AJH 2001; 14:186 –194

Review Course: Continued

Laragh’s Lessons in tensin converting enzyme in plasma12,13 that, by rapidly

Pathophysiology and Clinical removing two terminal amino acids from angiotensin I
creates the octapeptide, angiotensin II, the most powerful
Pearls for Treating Hypertension
arteriolar vasoconstrictor hormone.
However, despite these developments the roles of the
renin-angiotensin process in hypertensive disease or in
Lesson I: A Brief normal physiology remained in doubt. Finally, when a
History of Hypertension Research: large number of clinical studies failed to find any consis-
Renin Is Twice Rejected tent relationship between plasma renin levels and the pres-
ence or absence of common forms of clinical hyperten-
In 1892, Brown-Sequard, the father of modern endocri-
sion, Goldblatt’s renin hypothesis was rejected, and renin,
nology, proposed that the kidneys had an internal secretion
for the second time, became a dead issue. (Actually, this
(ie, a hormone) that causes hypertension. Building on this
misinterpretation of plasma renin measurements occurred
idea, in 1898 Robert Tigerstedt, Professor of Physiology at
because scientists were unwilling to recognize that hyper-
the Karolinska Institute and his student Per Bergman,
tension may not be single process; therefore, hypertension
reported1 that saline extracts of rabbit kidneys when in-
associated with low renin values might be mediated in-
jected into anesthetized rabbits, consistently produced
stead by a sodium volume excess.)
prompt and striking increases in blood pressure. In a
In the meantime, the 1950s produced the recogni-
meticulous series of studies he showed that this kidney
tion,14,15 isolation, and synthesis16,17 of the adrenal corti-
substance did not increase cardiac output, but increased
cal hormone aldosterone as the major regulator of sodium
blood pressure by constricting the resistance vessels. He
and potassium balance, through its renal actions to pro-
also described the more prolonged pressor response to
mote renal sodium retention and kaliuresis. The absence of
renin in nephrectomized rabbits. He called this substance
this hormone (Addison’s disease) leads to death from
renin, and suggested a role for it in causing human high
sodium depletion or from hyperkalemia18 and its presence
blood pressure.
in excess, as in adrenal cortical aldosterone-secreting tu-
However, this idea lost its credibility when, to Tiger-
mors (primary aldosteronism)19 causes sustained sodium
stedt’s astonishment, other distinguished European scien-
volume-mediated hypertension with hypokalemia. This
tists uniformly failed to confirm his findings. This was
work raised the possibility that aldosterone excess might
probably because sterile technique, antibiotics, and refrig-
also cause other hypertensive states. It was also shown that
eration were not used in most animal research, allowing
the plasma potassium level, as affected by dietary potas-
bacterial proteases to rapidly destroy renin if it was not
sium intake is a major normal stimulus for adrenal aldo-
used immediately. Renin also failed to survive the reaffir-
sterone release.20 Although it was proposed by Bartter and
mation of an association between renal necrotizing arte-
associates21 that aldosterone participated in the regulation
riolitis and malignant hypertension described by Volhard
of plasma and fluid volumes, the framework of signals in
and Fahr in 1914.2
which sodium volume exercised this participation re-
Renin remained a dead issue until 1934 when Harry
mained obscure and its connection with hypertensive
Goldblatt, in his classic studies of renal artery constriction
states other than that occurring in primary aldosteronism
by a clamp, produced chronic hypertension in dogs ex-
was not suspected. That there might be a connection
tremely similar to human hypertension.3 Interest in renin
between the kidneys and the adrenals emerged as a pos-
was quickly revived, and this time the original experiment
sibility, however, in 1958 after Gross22 showed an inverse
of Tigerstedt and Bergman1 finally was widely con-
relationship between dietary salt intake and renal renin
firmed.4 – 6 In the same year, Goldblatt7 and Wilson and
content in rats.
Pickering8 described the production by renin of malignant
In 1960, Stanley Ulick and I, together with our associ-
hypertension with fibrinoid necrosis in dogs and rabbits. A
ates,23,24 made it possible to explore the plasma levels of
few years later Braun-Menendez et al9 and Page and
aldosterone in various hypertensive states by developing
Helmer10 independently showed that renin itself was not a
and applying a double isotope radioassay that allowed
pressor agent. They showed that renin is a circulating
accurate measurement of the minute amounts of aldoste-
enzyme that hydrolyzes an inactive decapeptide, angioten-
rone secreted daily. We demonstrated that patients with
sin I, described by Skeggs and colleagues11,12 from a
malignant hypertension virtually always secrete huge
circulating protein renin substrate13 now called angio-
amounts of aldosterone, even more than produced by
tensinogen. Skeggs also discovered that it was the angio-
adenomatous primary aldosteronism. Moreover, our

0895-7061/01/$20.00 © 2001 by the American Journal of Hypertension, Ltd.

