Download Acute Effects of Cardiac Glycosides on Aldosterone Secretion in

Acute Effects of Cardiac Glycosides on
Aldosterone Secretion in Dogs with
Hyperaldosteronism Secondary to
Chronic Right Heart Failure
By Charles C. J. Carpenter, M.D., James O. Davis, Ph.D., M.D.,
Charles R. Wallace, D.V.M., and William F. Hamilton, Ph.D.
With the surgical assistance of Alfred Casper
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• Since the report of Deming and Lnetscher 1
that patients with congestive heart failure
excrete abnormally large amounts of a saltretaining substance in the urine, considerable
attention has been focused on the role of
aldosterone in congestive heart failure. Although there is a large body of evidence2 to
demonstrate that excessive aldosterone secrelioji plays an important role in the marked
Xa retention in congestive heart failure, some
investigators have failed to find increased
secretion of this mineralocorticoid in clinical"' 4 and in experimental1"' heart failure. The
mechanisms leading to excessive aldosteroue
production in cardiac failure and the mechanisms by which aldosterone secretion is decreased as cardiac compensation is achieved
have been the subject of much recent investigation.- 0 9 Although cardiac glycosides have
been reported to reduce adrenal blood flow
and aldosterone secretion in normal dogs,10
the possibility must be strongly considered
that improved cardiovascular function leads
to the decrease in aldosterone production
after digitalization in heart failure. 11 ' 12
Tlie present study was designed with a dual
purpose: first, to make a definitive evaluation
of' the aldosterone secretion rates in animals
with experimental congestive heart failure,
and secondly, to study the effect of rapid digitalization on the aldosterone secretion rates
of dogs in frank congestive heart failure.
From the Section on Experimental Cardiovascular
Disease, Laboratory of Kidney and Electrolyte
Metabolism, National Heart Institute, Bethesda,
Maryland, and the Department of Physiology, Medical
College of Georgia, Augusta, Georgia.
Received for publication August 4, 19G1.
178
Methods
Experimental right heart failure was produced as described below in eight mongrel clogs,
weighing 15 to 20 Kg. In addition, studies were
performed on one eight-year-old hunting dog with
spontaneously occurring congestive heart failure.
The eight dogs with experimental congestive heart
failure were kept in metabolic cages and maintained on a synthetic diet containing 60 mEq. of
Xa and IS mEq. of K per day for at least two
weeks prior to the acute studies. The dog with
spontaneously occurring heart failure received a
diet containing approximately SO mEq. of Xa and
80 mEq. of K per day during the week preceding
the acute studies. Urinary Xa, excretion was determined by flame photometry. Right atria] pressures
were measured at frequent intervals with a water
manometer attached to a polyethylene catheter
which was inserted via the femoral vein into the
right atrium. All pressures were referred to a level
6 cm. above the table surface. Aldosterone and
corticosterone secretion rates were determined by a
method described previously, using the double
isotope derivative technique of Klima.n and
Peterson.14
In six dogs, right heart failure was produced
by progressive pulmonic stenosis by the method
of Davis, Hyatt, and Howell.15 A nylon ligature
was placed around the main pulmonary arteiy
trunk, and then tightened in two or three stages
at one-week intervals until signs of right-sided
congestive heart failure ensued. Three to five days
after the final tightening of the pulmonary artery
ligature, the right adrenolumbar vein was cummin ted under light Xa pentobarbital anesthesia ; no
fixed dose of anesthesia was given because dogs
with heart failure vary markedly in their response
to anesthetics. Two groups of control samples of
adrenal venous blood were then collected at 30- to
50-niinute intervals. All blood removed throughout
this study was immediately replaced by homologous
transfusion. Following control collections, each of
the clogs was given 1.25 to 1.50 mg. of digoxin intravenously. Samples of adrenal effluent were then
collected at 30- to 60-minnte intervals for the threeCirculation Research, Volume X, February 1962
179
CARDIAC GLYCOSIDES ON ALDOSTERONE SECRETION
TABLE 1
Average Values for the Effects of Uigoxin on Steroid Secretion mid Cardiovascular
Function in Dogs with Congestive Heart Failure Secondary to Controlled Progressive
Pnlmnnic Stenosis'"
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Control t
1 liour nftcr digoxint
90 to 180 minutes
:ifter digoxint
1 hour after
pulmonary artery
ligature retightenedt
Xornial dogs
stressed by
hipsirotoiny (N=2(>)
Mean
arterial
pressure
(mm. Hg)
Inferior
vena cava
pressure
(mm. H-O)
Aldosterone
secretion
(ins./min.)
