
patients with similar degrees o f renal failure had "j" P < 0.05
T-PCO.OL
equally high outputs. Dustan and Tarazi stated
Total body weight in newborn spontaneously hypertensive rats (N
that "the feature distinguishing the two groups = 44) was 4.73 g ± 0.06 versus the total body weight of Wistar-
o f uremic patients is peripheral vascular resist- Kyoto rats (N = 46), 5.27 g ± 0.06 (P < 0.01).
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Onesti et al 32 f o u n d that an elevated blood pres- pressor agents, such as norepinephrine, as strips
sure did not develop in half o f the anephric from the hypertensive arteries. Bohr and Berecek
patients given salt loads, despite a marked in- obtained similar results in pigs made hypertensive
crease in blood volume. Dogs with hypertension by DOCA-salt administration in which the hind
induced by metyrapone administration show n o leg was protected from systemic hypertension by
correlation between rise in blood pressure and iliac or femoral occlusion.
increase in intracellular fluid volume. 3 3 ' 3 4 Never- Veins also show increased reactivity to pressor
theless, compelling evidence shows that hyper- agents, both in experimental and human hyper-
tension is caused primarily by increased arterial tension. Such changes cannot be secondary to
sensitivity and responsiveness to pressor agents. increased pressure in the venous system and
T h e evidence o f increased vascular reactivity must, therefore, reflect a basic abnormal hyper-
in hypertensive states, based on results o f studies reactivity of the entire vasculature. 46 ' 47
o f systemic circulation, regional vascular beds, or T h e s e experiments demonstrate beyond doubt
isolated arterial strips is overwhelming. T h e evi- that vascular hyper-reactivity exists in various
dence is clearer f r o m results o f studies o f precap- hypertensive conditions, both experimental and
illary regions, such as in the bulbar conjunctiva human, and is present in the prehypertensive
and in the nail folds of patients with essential state. T h a t this could be due to factors other than
hypertension. 3 6 Results of these studies show an circulating substances is difficult to believe. This
increased vasomotor activity o f the precapillary hyper-reactivity is enhanced by high sodium chlo-
vessels and of the meta-arteriolar sphincters. ride intake and is decreased or prevented by
Additional and more important evidence acute and severe restriction or depletion o f so-
comes from the use o f the superior mesenteric dium. 4 8 - 5 1 Enhancement is also caused by vaso-
artery preparation in the rat. 37 If this preparation pressin, angiotensin II, and aldosterone.
is perfused with an artificial medium such as If present data point out so strongly that the
Tyrode's or Krebs' solution, the pressor response primary event leading to hypertension is an in-
to a standard ED 5 0 dose o f norepinephrine (i.e., creased sensitivity and responsiveness o f the re-
the dose that produces half the maximal re- sistance arterioles to pressor agents, what then is
sponse) will be an increase in blood pressure. responsible for this fundamental disturbance? I
T h i s p h e n o m e n o n is reproducible over a period strongly believe that the reason is related to
o f hours. T h e reactivity o f the denervated mes- disturbances in aldosterone and related mineral-
enteric artery preparations from rats with spon- ocorticoids and in sodium regulation. Most spe-
taneous hypertension or from renal experimen- cifically, the peripheral resistance results from a
tal, renal saline, o r DOCA-salt hypertension balance between, on o n e hand, the activity of the
shows significantly greater responsiveness to the sympathetic nervous system and the circulating
same ED 5 0 dose o f norepinephrine compared concentration o f catecholamines, especially nor-
with the response o f normal rats given the same epinephrine, and on the other hand, the state of
preparations. 3 7 - 4 1 Furthermore, an increased tonicity, sensitivity, and responsiveness o f the
pressor response to norepinephrine and other contractile proteins o f the resistance arterioles.
pressor agents can be demonstrated before the T h e evidence linking the adrenal cortex and
onset o f hypertension in Goldblatt hypertensive aldosterone to hypertension is substantiated by
animals. 4 2 Significantly increased reactivity o f ar- the following facts:
terial strips and of the mesenteric artery prepa- 1. Hypertension cannot be induced in ani-
ration is also evident before the d e v e l o p m e n t of mals in the absence o f adrenal cortex and dietary
hypertension in the 2K-1C Goldblatt dogs, in salt.