PII S0895-7061(00)01317-0 Published by Elsevier Science Inc.
AJH–February 2001–VOL. 14, NO. 2 LARAGH’S LESSONS FOR TREATING HYPERTENSION
study24 showed, contrary to previous claims,25 that these
massive aldosterone excesses of malignant hypertension
were in fact quite unique, because in benign essential
hypertension aldosterone values were normal.
Suspecting that the excess adrenal aldosterone secretion
in malignant hypertension was triggered by a renal signal,
the kidney being the most compromised organ in malig-
nant hypertension, my colleagues and I cautiously infused
angiotensin II, the pressor peptide released by plasma
renin, into normal volunteers and showed a striking,
prompt, and unique increase in aldosterone secretion.26
These experiments revealed a signaling system between
the kidneys and the adrenals starting with kidney renin
release, and the formation of angiotensin II in plasma to
(1) increase blood pressure and also to (2) stimulate adre-
nal aldosterone26,27 secretion to thereby promote renal
sodium retention and potassium loss. In this way, the three
key elements in the hypertension equation, arteriolar va-
soconstriction and body sodium and potassium content,
are coregulated by a single system, blood pressure through
plasma angiotensin levels and body sodium and potassium
content by plasma aldosterone. At the same time, this
research implicated uncontrolled overactivity of this new
renin-angiotensin-aldosterone control system for causation
of malignant hypertension and of its fatal generalized
vascular injury. The revelation of this biologic control
system and the relevance of its overactivity for causing
severe malignant hypertension launched an immediate ex-
plosion in hypertension research that has forever changed
the understanding and treatments of hypertensive vascular
diseases, and its related cardiac, cerebral and renal vascu-
lar injury, which continues to dominate cardiovascular
research today. (For a more complete historical review,
see also Reference 28.)
Lesson II: Insights From
Studies of Malignant Hypertension
Studies of malignant hypertension led to: (1) discovery of
the plasma renin-angiotensin aldosterone hormonal con-
trol system for coregulating blood pressure (by angioten-
sin) and body sodium and potassium content (by aldoste-
rone) in humans. (2) At the same time, this research
implicated unabated overactivity of this renin-angiotensin
aldosterone system with high plasma renin angiotensin
levels as the cause of malignant hypertension, of its high
aldosterone levels and hypokalemia, and of its severe
vascular injury to heart, brain, and kidney vessels, leading
rapidly to fatal heart attack, heart failure, kidney failure, or
stroke.
Furthermore, the latter research, by revealing the dev-
astating cardiovascular effects of massive overactivity of
the renin-angiotensin-aldosterone control system in malig-
nant hypertension, provided the template for implicating
milder elevations in plasma renin that occur in medium
and high renin essential hypertension for causing their
187
hypertension and albeit more gradually, also causing their
later heart attack or strokes.
What Is Malignant Hypertension?
Malignant hypertension is the most severe and rapidly
fatal form of human hypertension. The syndrome of ma-
lignant hypertension (MHT), as originally described by
Volhard and Fahr in 1914,2 is characterized by severe,
accelerating hypertension, accompanied by evidence of
renal disease and also by signs of vascular injury to the
heart, brain, retina (grade III or IV), and kidneys and by a
rapidly fatal course, ending in heart attack, heart failure,
stroke, or kidney failure. Malignant hypertension is also
consistently characterized by hypokalemia. It can be a
sequel to benign hypertension or it can be caused by
severe renal artery stenosis or by advancing small vessel
renal diseases such as occurs in lupus, periarteritis, or
scleroderma.
When we discovered that hypokalemia was a charac-
teristic feature of malignant hypertension we realized that
hypokalemic primary aldosteronism due to an adrenal
tumor always had to be ruled out diagnostically. At
present, this is easily accomplished by a plasma renin test.
The world has learned that primary aldo patients always
exhibit very low plasma renin values PRA ⬍0.65. In sharp
contrast, MHT is always characterized instead by medium
to very high plasma renin values. The renin values are very
low in primary aldosteronism because the aldosterone
excess causes massive renal sodium retention and potas-
sium wastage. It is the sodium volume retention that
suppresses renal renin secretion in their normal kidneys to
near zero, because the sodium-volume excess takes over
full support of their high blood pressure.
How the Renin-Angiotensin-
Aldosterone System Was
Discovered and its Overactivity
Implicated as the Cause of Malignant
Hypertension and its Fatal Vasculitis
In 1960 we published four articles23,24,26,27 in rapid suc-
cession that abruptly put renin on the biologic map. Our
group had been studying the role of aldosterone, the re-
cently discovered powerful adrenal cortical hormone,
which acts on the kidneys to increase sodium retention and
promote the elimination of potassium. It is present in tiny
amounts in the body (10⫺12 M concentrations). We spent
4 years developing a double isotope label method to mea-
sure it accurately.23,29 We showed that aldosterone secre-
tion was high in heart failure patients29 and, in these
individuals was likely causing their fluid retention and
edema. There were also great hopes in the field that an
aldosterone excess, by retaining sodium in the body, might
be a cause of essential hypertension, and there were re-
ports indicating that their aldosterone levels were high.2
To the contrary, with our method, we found that aldoste-
rone secretion was quite normal in essential hypertension.
188 LARAGH’S LESSONS FOR TREATING HYPERTENSION AJH–February 2001–VOL. 14, NO. 2