Corticosterone
secretion
Adrenal
blood flow
(ml./min.)
0.094
O.OG.'!
0.03S
2.25
2.S0
2.29
2.14
110
1.92
122
in
1.70
120
102
0.092
2.09
1.85
SI
1ST
0.024
±0.017
2.:i4
±0.84
(/iff./min.)
*A more detailed form of this table lias been deposited as document number 684S
with the ADI Auxiliary Publications Project, Photoduplication Service, Library of
Congress, Washington 25, 1"). C. A copy may be secured by citing the document number
and by remitting $1.25 for photoprints, or $1.25 for 35 mm. microfilm. Advance payment
is required. Make checks or money orders payable to: Chief, Pliotoduplication Service,
Library of Congress.
lAverages include only dogs 1 through 4, since dog 5 expired shortly after further
constriction of the pulmonary artery, and no postdigoxin collections were obtained in dog 6.
hour period following' the di'^oxin injection. Following1 the three-hour collection, in five of the six
dogs the pulmonary artery ligature was tightened
until the mean right ntrinl pressure (RAP) exceeded ISO nun. of water. Samples of adrenal venous
blood were then collected one hour after pulmonary
artery reconstruction. During- each acute experiment, the arterial pressure was measured with a
Stathnm strain gauge atta.ehed to an indwelling
abdominal aortic catheter and was recorded continuously on a Sanborn apparatus. Right atrial
pressure was determined by an indwelling polyethylene catheter connected to a, water manometer.
In two dogs, heart failure was produced by a.
modification"'of the technique described by Barger
et ill.17 Tricuspid insufficiency was produced surgically by cutting the chordae tendineae of the
tricuspid valve. Two to seven months after this
procedure, a nylon ligature was placed about the
main pulmonary artery of each of these dogs. No
subsequent tightening of the pulmonary artery
ligature was required to produce right heart
failure, characterized by sustained elevation of
RAP and almost complete Xa retention, in either
of these animals. Three to five days after the
pulmonary artery ligature had been placed, adrenal
effluent was collected before and after digoxin
administration, as described above.
One dog, an eight-year-old, 20-Kg. pointer, had
collapsed while hunting and his disorder had been
diagnosed by his owner, a physician, as being conCirenlation Research. Volume X, February 1962
gestive heart failure. This animal was then maintained on digitoxin and a variety of diuretics
over the following three months; despite therapy,
the dog continued rapidly to accumulate ascitic
fluid and required paraeentesis at two-weelc intervals during this time. Digitoxin was discontinued
one month prior to the present studies, and
chlorothiazide was the only medication which the
animal received during this period. Eight atrial,
right ventricular, and pulmonary wedge pressures
were determined prior to adrenal vein cannulation
via standard catheterization technique. The right
adrenolumbar vein was then enminiated under Na
pentobarbital anesthesia, and four control collections of adrenal venous blood were obtained over
a 90-minute period. Following control collections,
the animal was given a total of 1.0 ing. of ouabain
intravenously over a 30-minute period. Two more
samples of adrenal effluent were collected 60 to
80 minutes after the beginning of the ouabain
injection.
Results
CONTROL HEMODYNAMIC STUDIES IN
EXPERIMENTAL AND NATURALLY
OCCURRING RIGHT HEART FAILURE
In the six animals in which controlled progressive pulmonic stenosis was produced, all
dogs appeared in excellent health and none
developed signs of right ventricular failure
following the initial placement of the pulino-
180
CARPENTER, DAVIS, WALLACE, HAMILTON
TABLE 2
Dogs icith Right Heart
Pulmonic Stenosis
Dog
7
8
Failure
Time (min.)
Secondary
to Combined
Aldosterone Corticosterone
secretion
secretion
(jug./min.)
(tig./min.)
Tricuspid
Insufficiency
Adrenal
blood flow
(ml./min.)
Mean
arterial
press"re
(mm. Hg)
pressure
(mm. H J O )
Inferior
vena cava
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0
15
30
Digoxin (1.35 mg., I.V.)
