Hypertension. 2001;37:806-810
(Hypertension. 2001;37:806.)
© 2001 American Heart Association, Inc.
K+ Depletion and the Progression of Hypertensive Disease or Heart Failure
The Pathogenic Role of Diuretic-Induced Aldosterone Secretion
John H. Laragh;
Jean E. Sealey
From the Cardiovascular Center, Weill Medical College of Cornell
University, New York, NY.
Correspondence to Dr John Laragh, Cardiovascular Center, Weill Medical College of Cornell University, 1300 York Ave, Room A-863, New York, NY 10021.
Key Words: potassium hypertension heart failure aldosterone spironolactone
 |
Introduction
|
|---|
After
the introduction of chlorothiazide in
1958,
1 as the
first of many
sulfonamide thiazide diuretics, these orally
active
diuretics rapidly became the cornerstone for treatment
of
patients with congestive heart failure (CHF) and other edematous
states. These diuretics were also widely adopted for primary
or
adjuvant antihypertensive drug therapy. Since the beginning,
it was
recognized that such natriuretic-diuretic therapy
in
both of these disorders is regularly accompanied by demonstrable
body potassium and magnesium deficiencies, often reflected
by
significant, albeit generally mild, observed decrements
in plasma
K
+ and Mg
2+
levels. But because no particular problems
were recognized with broad
use of these diuretics, over the
years physicians became
increasingly sanguine about their occurrence.
Accordingly, thiazide
diuretics and then, beginning in 1966,
the similar but more
powerful loop diuretics (eg, furosemide)
also became broadly
used as primary or adjuvant treatments
for high blood pressure and for
the edematous state of CHF,
cirrhosis with ascites, and nephrotic
syndrome.
 |
Superior Features of Spironolactone Over
Sulfonamide Diuretics for Treating Hypertension or CHF
|
|---|
The first selective aldosterone receptor
antagonist, spironolactone
(Aldactone), was introduced in
clinical medicine in 1958.
2
By blocking the action of aldosterone, it proved to be a
potent
natriuretic-diuretic and
K
+-retaining agent. Thus, it produced
diuresis and weight loss with no loss of
K
+ or Mg
2+,
something
our group views as a great conceptual therapeutic advantage
over thiazides. The lack of any demonstrable morbidity from
thiazide-induced K
+ depletion and the
impressive prompt diuresis
that these drugs produced at a low
cost, however, carried the
sulfonamide diuretics into a
leadership position for treatment
of hypertension or edematous states
that continues today.
Our preference for the aldosterone
antagonist approach, however, was enhanced by 2 facts.
First, in outpatient trials, in >20 reports of head-to-head
comparisons of spironolactone with a thiazide diuretic,
spironolactone proved to be at least as effective as the thiazides for
correcting hypertension2 ; and
second, spironolactone treatment proved to be considerably more potent
than thiazides and/or furosemide for full diuresis of patients
with CHF or cirrhosis with ascites, often working after a failed
thiazide/Lasix trial. Its power in these latter 2 situations was
therefore amazing. Furthermore, these latter results correctly implied
a large role for aldosterone excess in the pathogenesis of
these conditions.
In addition to cost, however, there are 2 problems with
spironolactone that have stalled its acceptance: First is its
very gradual action, which made it appear to be less effective and
therefore less attractive to anxious physicians and patients. It takes
3 to 5 weeks of daily therapy to express its full effect. This is
because spironolactone blocks only that 2% of the daily renal sodium
resorption that is governed by aldosterone. At this rate,
however, cumulative sodium loss becomes large, so that after 4 weeks or
so, it may easily exceed what could be achieved over the same time with
a loop diuretic. This scenario is similar to what happens after
total adrenalectomy in animals. These animals die of salt loss and/or
hyperkalemia (the model counterpart of an Addisonian
crisis), but this takes 6 weeks to develop, and the process can of
course be delayed or avoided by feeding NaCl. The second problem with
spironolactone was that it caused unpleasant dose-related
antiandrogenic side effects, especially in the dose of 50 to 100 mg/d
used at first. These are gynecomastia in men and menstrual
disturbances in women. But as time went on, we learned that
this could be largely avoided by giving only 12.5 to 25
mg/d.