However, in 1958, a patient was referred to us with ma-
lignant hypertension. We found hypokalemia (K⫹ ⫽ 3.2)
and grade IV retinopathy. We first thought he could have
primary aldosteronism because we found his aldosterone
secretion to be enormous, 880 ␮g/day, almost 10 times
normal. We advised adrenal surgery at which we found no
adrenal adenomas, but instead bilateral adrenal hyperpla-
sia. We studied 13 more such MHT patients. All had
hypokalemia with enormously increased aldosterone se-
cretion rates.
These were not easy times. There were no effective anti-
hypertensive drugs to control accelerating MHT. These pa-
tients were headed for early death. Bilateral adrenalectomies
in three patients produced no clinical benefit. Postoperative or
postmortem studies in six patients confirmed that they all had
bilateral adrenal cortical hyperplasia.24 This bilateral hyper-
plasia meant that their adrenal glands were receiving a hu-
moral signal from an extraadrenal source, but where? Adre-
nocorticotropic hormone, the tropic normal for cortisol
release could be excluded. The most likely source to us was
the kidneys because, as Volhard and Fahr2 had shown, the
kidneys are the most damaged organ in MHT.
We concluded that it might be that renin, the forgotten
substance, was being secreted or abnormally extruded into
the blood by the damaged kidneys and that this somehow
signaled the adrenal cortex to release aldosterone.24 Ob-
viously, we could not administer an impure renin protein
to healthy humans. But fortunately, angiotensin II, the
pure octapeptide pressor hormone, the sole product of
plasma renin’s enzymatic action had just been synthesized
and was available for clinical studies by Ciba. We cau-
tiously infused angiotensin II intravenously in tiny doses
so as to only increase control blood pressures 5 to 10 mm
Hg at most.26 We did 40 control infusion studies using
various other pressor agents and eight using angiotensin II.
We found that only angiotensin II markedly and promptly
stimulated adrenal secretion of aldosterone.
The Pathogenesis of
Malignant Hypertension:
A Control System out of Control
Thus, we had a very good explanation for the massive
aldosterone release that we found in MHT.26,27 It was the
result of unabated kidney release of renin that created high
plasma renin-angiotensin levels, which, in turn (as we just
demonstrated), powerfully and selectively stimulated al-
dosterone release. The high plasma angiotensin II levels
increase blood pressure by vasoconstriction, but because
angiotensin II also stimulates aldosterone release, aldoste-
rone in turn causes more renal sodium retention and more
kaliuresis leading to higher and higher blood pressures and
to more and more kaliuresis. The renin system servocon-
trol mechanism is damaged so that neither salt retention
nor high blood pressure can turn off kidney renin release as
they normally would. A vicious runaway circle develops
from more kidney renin release producing more plasma
renin, more plasma angiotensin, more hypertension, more
potassium loss, and more and more vascular injury to