40
70
100
145
0.153
0.180
0.226
3.72
4.22
4.22
1.80
2.33
1.52
75
82
75
190
188
390
0.295
0.292
0.247
5.80
3.13
3.67
2.33
0.90
0.90
82
83
87
195
192
195
0
24
30
Digoxin (1.25 mg., I.V.)
40
100
110
150
156
162
0.100
0.100
0.099
2.02
1.61
1.72
1.96
1.63
1.68
122
133
132
208
206
209
0.050
0.074
0.090
0.100
0.096
1.24
1.61
1.43
1.58
1.42
1.87
2.01
1.71
1.82
1.93
136
3 35
136
.136
136
212
218
218
nary artery ligature. After each successive
tightening of the pulmonary artery ligature,
an increment in venous pressure was noted.
After the pulmonary artery ligature had been
tightened two (three dogs) or three (three
dogs) times, right ventricular failure occurred, manifested by a sustained elevation
of EAP above 150 mm. of water and virtually
complete Na retention. In no animal did the
urinary Na excretion exceed 5 niBq. during
the 24-hour period prior to adrenolumbar vein
cannulation. After induction of anesthesia
and adrenolumbar vein cannulation, mean
arterial pressures ranged from 98 to 122 mm.
IIg, and venous pressures varied from 144 to
190 mm. of water in the six animals (table 1).
In both of the dogs in which combined tricuspid insufficiency and pulmonic stenosis
were produced, a marked increase in right
atrial pressure (200 to 220 mm. water) with
evidence of severe tricuspid regurgitation
occurred following cutting of the chordae tendineae. Both animals developed ascites following this procedure, but neither exhibited
the persistent virtually complete Na retention
which is characteristic of the early phase of
and
2.18
218
experimental congestive heart failure.30 However, when the nylon ligature was placed
about the pulmonary artery, each animal developed severe congestive heart failure, manifested by a further increment in RAP and
virtually complete Na retention. The slight
constriction produced by the padding around
the ligature was adequate to cause severe cardiac decompensation in these animals with
pre-existing tricuspid insufficiency. After induction of anesthesia and adrenolumbar vein
cannulation, mean arterial pressures ranged
from 75 to 133 and venous pressures varied
from 188 to 209 in the two animals (table 2).
In the dog with naturally occurring congestive heart failure, preoperative studies showed
atrial fibrillation with a ventricular rate of
200 per minute, massive cardiomegaly (total
heart volume by x-ray was 52 cc./Kg., or three
times normal) ,18 and a mean frontal plane
electroeardiographic axis of +90 degrees.
Catheterization revealed a mean right atrial
pressure of 182 mm. of water, a right ventricular pressure of 47/8 mm. Hg, a mean
pulmonary artery pressure of 32 with extremes of 47/25 mm. Hg, and a mean pulmoCirculation Research, Volume X. February 196S
181
OABDIAO GLYCOSIDES ON ALDOSTERONE SECRETION
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nary wedge pressure of 14 mm. Hg. Subsequent pathological examination of this dog
revealed generalized cardiomegaly, scarring
of both the tricuspid and the mitral valves,
and the presence of 24 heart worms (dirofilaria immitis) in the right ventricle and the
main trunk of the pulmonary artery. The
high pulmonary wedge and pulmonary arterial pressures, together with the pathological
finding of a scarred mitral valve, suggest that
right ventricular failure occurred as a result
of pulmonary hypertension secondary to mitral valve disease; the possibility must also
be considered that dirofilaria immitis infestation had resulted in pulmonary endarteritis
with consequent pulmonary hypertension and
cor pulmonale.10
ALDOSTERONE SECRETION I N TXPERIMEVT4L « w n NAT"RALLY OCCURRING
RIGHT HEART FAILURE
In each of the six dogs with controlled progressive pulmonic stenosis, the control aldosterone secretion rate was clearly elevated
above the average value for normal dogs (fig.
1, table 1). The average value for the group
of six dogs with heart, failure secondary to
controlled pulmonic stenosis was 0.089 p.g./
min., which represents a 267 per cent increase
over the average secretion rate of 0.024 ±
0.017 rg./min. observed previously0 in normal
dogs during use of identical experimental and
chemical methods. This difference is highly
significant statistically (t = 3.85; P < 0.01).