DOCA-salt hypertension in rats and pigs, in 2. T h e excessive production or administra-
Grollman hypertensive hamsters, and in hyper- tion o f large amounts of aldosterone, deoxycor-
tensive rabbits with aortic coarctation. 1 4 ' 1 5 ticosterone (DOC), 1 1 - O H - D O C , and 18-OH-
T h e strongest evidence comes from the exper- D O C results in an increase in blood pressure to
iments of Nolla-Panades 4 3 and from those of hypertensive levels. This type o f hypertension
Bohr and Berecek. 4 4 ' 4 5 T h e former, using rats can be prevented by severe sodium restriction or
m a d e hypertensive by coarctation of the aorta, made more severe by high sodium chloride in-
showed that strips from the arteries protected by take. Administration o f the adrenocorticotropic
the aortic constriction from the increased arterial h o r m o n e ( A C T H ) to sheep and rats with saline
pressure had the same hyper-responsiveness to in drinking fluid results in the rapid develop-
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ment of hypertension. Recently, Komanicky and Table 2. Plasma aldosterone concentration
Melby 5 2 demonstrated, after three weeks o f sub- Radio-
cutaneous aldosterone infusion by a m i n i p u m p at DIDA immunoassay
100 /tig/day, that hypertension occurred in rats Control subjects 7.5 ± 5 6.9 ± 4
with significant increases in heart and kidney (N = 20) (N = 69)
weights, whereas D O C A or saline administered
Mild essential hypertension
in a similar manner had n o similar effect. Normal renin 12 ± 6* 9.7 ± 6*
3. Several hypertensive syndromes in humans (N = 42) (N = 55)
are secondary to pathologic conditions o f the Low renin 12.7 ± 7* 11.4 ± 5*
adrenal cortex, such as primary aldosteronism, (N = 17) (N = 26)
Cushing's syndrome, a hypertensive form o f vir- * P < 0.01 versus control subjects (ng/dL) (mean ± standard devia-
ilizing adrenal hyperplasia, and the 17-hydrox- tion)
ylase deficiency syndrome. T h e Glasgow g r o u p DIDA = double isotope dilution assay
has described many reasons for the similarity in
causal mechanisms between primary aldosteron- ing, Page said, "Our view has always been that
ism (whether due to an adenoma or to bilateral the adrenal cortex contains some substance which
hyperplasia) and essential hypertension. 5 3 , 5 5 was necessary for the normal reactivity o f the
blood vessels to be maintained." 5 9
4. Clinically, hypertension often follows long-
6. A bilateral adrenalectomy in 2K-1C hyper-
term administration o f glucocorticoid h o r m o n e s
tensive rats reduces blood pressure to control
for the treatment o f allergic, rheumatic, and
levels, but hypertension returns in all rats that
dermatologie conditions. T h e amount o f sodium
have u n d e r g o n e an adrenalectomy when they are
ingested plays an important role. Similarly, the
given a 1 % sodium chloride solution as drinking
administration of 9a-fluorocortisol, a potent min-
fluid. 6 0
eralocorticoid used in the treatment o f adrenal
insufficiency and o f orthostatic hypotension, is Since the adrenal cortex, mostly through its
frequently accompanied by hypertension. Again, secretion of aldosterone, regulates sodium distri-
the amount o f salt in the diet is critical. bution and excretion, evidence o f fundamental
disturbances o f both aldosterone and sodium in
5. Results o f studies d o n e in the late 1 9 2 0 s
hypertension is convincing. A link between dis-
and early 1930s on the effects o f a bilateral
turbances o f aldosterone to hypertension can be
adrenalectomy have demonstrated that the ad-
based on the following facts:
renal cortex is essential for the maintenance o f
blood pressure and vascular tone. 5 6 ' 5 7 T h e fall in 1. A rigorously selected group o f patients
blood pressure, culminating in circulatory col- with mild and stable essential hypertension, and
lapse and death four to six days following the a blood pressure between 1 4 0 - 1 7 0 and 9 0 - 1 0 5
bilateral adrenalectomy, is closely related to se- m m H g and on a controlled sodium and potas-
vere losses in urinary sodium and decrease in sium intake of 135 and 90 m m o l / d a y , respec-
blood volume and with the progressive loss o f tively, were thoroughly studied.")" Plasma aldos-
arterial sensitivity and responsiveness to norepi- terone concentration measured in each o f two
nephrine. This is accompanied by greatly in- groups of control subjects and o f patients with
creased capillary permeability. Here, it is o f his- mild and stable essential hypertension, first by a
torical interest to quote the statements o f two o f double isotope dilution assay and second by a
the great researchers in hypertension at a sym- radioimmunoassay, showed a significant mean
posium held in N e w York City in 1945. Goldblatt increase in hypertensive patients when compared
stated: "Of the various glands of internal secre- to control subjects 6 1 , 6 2 (Table 2).