FIG. 1. Renal-adrenal, renin-angiotensin-aldosterone hormonal system for normal control of blood pressure and of sodium and potassium
balance: its uncontrolled overactivity causes malignant hypertension. The causal role of the renal–adrenal hormonal axis in malignant
hypertension is shown, in which runaway renin release from damaged kidneys leads to a massive excess of plasma angiotensin, and hence
of aldosterone, leading to hypertension, hypokalemia, severe vasculitis of the heart, brain, and kidneys, and an early demise. The syndrome
can be reversed by specific anti-renin system drug therapies or by a bilateral nephrectomy. In contrast, primary aldosteronism, which results
in equally high blood pressures (BP) and aldosterone values and similar hypokalemia, is characterized by very low plasma renin angiotensin
values and practically no vascular injury. ACTH ⫽ adrenocorticotropic hormone. Drawn from Ref. 27.
AJH–February 2001–VOL. 14, NO. 2 LARAGH’S LESSONS FOR TREATING HYPERTENSION
heart, brain, and kidney vessels leading to rapidly fatal
heart attack, heart failure, kidney failure, or stroke. This
proposed pathogenic scenario for human malignant hyper-
tension is depicted in Fig. 1.
Clinical Pearl #2: Malignant
Hypertension and Primary
Aldosteronism Express Quite
Different Types of Hypertension
Malignant hypertension and primary aldosteronism share
these features; 1) severe elevations of blood pressure and
2) marked increases in aldosterone with hypokalemia. But
the similarity stops there.30 Malignant hypertension is a
vicious, rapidly fatal disorder, in which renin and angio-
tensin levels are very high, whereas primary aldosteronism
is a relatively benign long-standing form of hypertension
with few premature cardiovascular sequelae, in which
renin and angiotensin levels are instead markedly sup-
pressed to near zero by the large body sodium volume
excess caused by the aldosterone excess from an autono-
mous adrenal tumor in a person with normal kidneys. This
comparison suggests that the elevated plasma renin angio-
tensin II levels of malignant hypertension are in fact the
cause of the ischemic vascular injury because hyperten-
sion with high aldosterone in the absence of plasma renin
(primary aldosteronism) exhibits no signs of premature
vascular injury to heart, brain, and kidney vessels.
Accordingly, there are at least three points to be derived
from this comparison:
1. Hypertension caused by too much renin angiotensin
(a low flow or “dry” hypertension) is much more
devastating than is a similar degree of hypertension
caused by too much salt and volume (a wet high flow
hypertension).
2. A pure salt excess, with high blood and extracellular
fluid volumes, hypertension, as in primary aldoste-
ronism, creates a high filtered sodium load that turns
off kidney release of renin while the resulting larger
distal sodium load promotes kaliuresis.
3. Thus, a similar degree of hypertension in humans can
be caused by a) too much salt, or b) too much renin,
or c) an inappropriate excess of one component rel-
ative to the other. We called this spectrum analysis
the volume vasoconstriction model.
For openers, this teaches us that there are always two
major final determinants of any blood pressure lev-
el23,31,32; (1) the amount of sodium (ie, volume) filling the
arterial tree with each heart beat, and (2) the caliber of the
arterioles,24 as set by plasma renin angiotensin levels.
Accordingly, when you analyze any hypertensive situation
the first goal is to determine whether it is a) primarily a
sodium volume or b) primarily a vasoconstriction (ie,
189
renin angiotensin)-mediated hypertension. Therefore, your
primary drug choice will be either an anti-sodium/volume
drug or an antirenin drug. If you choose the first drug type
incorrectly, lots of decision errors can follow because each
antihypertensive drug will generally induce reactive in-
creases in either the volume or the endogenous renin level
that in turn impairs antihypertensive action. But if your
primary drug type choice is correct, then the blood pres-
sure is easy to control, very often by one drug type. If only
partially successful, choosing the second drug type is also
a simple problem (more on this later).
Lesson III: How the Renin
System Works: Tiny Amounts
of Infused Angiotensin Cause
and Sustain Hypertension in
Humans: Noradrenaline Does Not
Fig. 2 illustrates the renin system servocontrol mechanism
that regulates blood pressure in normal humans. In this
study,33 we infused angiotensin II into normotensive
people for up to 11 days to increase their blood pres-
sure. You can see how this 35-year-old nurse on our
research ward became mildly hypertensive. The goal
was to raise her blood pressure of 110/60 mm Hg to
about 130/85 mm Hg and to keep it there for 11 days.
When we stopped the infusion, she had a big natriuresis
and promptly returned to her prior level of normoten-
sion. What happens when angiotensin II is present in the
blood in slight excess? This woman gained 2 kg in
weight over the first 5 days because the angiotensin in
her blood stimulated a large increase in adrenal aldo-
sterone secretion (third panel) and this caused sodium
retention by her kidneys (second panel from top), as
indicated by the absence of salt in the urine during the
first 5 days. Then she leveled off at her new weight and
reestablished neutral sodium balance. When we stopped
the angiotensin infusion she promptly got a big sodium
diuresis, and her weight and blood pressure anxiety
returned to her normal baseline.
The bottom panel of Fig. 2 is key, because this illus-
trates that, when angiotensin II was given continuously to
this healthy person, less and less of it was needed to keep
her blood pressure elevated from day 5 to day 10. Thus,
we needed to reduce progressively the amount of angio-
tensin given (one-fifth to one-tenth of the original amount)
as she became more and more sensitive to its blood pres-
sure-raising action. This increased pressor sensitivity oc-
curred because the angiotensin, by aldosterone stimula-
tion, had progressively overinflated the blood volume by
causing renal sodium and water retention.
These data show that tiny, diminishing amounts of
angiotensin over days can make you and I chronically
hypertensive by causing salt retention to amplify the hy-
pertensive response. Thus, a mild angiotensin excess in the
190 LARAGH’S LESSONS FOR TREATING HYPERTENSION AJH–February 2001–VOL. 14, NO. 2