In the dogs with combined tricuspid insufficiency and pulmonic stenosis (table 2), the
control aldosterone secretion rates were likewise markedly elevated. In dog 7, which had
aseites for seven months prior to the steroid
secretion studies, the average control aldosterone secretion rate of 0.186 fxg./min. was
twice as great as the mean control value for
the remainder of the dogs in the present
study; while in dog 8, which had been forming
aseites for six weeks prior to the acute studies, the aldosterone secretion rate approximated that of the animals with right heart
failure secondary to controlled pulmonic stenosis. In the dog with naturally occurring
heart failure, the four control values for
Circulation Research, Volume X, February 198t
«
22
20
•
.18
.16
.14
•
.12
a •
1
10
•
08
#
.06
•
" • • • *
•
i•
04
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I 2 3 4 5 6 7 8 9 10
NORMAL DOGS
I 2 3 4 56
76
9
COM ROUE!
puiaiiic STENOSIS
TMUSPID
miimui
IISUFFICIEIO OCCIIRIK
>ND PMtNIC
STWSIS
DOGS WITH RIGHT HEART FAILURE
FIGURE 1
Aldosterone secretion rates in dogs with experimental and naturally occurring right heart failure
compared to aldosterone output in normal dogs.
aldosterone output were also very high (fig.
2), and the mean value of 0.085 jug./min. was
essentially the same as that observed in the
group of dogs with right heart failure secondary to controlled pulmonic stenosis.
HEMODYNAMIC EFFECTS OF
DIGITALIZHrON I N DOGS WITH
RIGHT HEART FAILURE
In one of the animals with controlled progressive pulmonic stenosis, ventricular fibrillation occurred shortly after the injection of
1.5 mg. of digoxin. In each of the remaining
five dogs with pulmonic stenosis, a definite
increase in arterial pressure and a marked
decrease in right atrial pressure occurred
following digoxin administration. The increase in arterial pressure and the decrease
in RAP were observed within 10 minutes
after digitalization. The mean arterial pressure increased sharplj' during the first 15
minutes after the glycoside injection, reached
a maximum level (from 124 to 135 mm. of
Hg) between 60 and 90 minutes after digoxin
administration, and persisted at the higher
level until further pulmonary artery constriction was effected (table 1, fig. 3). The RAP
decreased progressively during the first hour
after the digoxin injection reached a minimum level (from 96 to 110 mm. water) between 60 and 90 minutes after digitalization,
T82
CARPENTER, DAVIS, WALLACE, HAMILTON
age control value of S8 mm. ITg to a maximum of 110 mm. Hg, and a marked fall in
RAF from a control level of 140 mm. water
to a minimum of 38 mm. Avater. An increase
in arterial pressure and a decrease in RAP
wore observed within five minutes after the
beginning of the ouabain injection; these
changes were maximal 40 to 50 minutes after
the onset of glycoside administration (fig. 2).
ALDOSTERONE SECRETION FOLLOWING
ADMINISTRATION OF DIGOXIN OR
OUABAIN TO DOGS WITH RIGHT
HEART FAILURE
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FIGURE 2
Effects of uuabahi injection on aldosterone ami
corticosterone secretion rates, adrenal blood floic,
inferior vena cava pressure, and mean arterial
pressure in a clop icith naturally occurring right
It art failure.
and remained at this level until further constriction of the pulmonary artery ligature
was performed (table 1, fig. 3). Following
subsequent tightening of the pulmonary
artery ligature, an immediate fall in arterial
pressure (to levels of 82 to 96 mm. of Hg)
and a marked rise in venous pressure (to 175
to 206 mm. of water) occurred in all five
dogs. In four of the five dogs (dogs 1 through
4 of table 1) the arterial and venous pressures stabilized at the new levels, with very
little variation during the remaining 90 minutes o£ observation. In the fifth dog, the
arterial pressure showed a progressive decline
after the final tightening of the pulmonary
artery ligature, and this animal expired before further collections of adrenal venous
blood could be made.
During the two-hour period following administration of digoxin to the dogs with combined tricuspid insufficiency and pulmonic stenosis, slight increases in EAP were observed
and minimal increases in mean arterial pressure could be detected on the pressure tracings in both animals (table 2).
In the dog Avith naturally occurring heart
failure, administration of ouabain led to a
rise in mean arterial pressure from an aver-
In each of the dogs Avith controlled progressive pulmonie stenosis in -which postdigoxin studies Avere completed, a decrease
in aldosterone output occurred Avithin 90
minutes after digitalization (table 1, fig. 3).