With this latter information in hand, one of us (J.H.L.)
over the years achieved success after success as a consultant
for treating desperate cardiac patients, already receiving full doses
of Lasix and an ACE inhibitor, by adding a small daily dose
of spironolactone and then observing, time and time again, dramatic
natriuresis and diuresis without urinary
K+ loss but with clearing of all edema fluid
plus an obvious improvement in total cardiovascular
performance that sometimes added years to the lives of these
patients.
 |
The RALES Heart Failure Trial
|
|---|
We shared these experiences and views about
spironolactone
with Dr John Alexander, with whom we had worked on
captopril
when he was at Squibb. He had moved to Searle, where he set
out to revive interest in their spironolactone product (Aldactone).
He planned a clinical trial in CHF. In a test run, they confirmed
our
experiences that 12.5 to 25 mg/d would be enough to do
the job, and
with Bert Pitts leadership, they designed
and performed the now
famous RALES Trial reported late in
1999.
3 This trial of 1665
patients with severe CHF was planned for
3 years but had to be
discontinued after 24 months because
the death rate from cardiac causes
was already reduced by an
amazing 30% in the group that received
spironolactone therapy
superimposed on their full drug regimen. All of
these benefits
occurred with only a small (0.3 mm/L) but highly
significant
increase in plasma K
+ levels in
the treated group.
 |
Muscle K+ Depletion:
A Common Pathogenic Factor in Thiazide-Treated CHF and Hypertensive
Patients
|
|---|
The spectacular results of the RALES trial in CHF
patients
teach us that sulfonamide-diureticinduced
K
+ and Mg
2+
deficiencies may not be benign. This per se could create serious
dysfunction in cardiac and skeletal muscle performances, which,
in CHF, might hasten progression of heart failure. This possibility
is
strongly supported by the large measured deficiencies in
muscle
K
+ and Mg
2+ with
increased muscle Na
+ content in muscle
biopsies of either diuretic-treated CHF or
diuretic-treated
hypertensive patients in studies reported by
Dyckner et
al
4 5 6
(Table 1
). They also demonstrated impressive
corrections
of those muscle disturbances by superimposed
spironolactone
therapy, which blocks the kaliuretic and magnesiuretic
actions
of endogenous aldosterone. These
results teach us anew that
the K
+ (and
Mg
2+) loss in these patients is caused or
amplified
by the diuretic-induced high plasma renin and
angiotensin,
and thence plasma aldosterone,
levels occurring in CHF, which
are also induced in hypertensive
patients by their similar
renin-aldosterone system response
to the thiazide-induced sodium-volume
loss.
7 8 9
Accordingly, this kidney renin secretory response
in either CHF or
hypertension can be turned off by restoring
NaCl to improve volume and
flow, after which renin and aldosterone
fall dramatically,
but this treatment may restore hypertension,
and it is not safe to
apply in most CHF
patients.
7
Thus, in CHF, heart failure begins in the heart with its
failure as a pump,10 leading
to poor renal perfusion that causes the kidneys to release renin,
causing plasma renin-angiotensin to rise, which in turn
stimulates aldosterone release, which causes
Na+ retention (and edema), but if
aldosterone is high and if distal tubular sodium supply is
also too high, as occurs with diuretic
therapy,11 kaliuresis will
be sustained. Thus, in this setting of chronic diuretic
therapy, the volume depletion of thiazide or loop diuretics
causes renin and especially, thence,
aldosterone11 12
to increase, causing aldosterone to maintain chronic
kaliuresis. All of this is correctable by spironolactone blockade of
the aldosterone receptor. Long ago,
Davis10 demonstrated the
crucial role of aldosterone in dog heart failure. This
heart failure was dramatically corrected by total adrenalectomy, and
then it could be restored by aldosterone
replacement.10
Spironolactone does the same job in patients, albeit much less
dramatically or completely than would a surgical
adrenalectomy.
 |
Pathogenic Role of Thiazide-Induced
K+ Depletion in Hypertensive
Patients
|
|---|
Great clinical discoveries, like this one from the
RALES Trial,
3 revealing a
discrete pathogenic role for thiazide-induced
increased distal tubular
sodium supply enabling the endogenous
aldosterone excess to sustain
kaliuresis
11 and thereby
facilitating
the progression of CHF via depletion of myocardial and
vascular
K
+, are often first made in the
most egregious forms of a disease.