tion that were investigated, the only o n e which 2. A significant increase in urinary excretion
has been definitely implicated in the genesis and o f the 3-oxo conjugate metabolite of aldosterone
maintenance o f experimental renal hypertension was observed in patients with essential hyperten-
is the adrenal. . . . T h e r e is clear indication that sion. 6 1 - 6 3 Data from Brunner et al 64 appear to
deprivation o f the adrenocortical h o r m o n e s in- confirm these findings.
terferes with the humoral mechanisms o f hyper- 3. In two-month-old spontaneously hyperten-
tension by reducing the amount o f renin sub- sive rats (systolic pressure, 171 m m H g vs. 115
strate in the blood and possibly with the sensitiv- m m H g in Wistar-Kyoto rats, [P < 0.001]), the
ity of the arterioles to the effect of the hypothet- basal plasma levels of aldosterone and o f corti-
ical vasopressor substance." 58 At the same meet- f Including arteriography
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costerone were f o u n d to be increased with a Table 3. Effect of salt loading on aldosterone in
significantly enhanced response from the admin- patients with benign essential hypertension*
istration of A C T H when compared with the Wis- Benign
tar-Kyoto control rats. 65 essential
Normal subjects hypertension
4. Stable hypertension in rats results f r o m the (N = 14) (N = 25)
constant subcutaneous infusion o f aldosterone Aldosterone
( 1 0 0 /ug/day for 3 weeks) 5 2 ; Komanicky and Secretion rate 102 32 98|
Melby also produced hypertension with low-dose (Mg/day)
infusion of aldosterone for six weeks without the Excretion rate 10.5 3 9.8t
development o f hypokalemia or metabolic alka- (/ug/day)
Plasma level (patient supine) 4-8 1 4.5
losis (personal communication). (ng %)
5. Patients with essential hypertension show Sodium intake 120 >300 >300
a blunted or suppressed aldosterone response d u e (mmol/day)
to the stimuli o f severe sodium restriction, so- * Data adapted from Collins et al70
dium and volume depletion following furosemide • f P < 0.001
administration, and severe hemorrhage despite a
rise in plasma renin activity identical to that seen sential hypertension when compared with control
in control subjects. 66 " 69 subjects. 5
6. Plasma aldosterone concentration is inap- 9. T h e Glasgow g r o u p demonstrated that pri-
propriately high in an older population in rela- mary aldosteronism d u e to bilateral nodular hy-
tion to the plasma renin activity and in the perplasia of the adrenal cortex is a simple variant
younger hypertensive patients with low plasma o f essential hypertension since each condition
renin activity levels. results in the same biochemical characteris-
7. T h e most important finding is probably tics. 53, 55 Extension of these studies to patients
that reported by Collins et al 70 and Luetscher et with primary aldosteronism caused by an adrenal
al 71 that patients with essential hypertension on a adenoma led the authors to the same conclusion
high sodium chloride intake ( 3 0 0 m m o l / d a y ) for this group. 7 2
have substantially less suppression o f their aldos- 10. T h e experiments o f Mendlowitz et al 7 3 , 7 4
terone secretion rate, excretion rate, and plasma demonstrated a great contrast in the digital vas-
concentration when compared with control sub- cular reactivity of control subjects when com-
jects (Fig. 5, Table 3). Because o f the average pared to patients with essential hypertension (Ta-
sodium chloride content o f diets in Western ble 4). T h e s e latter patients showed a selective
countries, this suggests an inappropriately high increased digital reactivity in response to norepi-
aldosterone secretion rate and plasma concentra- nephrine when pretreated by aldosterone in con-
tion in relation to the amount of salt ingested. trast to the absence o f change in control subjects.
8. Infusions o f angiotensin II at increasing Yet, the control subjects showed digital vascular
rates are accompanied by a greatly exaggerated hyper-reactivity to prednisone in contrast to
plasma aldosterone response in patients with es- much lesser changes in patients with essential
hypertension.