Minimum aldosterone secretion rates were
observed between 90 and 180 minutes after
the digoxin injection; the average aldosterone
production for this period was 0.038 /.tg./
mill., representing a 55 per cent decrease
from the control period. After further constriction of the pulmonary artery ligature,
aldosterone output increased sharply in each
of the four dogs in -which collections Avere
made (table 3, fig. 3). The average aldosterone secretion rate one hour after the additional tightening of the pulmonary artery
ligature was 0.092 ^g./min., representing a
130 per cent increase OA'er the preceding postdigoxin period (table 1, fig. 3). Control corticosterone secretion rates Avere at the elevated
levels characteristic of dogs stressed by laparotomy and did not vary significantly during any phase of the experiment (fable 1).
Only minor variations in adrenal blood flow
occurred during the course of individual experiments. Although the mean adrenal blood
floAv AA'as slightly decreased during the period
in Avhich the lowest aldosterone secretion
rates Avere observed, it is significant that no
diminution in adrenal blood flow occurred
during this period in dog 4, the animal in
which the most marked decrease in aldosterone output Avas seen following digitalization
(table 1).
In the two dogs with combined tricuspid
insufficiency and pulmonic stenosis, a slight
Circulation Research, Volume X, February 1902
183
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Discussion
The present experimental data demonstrate
that hypersecretion of aldosterone is a consistent finding in dogs with experimental
congestive heart failure secondary to controlled progressive pulmonic stenosis or to
combined tricuspid insufficiency and pulmonic stenosis, and is also present in naturally occurring congestive heart failure in
the dog. It should be pointed out that in this
series of experiments, Na retention was virtually complete in all animals with heart
failure at the time the aldosterone secretion
rates were determined. These results confirm
the earlier studies,20 in which the aldosterone
secretion by dogs with experimental right
heart failure was measured by a biological
assay technique. In the present study, the
control aldosterone secretion rate in one of
the dogs with combined tricuspid insufficiency
aud pulmonic stenosis was considerably
Circulation Research, Volume X, February 1962
EAN ARTERIAL
'
—
O
mil
CAVA PRESSUR:
3
ii
"
1
*
* " 100
\ .
I 75
1
-
INFERIOR
increase (dog 7) and a slight decrease (dog
8) in aldosterone output occurred one hour
after digoxin injection, but the 100-miivute
postdigoxiu values were essentially the same
as the control values in both animals (table
2). Corticosterone secretion, rates remained
at the high level characteristic of: normal
dogs stressed by laparotoiny throughout both
experiments. Adrenal blood flow remained
essentially constant throughout all periods in
dog 8, but showed a significant (50 per cent)
decrease 60 to 100 minutes after digoxin injection in dog 7; it is noteworthy that no
change in aldosterone output occurred concomitant with the marked diminution in
adrenal blood flow in dog 7.
Ouabain administration to the dog with
naturally occurring heart failure led to a
marked fall in aldosterone secretion rate to
25 per cent of the control value at 55 minutes
and a further decrease to 17 per cent of the
control value at 75 minutes after the onset
of the glycoside injection (fig. 2). Corticosterone secretion remained at the elevated
control level throughout the experiment, despite a 50 per cent fall in adrenal blood
flow following the glycoside administration
(fig- 2).
.000 PRESSUR
CARDIAC GLYCOSIDES ON ALDOSTERONE SECRETION
"a
*
8
£
20
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OIGOXIN
1.25 MG.I.V.
100
1
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200
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PULHONARY ARTERY
LIGATURE TIGHTENED
I
100
MINUTES
FIGURE 3
Effects of udmillintrution of digoxin and subsequent further constriction of the main pulmonary
artery on aldosterone secretion rate, inferior vena
cava pressure, and mean arterial pressure in a dog
with experimental right heart failure secondary to
controlled progressive pulmonic stenosis.