Accordingly, by extrapolating from
these findings in CHF, one
can recognize the very same long-term
thiazide-induced biochemical
pathophysiology (ie, high
aldosterone and low K
+ levels)
as
it occurs, not only in milder forms of heart failure but also
in
that vast population of diuretic-treated hypertensive patients
who are available. Thus, practically all thiazide-treated hypertensive
patients do exhibit lower plasma K
+ levels
than before their
thiazide therapy.
 |
Hypokalemia With Diuretic Use in
the SHEPS Trial
|
|---|
The recent subgroup analysis of the
Systolic Hypertension in
the Elderly (SHEPS)
trial
13 is directly relevant
to the latter
issue. A subgroup of this study, which used low-dose
chlorthalidone,
revealed that 7.2% of the treated hypertensive
patients exhibited
plasma K
+ values
<3.5.
3 Surprisingly, in
these diuretic-treated
hypokalemic patients, all of the
potential protection from
morbid cardiovascular
sequelae was lost.
13 This
loss of cardioprotection
occurred even though their blood pressures
remained reduced
below even the control group
(Table 1
). These findings resemble
earlier findings in the
MRFIT trial of a 2.4-fold greater risk
of sudden death associated with
higher-dose diuretic
therapy.
14 15
Moreover, these relationships are entirely in keeping with
earlier
studies by Cannon and
colleagues
8 9 that
showed
that urinary K
+ loss in
diuretic-treated patients, who have
either hypertension or
heart failure, is consistently closely
related to the height of
endogenous aldosterone secretion rates
(Figure 1
). They also showed that the kaliuresis of
diuretic
therapy does not occur in adrenalectomized patients,
thereby
proving that it is the aldosterone response to
diuretic-induced
sodium-volume depletion, not the
diuretic itself, that causes
the
kaliuresis.
9 Moreover, we
have learned that higher renin
and aldosterone levels in
response to diuretic treatment can
also reverse its
antihypertensive
effect.
12

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Figure 1. The ratio of urinary potassium to sodium during a 48-hour period of diuresis with ethacrynic acid or furosemide is plotted against the aldosterone secretion rate in a group of patients. Aldosterone secretion rates were determined on the day preceding diuresis. The urinary K+/Na+ ratio was directly related to the aldosterone secretion rate even though the patients had different diseases, received different amounts of dietary sodium, and differed markedly in their natriuretic responses to therapy. From Cannon PJ, Heinemann HO, Stason WB, Laragh JH. Circulation. 1965;31:58.
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 |
K+ Depletion Impairs
Cardiac Performance
|
|---|
We know that body K
+
depletion can occur without subnormally
reduced plasma
K
+ levels, so that what we are seeing in
hypokalemic
patients could be a tip of the iceberg situation. In this
regard,
thiazide diuretic treatment of hypertensives is
associated
with more ventricular
arrhythmias
16 17
and higher sudden
death
rates,
18 and these events
are avoided by spironolactone
treatment.
18 In this
context, too, it should be related that
most diuretic-based
long-term trials of hypertensive patients
have failed to show
significant protection from myocardial
infarction. This is in accord
with the fact that cardiovascular
protection
disappeared in the hypokalemic subgroup of the SHEPS
trial, even though
their blood pressures were reduced even
more than in the controls
(Table 2
).
3 Thus,

6% of diuretic-treated
patients are suffering from a second,
thiazide-induced, iatrogenic
disorder (ie,
K
+ depletion) that more than cancels out the
primary purpose of this treatment, to protect from later cardiac
morbidity. It follows that if 50 million hypertensive patients
took
thiazides regularly, this iatrogenic potassium deficiency
disorder
might afflict >3 million ambulatory hypertensives.