ALDOSTERONE WATER ADX NORMAL HYPERTENSIVE
EXCRETION BLANK PTS CONTROLS / NORMAL LOW HIGHx
n/^y PRA PRA PRA
12 Table 4. Digital vascular reactivity* in essential
r r 7 hypertension"!"
Normotensive Essential
subjects hypertension
(N = 15) ( N = 15)
6. -
Aldosterone Î ÎTT
I (1 mg IM X 3 days)
2 _ Prednisone
X I (30 m g / d a y X 7 days)
(100 mg IV)
ÎÎ
ÎÎ
No change
No change
Fig. 5. Effects of high sodium intake (> 300 mmol/day) on
aldosterone excretion in patients with mild essential hypertension. * Response to norepinephrine
ADX PTS = adrenalectomized patients, PRA = plasma renin activity, "j" Data adapted from Mendlowitz et al73,74
and S.E. = standard error. (From Luetscher et al," p 287. By IM = administered intramuscularly, and IV = administered intra-
permission of the authors and publisher) venously
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Such disturbances in aldosterone regulation phatase p u m p inhibited by ouabain and by the
may possibly be linked to the defect in the sodium natriuretic factor recently described by d e War-
transfer across the cell membrane in patients with dener and MacGregor, 8 4 (c) the N a + - K + co-trans-
essential hypertension, as suggested by the work port, which is sensitive to furosemide, (d) the
o f Moura and Worcel. 7 5 T h e well-established evi- Na + -Li + counter-transport, which is inhibited by
dence linking sodium to hypertension, the focus phloretin, and finally, (e) the Na + -Ca 2 + counter-
o f intense interest by researchers, can be sum- transport. 8 5
marized as follows: Although a disturbance in sodium transport
1. T h e antihypertensive effectiveness o f a se- across cell membranes exists with hypertension,
vere dietary sodium restriction by itself, by the mechanisms are n o t yet clear. Presently, a
Kempner's rice and fruit diet in 30% to 50% o f great deal of confusion has developed since re-
patients with essential hypertension, and by thia- sults obtained by various groups show either
zide diuretics in m o r e than half o f patients with marked overlapping o f values between hyperten-
essential hypertension has been well demonstra- sive and normotensive groups or are directly
ted. As emphasized by T o b i a n et al 76 and by L. conflicting. T h e nature o f the disturbances in the
Page, 7 7 a life-long low sodium chloride intake o f sodium transport process is being elucidated, and
less than 6 0 - 7 0 m m o l / d a y is associated with the whether or not these disturbances are associated
virtual absence of hypertension even a m o n g hu- with an increase in free cytosolic calcium, as
man subjects susceptible to it. suggested by Blaustein 8 5 to explain the increased
2. Dahl 7 8 has conclusively shown that by in- sensitivity and responsiveness o f the small arter-
breeding Sprague-Dawley rats, a strain can be ioles, remains to be demonstrated.
produced which is extremely sensitive to small T h e reported effects o f aldosterone o n the
amounts of ingested salt that rapidly develops Na + -K + adenosine triphosphatase activity are
hypertension, and another strain can be pro- confused and contradictory. Possibly, the activity
duced which is extremely resistant to large o f aldosterone on the transport o f sodium across
amounts of ingested salt and remains normoten- cell membranes could b e exerted through the
sive. Similarly, large amounts o f salt f e d to hu- Na + -K + co-transport, the Na + -Li + counter-trans-
mans are followed by significant increases in port, or the Na + -Ca 2 + e x c h a n g e system. Since
blood pressure up to hypertensive levels. patients with primary aldosteronism show a
3. Populations living on a high salt diet 7 8 - 8 2 markedly increased sodium content in tissues, the
have a significantly higher incidence o f hyperten- m o d e of action of aldosterone in increasing intra-
sion, whereas populations living on a low salt diet cellular sodium transport remains to be clarified.
show virtually n o hypertension or any rise of Haddy et al 86 have demonstrated the inhibition
blood pressure with age. T h e c o m m o n factor o f the N a + - K + adenosine triphosphatase p u m p in
between these populations is not only a low intake rats with various types o f low renin hyper tension.