higher than the secretion rates in the
other seven dogs with experimental right
heart failure. This finding probably reflects
the fact that this animal had been forming
ascites for a longer period of time (seven
months compared with 3 to 42 days for the
other seven dogs) prior to the time of the
acute studies, and consequently had more
marked hypertrophy of the adrenal zona
glomerulosa with a resultant greater capacity
for aldosterone production. The observation
that aldosterone output may increase with
the duration of the clinical course of ascites
has previously been made in regard to dogs
with thoracic inferior vena cava constriction.21
The failure of Driscol and associates1"' to
find increased aldosterone output in dogs
with controlled progressive pulmonic stenosis
apparently resulted from the absence of cardiac failure in their animals at the time that
adrenal effluent was collected; this explanation is suggested by the fact that the venous
pressures in their experimental animals
ranged from 63 to 112 mm. of saline. In the
present experiment, as in earlier studies,15
no animal with a right atrial pressure less
than 140 mm. of water exhibited the virtually
complete Na retention Avhich is characteristic
184
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of frank congestive heart failure. As pointed
out previously,15 a stable state of cardiovascular hemodynamics is rarely observed following the production of right ventricular
failure by progressive pulmonic stenosis. It
appears likely that, in all of the six dogs reported by Driscol et al.,5 cardiac compensation had occurred prior to the time of adrenolumbar vein cannulation; no measurements
of Na excretion were reported by these investigators.
Muller and associates3 reported normal
rates of urinary aldosterone excretion in five
of six patients with congestive heart failure.
However, four of these five patients exhibited
normal Na balance at the time the aldosterone
excretion studies were performed. Patients
with congestive heart failure and edema may,
at times, have normal urinary Na excretion;
at some point in the course of congestive
heart failure, Na balance may occur at a new
steady state, during which the volume of
extracellular fluid, although markedly increased, remains fairly constant for several
days or weeks.12'10 Increased secretion of
aldosterone would not be expeced at a time
when such a patient was in Na balance. A
physiological basis for the new steady state,
in which the patient with cardiac decompensation exhibits Na balance and a normal rate
of aldosterone production, was suggested by
Davis and Ball.22 These investigators found
that application of a body cast to dogs with
virtually complete Na retention secondary to
thoracic caval constriction invariably resulted
in decreased urinary aldosterone excretion
and increased Na excretion; they then postulated that aldosterone secretion was decreased
as the result of an increase in intra-abdominal pressure which inhibited filtration of
fluid into the peritoneal cavity. It appears
reasonable to extend this explanation to patients with congestive heart failure and
ascites; thus, when edema fluid accumulates
in cardiac patients to the extent that increased tissue pressure prevents further filtration of fluid, a fall in aldosterone secretion
and an increase in Na excretion may ensue.
This sequence of events might account for
CARPENTER, DAVIS, WALLACE, HAMILTON
the finding of a normal aldosterone secretion
rate in one out of two patients with congestive
heart failure reported by Ulick, Laragh, and
Lieberman.4 Available evidence suggests that
aldosterone production is consistently increased during periods of Na retention in patients12- 23 or animals20 with congestive heart
failure.
In the present experimental dogs with
right heart failure secondary to controlled
progressive pulmonic stenosis, improvement
in cardiovascular hemodynamics as manifest
by a decrease in RAP was observed Avithin 10
to 15 minutes after digoxin administration;
the hemodynamie response was similar to
that reported previously11 in the same animal
preparation except that a greater increase in
arterial pressure was observed in the present
study. In every animal, marked improvement
in cardiovascular function occurred before
any change in aldosterone production was
observed. One hour after administration of
digoxin, at a time when striking hemodynamie
improvement was manifest in all animals, the
decrease in aldosterone secretion was insignificant in two dogs, moderate in one dog,
and maximal in only two of the five dogs. In
three of the five dogs, the maximum decrease
in aldosterone output did not occur until approximately two hours after the initial improvement in cardiovascular hemodynamics
had been observed. Similar results were obtained from the dog with naturally occurring
congestive heart failure. Although definite
hemodynamie improvement occurred within
five minutes after the ouabain injection was
begun, minimal aldosterone output was not
observed until 80 minutes after the glyeoside
injection.
In the two dogs with combined tricuspid
insufficiency and pulmonic stenosis, no improvement in cardiovascular function was
observed following digitalization. The increase in RAP following digitalization apparently resulted from more forceful contraction
of the right ventricle in the presence of a
fixed degree of pulmonic stenosis and in the
absence of the tricuspid valve. In marked
contrast to the findings in the dogs with pure
Circulation Research. Volumo X, February 2968
185
CARDIAC GLYCOSIDES ON ALDOSTERONE SECRETION
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pulmonic stenosis, digoxin administration
had NO effect on aldosterone secretion in
either of the dogs with combined tricuspid
insufficiency and pulmonic stenosis.