FIG. 2. How “normal” amounts of infused angiotensin sustain hypertension in a normal volunteer. Prolonged continuous angiotensin infusion
in normal subjects for up to 11 days ends up producing hypertension, biochemically and hormonally similar to essential hypertension. Similar
noradrenaline infusions do not sustain hypertension because they induce pressure natriuresis and return to normotension. In the study
shown, the infusion of angiotensin was adjusted to maintain a mildly pressor response. Angiotensin II induced a marked, selective increase
in the adrenal cortical secretion of aldosterone, together with consequent sodium retention. As the sodium was retained, angiotensin II
became more pressor. Because of this increasing pressor sensitivity to angiotensin II, angiotensin infusion was serially reduced to a point
where aldosterone secretion fell back to near control levels. This sodium-mediated pressor sensitivity to angiotensin is created by an initial
gain in body sodium volume content that would normally turn off the need for endogenous angiotensin. As the infusion rates of angiotensin
were reduced tiny amounts of angiotensin, within the normal range, end up sustaining the hypertension; then when the angiotensin infusion
is stopped there is a prompt natriuresis with return of blood pressure to normal.31

blood fits the model requirements for causing sustained
essential hypertension. We could not show this for nor-
adrenaline, which we infused into 12 people. These sub-
jects do not develop sustained high blood pressure, even
when the dosage is increased in steps. Instead of activating
aldosterone, noradrenaline induces paroxysms of pressure
natriuresis with a fall back of blood pressure to normal.
Thus, given intravenously, only angiotensin fits the model
requirements for causing and maintaining long-term hy-
pertension in humans, by a process in which subtle sodium
retention appears to be the key cofactor.
This study33 indicates that what the hormone angioten-
sin II does, in you and me, is that it normally protects us
from salt and volume depletion or from too low a blood
pressure. Actually it does these two things rapidly when
we stand up every day. Angiotensin restores blood pres-
sure by constricting your arterioles, and it restores salt and
water balance over the next several hours by stimulating
aldosterone release to make the kidneys retain salt and
thus water to improve or restore our blood pressure and
flow in the upright positions and thereby turn off kidney
renin release.
Lesson IV: The Nomogram:
Plasma Renin Levels
Respond to How Much Salt We Eat
Fig. 3 shows our nomogram34 describing how the hor-
mone renin behaves in the blood of normotensive people.
In this study, we used our sensitive and precise method for
measuring plasma renin, crafted over the years 1960 to
1968, that has become a world reference standard for
accuracy, sensitivity, and reproducibility. If there is any
one thing that has been crucial to our work it has been this
methodology, one of many crucial contributions that Dr.
Jean Sealey and colleagues have made to our work.35 Fig.
3 shows how plasma renin levels behave in healthy am-
bulatory subjects in response to changes in dietary salt. It
shows that, when you eat a high-salt diet, blood renin
levels decrease toward zero; conversely, renin increases
sharply when you eat a low-salt diet, by about 20-fold.
What is beautiful about this hyperbolic normal curve is the
fact that it describes how our normal blood pressures
rarely change when we change our salt intake, because, as
fast as we lose sodium from our body, a perfectly balanced
stoichiometric increase in your own kidney renin secretion
AJH–February 2001–VOL. 14, NO. 2 LARAGH’S LESSONS FOR TREATING HYPERTENSION 191