Two studies by Young and associates illustrate how mild
potassium depletion produces impressive impairment of cardiac function
in normal dogs and healthy human volunteers. In the dog
study,19 mild
K+ depletion reduced the maximal rate of
filling in response to volume expansion by 51%, and in the human
study, a mean K+ value of 3.5 reduced peak
flow velocity measured by echocardiography by
14%.20
 |
K+ Depletion Is a
Sine Qua Non for Full Expression of Experimental Hypertensive Vascular
Damage to Heart, Brain, and Kidney Vessels in Various Hypertensive
Models
|
|---|
In rat genetic hypertension (SHRsp rats),
diuretic or dietary
K
+ depletion
appears to be a prerequisite for the occurrence
of subsequent heart,
brain, and kidney vessel cardiac injury,
all of which are accordingly
corrected or arrested by increasing
the dietary
K
+ intake or, even better, by treatment with
spironolactone.
21 22
The converse of these relationships is also true. In a
human
trial
23 and in our study of
stroke-prone hypertensive
animals,
24 high
K
+ diets were associated with stroke
protection
in humans. In the SHRsp rats, K
+
repletion was associated with
impressive reductions in their renin
levels and with arrest
of vascular pathology in the heart, brain, and
kidneys, along
with the stroke protection (see
Figures 2
and 3
).

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Figure 2. Graph showing plasma renin activity (PRA) values obtained in the 3 dietary groups of stroke-prone spontaneously hypertensive rats at 4-week intervals. Open circles indicate regular diet (n=7, week 0; n=6, week 4; n=6, week 8; n=13, week 12); open squares, low-NaCl/low potassium (n=8, week 4; n=13, week 8; n=11, week 12); and open triangles, high-NaCl/low-potassium diet (n=9, week 4; n=10, week 8; n=14, week 12). Note that plasma renin "escapes" from suppression by salt in the group destined for vascular injury and stroke. From Volpe M, Camargo MJF, Mueller FB, Campbell WG Jr, Sealey JE, Pecker MS, Sosa RE, Laragh JH. Hypertension. 1990;15:318326.
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Figure 3. Scatterplot showing distribution of renal vascular lesions (expressed as renal vascular damage index) according to plasma renin activity (PRA) (ng/mL/h) values in 3 groups at 12 weeks of diet. The animals with suppressed renin values (solid circles) exhibit much less stroke and vascular disease. From Volpe M, Camargo MJF, Mueller FB, Campbell WG Jr, Sealey JE, Pecker MS, Sosa RE, Laragh JH. Hypertension. 1990;15:318326.
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Several biochemical or cellular mechanisms have been
implicated to explain how K+ depletion
promotes cardiac and vascular injury, which is correctable by
K+ repletion. Thus, increases in
extracellular K+ levels within the
physiological range in 1-mmol/L increments from 3
to 7 mmol/L causes significant decreases in free radical formation
from vascular endothelial cells, smooth muscle
proliferation, and induced thrombus
formation.24 With
verification, these pathways could prove to be relevant clinical
targets for pharmacological control.
In summary, thiazide-induced K+
and/or Mg2+ depletion in hypertension and in
CHF is probably not benign. It impairs cardiac function, and it creates
or enhances the risk of morbid cardiac and vascular events. In
hypertensive patients, these effects of K+
depletion more than cancel the cardiovascular
protective value afforded by the concurrent sizable thiazide-induced
reductions in blood pressure. Moreover, increasing dietary
K+ without also blocking
endogenously high aldosterone levels probably
has little corrective value in diuretic-treated
patients,25 because unless
aldosterone is also blocked, the fed
K+ is directed into the urine by the
endogenous aldosterone
excess8 9 induced
in both CHF and hypertensive patients by thiazide diuretic
activation of the renin
system8 9 and by
the thiazide action to divert more sodium to the distal nephron.
Accordingly, short of stopping the thiazide therapy, the value of
specific aldosterone receptor antagonists, such
as spironolactone, for treating such patients with hypertension or
heart failure appears to be unique for dealing with this iatrogenic
predicament. Spironolactone treatment per se, that is, as a replacement
for thiazide therapy, could well prove to be an even simpler solution.
Newer analogues with possibly even fewer endocrine side effects will be
welcome.
Received November 2, 2000;
first decision December 13, 2000;
accepted December 13, 2000.
 |
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