In the present study, a decrease in aldosterone output was observed following digitalization only in those animals in which the
glycoside administration resulted in a definite improvement in hemodynamic function,
and in these animals, the maximal decrease
in aldosterone output did not occur until one
to two hours after the changes in cardiovascular hemodynamics had been initiated. Furthermore, a subsequent marked increase in
aldosterone secretion was invariably observed
in the digitalized dogs in which cardiac decompensation was again produced by further
constriction of the pulmonary artery ligatures. These results in dogs with right heart,
failure appear to differ from the findings of
Goinall and Slierrod10 which suggest that
cardiac glycosides may act directly on the
adrenal cortex to reduce aldosterone secretion
in normal dogs. The probable explanation
for the findings of these investigators is that
I he decrease in aldosterone output in their
experiments resulted from the very marked
fall in adrenal blood flow following the administration of acetylstrophanthidin to normal animals.
The question remains as to the specific
hemodynamic alteration which leads to an increase in aldosterone secretion in right heart
failure; and conversely, what functional
change results in a decrease in aldosterone
secretion as cardiac compensation is restored
by cardiac glycosides. Since it has been
firmly established that an aldosterone stimulating hormone (ASH) is produced by the
kidney,-4--r' and recent evidence suggests
that ASH is either renin or a renin-like substance,"" it might be suggested that aldosterone secretion is regulated by alterations in
renal blood flow. However, the recent finding-7 (and personal observations) that aldosterone secretion is within normal limits in
the majority of dogs in the acute phase of
benign experimental renal hypertension, in
which the renal blood flow is almost invariCirculation Research, Volume X, February 1962
ably reduced,-"- -!l indicates that a decrease
in renal blood flow alone does not provide the
stimulus necessary to increase aldosterone
output. The observation that both hyperplasia
and hypergranulation of the renal juxtaglomerular (JG) cells occur in animals with
hyperaldosteronism secondary to thoracic
caval constriction or to Na depletion30-31
points to the JG cells as the site of origin of
ASH. These findings are consistent with the
hypothesis advanced by Tobian32 that the JG
cells, located in the media of the renal afferent arteriole, act as sensitive receptors which
respond to diminished stretch in the afferent
arteriolar wall by an increase in secretion of
renin. The possibility is thus suggested thai
decreases in pressure or volume in the renal
afferent arteriole, not necessarily dependent
upon changes in renal blood flow, may result
in an increase in the rate of release of ASH
by the JG cells, and thus lead to an increased
aldosterone output. The decrease in aldosterone production observed after the administration of cardiac glycosides to animals with
right heart failure could then result from
increased pressure or volume in the renal
afferent, arteriole secondary to the improvement in hemodynamic function.
Summary
A marked elevation in the rate of aldosterone secretion was observed in eight dogs with
experimental congestive heart failure secondary either to controlled progressive pulmonic
stenosis or to combined tricuspid insufficiency
and pulmonic stenosis, and in one dog with
spontaneously occurring congestive heart
failure. In the dogs with pulmonic stenosis,
digitalization with digoxin resulted in improvement in cardiovascular function, and
subsequent further constriction of the pulmonary artery again led to right ventricular
failure; in each animal aldosterone output
decreased within 90 minutes after digitalization, and increased markedly within one hour
after further constriction of the pulmonary
artery. In the dog with naturally occurring
congestive heart failure, ouabain administration caused a similar striking hemodynamir
186
CARPENTER, DAVIS, WALLACE, HAMILTON
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improvement, and a marked reduction in
aldosterone secretion was observed within 55
minutes after the glycoside was given. In the
dogs with combined tricuspid insufficiency
and pulmonic stenosis, no hemodynamic improvement occurred after digitalization; in
these animals, the aldosterone secretion rate
did not change significantly during the twohour period following the digoxin injection.
These data demonstrate that changes in the
rate of aldosterone secretion in dogs with
right heart failure were closely correlated
with alterations in cardiovascular function;
in these animals, hemodynainie improvement
consistently led to decreased aldosterone production, and subsequent worsening of cardiovascular function resulted in increased aldosterone output.
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Acute Effects of Cardiac Glycosides on Aldosterone Secretion in Dogs with
Hyperaldosteronism Secondary to Chronic Right Heart Failure
Charles C. J. Carpenter, James O. Davis, Charles R. Wallace and William F. Hamilton
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Circ Res. 1962;10:178-187
doi: 10.1161/01.RES.10.2.178
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