o f sodium, but also a high potassium content in This inhibition comes from a circulating heat-
the diet. T h e importance of the high potassium stable ouabain-like agent present in plasma and
intake is not elucidated, although evidence exists appears to be under the influence o f the anter-
suggesting that a high potassium intake has a oventral third area of the brain. T h e suppression
certain protective effect against the severity of o f the Na + -K + adenosine triphosphatase p u m p
hypertension. would result in increased contractile activity and
4. Gordon et al 83 have shown a p r o l o n g e d responsiveness to vasoactive agents. D e Warde-
pressor response in normal rabbits on a high salt ner and MacGregor 8 4 have also provided recent
diet when cross-transfused with blood f r o m 1K- evidence o f a significant increase in a short-acting
1C hypertensive rabbits. N o such pressor re- factor present in plasma from hypertensive pa-
sponse occurred in the cross-transfused rabbits tients that inhibits the activity and would lead to
o n a normal diet. increased amounts o f sodium in urine and in
5. T h e intracellular sodium concentration in tissues. T h e activity o f this factor varies inversely
red cells, leukocytes, lymphocytes, and thymo- with that o f glucose-6-phosphate dehydrogenase
cytes in patients with essential hypertension is activity. If these findings are confirmed, they
substantially increased. At least five different would also explain the renal tubular defect con-
transport systems have b e e n described for the sisting o f the inability of the hypertensive kidney
transfer o f sodium across cell membranes: (a) to excrete a sodium load at normal pressures and,
passive transfer, (b) N a + - K + adenosine triphos- at the same time, the increased sodium concen-
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RENIN- ALDOSTERONE DOPAMINE ron for the fine adjusting of sodium homeostasis
ANGIOTENSIN 1 PGE, (Fig. 6).
X I / KININ
If the assumption that the direct and primary
JGC. I l 1 /
factor involved in hypertension is increased pe-
SINGLE NEPHRON
ripheral resistance and that the latter is directly
FILTRATION RATE
involved with disturbances o f aldosterone and o f
MACULA DENSA sodium regulation is correct, then hypertension
will be the result o f a disturbance of the equilib-
rium between the sympathetic nervous system
activity, on the o n e hand, and the state o f sensi-
tivity and reactivity of the contractile proteins in
NA BALANCE the arteriolar walls, on the other. T h e factors
Fig. 6. Some of the factors responsible for the fine adjustment involved on each side of the balance are illus-
of sodium balance in the distal and early collecting tubule. JGC = trated (Table 5). T h e increased peripheral resis-
juxtaglomerular cells. tance can therefore be expressed in three models:
1. Model 1: increased sympathetic nervous
trations reported in various cells both in the system activity and plasma concentrations o f nor-
presence of essential and experimental types of epinephrine such as that seen in pheochromocy-
hypertension. This hypothesis is attractive since toma, neurologic disorders, emotional stresses,
it links together the kidneys and increased arter- and in some patients with essential hypertension.
iolar resistance. 2. Model 2: increased renin-angiotensin
In this mosaic of factors, the kidney plays a system activity with increased plasma levels of
most important role as demonstrated by (a) the plasma renin activity and angiotensin II, such as
transplantation of a kidney from a hypertensive that seen in renovascular hypertension, malig-
rat (Dahl's salt-sensitive hypertensive rat or Milan nant hypertension, primary reninism, renal in-
or O k a m o t o spontaneously hypertensive rats) to farcts, and ectopic renin-producing tumors. This
a normotensive nephrectomized rat, which leads model is also accompanied by increased plasma
to hypertension in the latter; (b) the reverse ex- concentration of aldosterone because o f a de-
periment of transplanting a kidney f r o m a nor- creased metabolic clearance rate.
motensive rat to a hypertensive nephrectomized 3. Model 3: increased arteriolar sensitivity
rat, which lowers blood pressure to a normal level and reactivity to norepinephrine and to angioten-
in the latter; (c) the kidney as the source of the sin II, such as is postulated in essential hyperten-
renin-angiotensin system, o f the antihypertensive sion, primary aldosteronism, Cushing's disease,
factors, prostaglandin E 2 (PGE 2 ), and the neutral and 17-hydroxylase deficiency syndrome. This
lipid described by Muirhead, 8 7 and (d) the re- model would be associated with disturbances in
sponsibility o f the distal tubular area o f the neph- aldosterone regulation (Fig. 7) and in the sodium
Table 5. Factors involved in the arteriolar peripheral resistance
Peripheral Resistance
Autonomic nervous system Arteriolar smooth muscle
I
Central
1
Peripheral
Renin-angiotensin system
Aldosterone
Endorphins Na + "sensitivity"
Norepinephrine
Vasopressin Na + renal tubular defect
Rate of conjugation
Baroreceptors Na + cell membrane transport
Turnover rate
Serotonin Dopamine
Gamma-aminobutyric acid Natriuretic hormone
Brain* Prostaglandins
Area postrema Kallikrein
Tractus solitarius
Anteroventral region of the third ventricle
* As derived from Conomy et al81
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transport system across cell membranes. Such ALDOSTERONE
disturbances would render the contractile pro-
tein more sensitive and hyper-reactive to a nor-
mal or "inappropriate" plasma norepinephrine
level.