FIG. 3. Relationship of plasma renin activity in plasma samples obtained at noon and of the corresponding 24-h urinary excretion of
aldosterone to the concurrent daily rate of sodium excretion in normal subjects. For these normal subjects,34 the data describe a dynamic
hyperbolic relationship between both renin and aldosterone levels and the daily rate of sodium excretion, an index of intake. Of note is the
fact that subjects studied on random diets outside the hospital exhibited a similar relationship, a finding that validates the use of this
nomogram in studying outpatients or subjects not receiving controlled diets. From Ref. 11.

occurs, and this creates a just enough higher plasma renin
level, which causes compensatory blood vessel vasocon-
striction to keep the blood pressure at exactly the level
where it was before we avoided the dietary salt. The
reverse occurs when more salt is ingested: renin turns off
as a result of an increase in body sodium. This sodium
creates more fluid volume and this replaces renin to sus-
tain normal blood pressure hydraulically instead of by
renin-induced vasoconstriction. These interactions de-
scribe the twin reciprocal support of all blood pressure by
plasma renin angiotensin levels or by the sodium volume
status, with kidney renin release reacting to salt intake.
Thus, salt provides the primary support for our blood pres-
sure and renin has a backup role, kicking in to support normal
blood pressures whenever salt is not eaten. This renin vaso-
constrictor compensatory response likely occurs at the cost of
some reduction in flow to the tissues and of possibly more
heart work against a higher vascular resistance. Thus, a priori
sodium deprivation is not necessarily a good physiologic
tradeoff that can be universally recommended.
Lesson V: The Abnormal
Plasma Renin Levels in
Essential Hypertension
In contrast to normotensives is the behavior of plasma
renin in subjects with high blood pressure,36 as shown in
Fig. 4. Using our renin data from normotensive people34 to
build a nomogram (within the dotted line curves), hyper-
tensive patients exhibit an abnormally wide distribution in
plasma renin values35 about 30% have subnormal or low
renin values, about 50% have medium or “normal” values,
and 20% have overly high renin values. Thus, people with
high blood pressure differ from healthy persons. Our re-
search indicates that the low renin patients live the longest
and do not have as many heart attacks or strokes, although
they are older and may have higher blood pressures.36 In
contrast, the 20% in the high-renin group suffer the most
ischemic vasoconstrictive phenomena, strokes, heart at-
tack, heart failure, and kidney failure, and an earlier death.
These data thus show how human hypertension, long
called essential hypertension and considered to be homo-
geneous, is in fact a heterogeneous biochemical spectrum
of renin/salt disorders in which there are two different
primary mechanisms interacting (renin vasoconstriction is
primary in the medium- and high-renin groups, whereas
sodium volume mediation prevails in the low-renin pa-
tients). These two mechanisms are associated with differ-
ent susceptibilities to premature cardiovascular events
and premature death, and they are also characterized by
opposite response patterns to anti-renin as opposed to
the anti-sodium volume type of antihypertensive drug
types.
192 LARAGH’S LESSONS FOR TREATING HYPERTENSION AJH–February 2001–VOL. 14, NO. 2