Many other factors involved in hypertension,
such as prostaglandins, kallikrein, and dopamine,
are all related in some way to aldosterone or
sodium. Similarly, almost all drugs used at the
present time for the treatment o f hypertensive
patients act either by interfering with the sym-
pathetic nervous system activity at various levels,
such as reserpine, alpha-methyldopa, alpha- and
beta-blocking drugs, guanethidine, ganglionic
blockers; increasing sodium excretions and blunt-
ing arterial responsiveness to norepinephrine, 8 9
such as the thiazides and diuretics; or interfering Na INTAKE (mEq/Day)
with renin release or formation of angiotensin II, Fig. 7. Disturbances in mineralocorticôid activity, especially
such as propranolol and the converting e n z y m e aldosterone, in patients with essential hypertension on different salt-
inhibitors. T h e m o d e o f action o f two other anti- intake diets
hypertensive drugs, hydralazine and minoxidil, is
not well known at the present time. 2. Page IH. The mosaic theory 32 years later. Hypertension
1982;4:177.
3. Page IH. Speaking to the doctor: his responsibilities and
Conclusion opportunities. Selected editorials from Modern Medicine.
New York, New York Times Media, 1981, pp 1-320.
Dr. Page stated at the end of a lecture in 1937 4. Trippodo NC, Frohlich ED. Similarities of genetic (sponta-
that neous) hypertension: man and rat. Circ Res 1981;48:309-
The chief physiological mecha- 319.
nisms involved in the maintenance of 5. Folkow B, Hallback M, Lundgren Y, Weiss L. Background
arterial blood pressure are: of increased flow resistance and vascular reactivity in sponta-
1. Blood volume neously hypertensive rats. Acta Physiol Scand 1970;80:93-
2. Blood viscosity 106.
3. Cardiac output 6. Zweifach BW, Shorr E, Black MM- The influence of the
4. Resistance to flow of blood adrenal cortex on behavior of terminal vascular bed. Ann NY
in the blood vessels, chiefly Acad Sci 1953;56:626-633.
in the arterioles. 7. Lais LT, Brody MJ. Mechanism of vascular hyperresponsive-
The first three have been proved ness in the spontaneously hypertensive rat. Circ Res 1975;36-
to be normal in patients suffering 37 (suppl l):216-222.
from essential hypertension and can 8. Friedman SM. Arterial contractility and reactivity. [In] Ge-
therefore be dismissed. Increased nest J, Koiw E, Kuchel O, eds. Hypertension: Physiopathology
impedence to blood flow by arterioles and Treatment. New York, McGraw-Hill, 1977, pp 470-484.
which are hypertonic, is generally 9. Hutchins PM, Darnell AE. Observation of a decreased num-
agreed to be responsible for the ele- ber of small arterioles in spontaneously hypertensive rats. Circ
vated arterial pressure. Res 1974;34-35 (suppl 1):161-165.
It has been my working hypothesis 10. Gutiletta AF, Benjamin M, Culpepper WS, Oparil
that the secretions of some endocrine S. Myocardial hypertrophy and ventricular performance in
glands, for example the adrenal cor- the absence of hypertension in spontaneously hypertensive
tex, are concerned with the mainte- rats. J Mol Cell Cardiol 1978;10:689-703.
nance of the vascular system in a state 11. Komanicky P, Melby JC. DOCA produces cardiomegaly
of reactivity.90 without hypertension in the rat (abst). Clin Res 1979;27:254A.
In 1982, those of us working in the field agree 12. Moritz AR, Oldt MR. Arteriolar sclerosis in hypertensive
more strongly n o w than ever before. T h i s is my and nonhypertensive individuals. Am J Pathol 1937;13:679-
tribute to Dr. Page's vision. 728.
13. Furuyama M. Histometrical investigations of arteries in ref-
erence to arterial hypertension. Tokoku J Exp Med
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