FIG. 4. Plasma renin and aldosterone levels in untreated essential hypertension. Relationship of the ambulatory noon plasma renin levels
(left panel) and 24-h urinary aldosterone excretion rates (right panel) to the concurrent daily urinary sodium excretion used as an index
of intake. The dashed lines define the normal range derived from a study of normotensive people. A total of 219 patients with untreated
essential hypertension were studied, some on several occasions at different levels of sodium intake. Low-renin essential hypertension (solid
triangles); normal renin essential hypertension (open circles); high-renin essential hypertension (solid squares). These three major
groups are defined by the appropriateness or normalcy of the plasma renin activity for the rate of sodium excretion, which is used as an index
of dietary intake of sodium balance. Additional abnormal groups are defined when aldosterone (right panel) is included in the analysis.
Plasma renin activity results are expressed as nanograms of angiotensin I produced/hour per milliliter. The values shown should be multiplied
by 0.64 to conform to the National Bureau of Standards angiotensin I reference standard. From Ref. 11.

Lesson VI: The Plasma Renin
System is the Servocontrol for
Blood Pressure and Sodium
and Potassium Balance
Fig. 5 shows how the renin system works in all of us as a
servocontrol. It all begins in the juxtaglomerular cells of
the kidneys. When you or I stand up in the morning, renin
is promptly released into the blood by the kidneys. Renin
makes angiotensin, which instantly constricts the blood
vessels, so that the blood pressure does not decrease at all
when you stand up; in fact, it actually goes up a little.
Then, over a more leisurely period of several hours,
plasma angiotensin II also stimulates the adrenals to re-
lease aldosterone into the blood, causing dietary salt to be
retained; this restores the blood volume, because sodium is
the major osmotic force for creating the blood volume, and
the volume of extracellular fluids bathing all tissues. In
this way dietary sodium creates and sustains the fluid
volume of the circulation. It follows that, in this feedback
servocontrol, when blood pressure increases, or when salt
intake becomes excessive, the kidneys respond by turning
off renin release, allowing more salt to leave the body and
the blood pressure to decrease. Thus, the long-term regu-
lation of blood pressure and of body salt, as set by the
renin system servocontrol, is a major everyday survival
mechanism for all of us. To maintain blood pressure, and
body fluid content, dynamic angiotensin II-induced con-
striction of blood vessels (or relaxation with its with-
drawal) is the immediate response, whereas an induced
sodium volume retention, or diuresis, provides for the
companion longer term sodium volume control.
Knowing this, it is easy to understand that there are two
interrelated points of attack for the analysis and treatment
of high blood pressure. First, you can block angiotensin
formation or action to thereby reduce arteriolar constric-
tion; second, you can induce a sodium diuresis and reduce
the blood volume. For the latter, diuretic treatment is often
effective in itself in low-renin hypertensive patients. Their
plasma renin values are already low, apparently because a
body sodium volume excess has already had a suppressive
effect. Accordingly, with diuretic therapy, as salt and wa-
ter are removed, blood pressure will decrease and then
plasma renin will increase reactively to normal, all of
AJH–February 2001–VOL. 14, NO. 2 LARAGH’S LESSONS FOR TREATING HYPERTENSION 193

FIG. 5. Circulating renin-angiotensin-aldosterone system. Renin, secreted in response to reduced arterial pressure or reduced renal tubule
sodium, produces angiotensin I from circulating angiotensinogen (renin substrate). Angiotensin converting enzyme then converts angioten-
sin I into angiotensin II. Angiotensin II increases pressure by direct arteriolar vasoconstriction and stimulates adrenal aldosterone secretion.
Together, aldosterone and angiotensin II cause renal sodium retention. The resultant fluid accumulation leads to improved flow. These
pressure and volume effects in turn lead to suppression of renal renin release. Dashed line indicates negative feedback. From Ref. 37.

which verifies that they had salt hypertension in the first
place, which had suppressed their renin levels.
JOHN LARAGH
Editor-in-Chief
American Journal of Hypertension
515 Madison Avenue, Suite 1212
New York, NY 10022
Address correspondence and reprint requests to: Dr. John Laragh, Amer-
ican Journal of Hypertension, 515 Madison Avenue, Suite 1212, New
York, NY 10022; e-mail: jsealey@mail.med.cornell.edu
This article is a continuation of a monthly series that began with the
January, 2001, issue.
References
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