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INCREASEDALDOSTERONESECRETIONFOLLOWINGACUTECONSTRICTIONOF THE
INFERIOR VENACAVA'
By JAMES 0. DAVIS, BERNARDKLIMAN, NICHOLAS A.
YANKOPOULOS,ANDRALPHE. PETERSONWITH THE SURGICAL ASSISTANCE OF
ALFREDCASPER
(From the Section on Experimental Cardiovascular Disease,
Laboratory of Kidney and Elec-trolyte Metabolism, National Heart
Institute, and the Institute of Arthritis and
Metabolic Disease, Bethesda, Md.)
(Submitted for publication June 6, 1958; accepted August 25,
1958)
Aldosterone secretion (1) and aldosterone ex-cretion in urine
(2) are markedly elevated in dogswith chronic right heart failure
and in dogs withchronic ascites secondary to thoracic caval
con-striction. It was suggested that the adrenal cor-tex is
stimulated to secrete aldosterone by factorsresulting from a high
venous pressure and theconsequent loss of fluid and electrolytes
fromthe blood stream. The precise nature of thesefactors remains to
be defined.
The purpose of the present study was threefold:1) to determine
the effects of acute caval con-striction on aldosterone secretion
in an attemptto develop an acute experimental preparation
forevaluation of factors influencing aldosterone secre-tion; 2) to
evaluate the effect of changes in vascu-lar volume on aldosterone
output; and 3) to applya radioisotope derivative technique
developed bytwo of us (B. K. and R. E. P.) for the determina-tion
of aldosterone and corticosterone in 2 ml.samples of adrenal vein
plasma.
METHODS
The material for this study consisted of 11 mongreldogs. Three
types of experiments were conducted. InExperiment I (four dogs),
the effects of acute constric-tion of the thoracic inferior vena
cava were studied. InExperiment II (four dogs), the inferior vena
cava wasconstricted immediately above the entrance of the
adreno-lumbar veins. Experiment III (three dogs) was per-formed to
ascertain the influence of thoracic caval con-striction while an
intravenous infusion of dextran wasadministered to maintain or to
increase plasma volume.Dextran (Expandex®) was injected as a 6 per
cent solu-tion in isotonic sodium and potassium chloride;
theosmolality of the solution was 290 mOsm.
The design of the study consisted of observations dur-ing a
control period of one hour and for three to four
1 Reported at the spring meeting (1958) of the Ameri-can
Physiological Society.
hours following caval constriction. Three series of con-trol
observations were made at 30 minute intervals.The experimental
alteration, which consisted of cavalconstriction alone or with an
accompanying dextran in-fusion, was then introduced and six to
eight groups ofdeterminations were made at similar intervals during
theexperimental period.
In all experiments a nylon ligature was placed aroundthe
inferior vena cava before control observations weremade. The
ligature was extended through a silver can-nula to the outside of
the chest wall so that constrictioncould be accomplished later
without opening the chestbetween the control and experimental
periods. The ani-mals received 100 per cent oxygen through an
endo-tracheal tube attached to a pneophore at a pressure of 15cm.
water. Adrenal vein blood was collected and meas-urements of
adrenal blood flow were made by a tech-nique described previously
(1). Ten ml. of adrenal veinblood and 10 to 14 ml. of peripheral
blood were removedfor each group of analyses; donor blood was given
im-mediately to replace the blood withdrawn. Arterial andvenous
pressures were measured in the abdominal aortaand inferior vena
cava, respectively, by continuous re-cording with Statham strain
gages and a Sanborn re-cording system. Venous pressure was referred
to a level6 cm. above the table surface. Dextran was given bymeans
of a constant infusion pump into an externaljugular vein.
Aldosterone and corticosterone were determined in 2ml. samples
of adrenal vein plasma by a double isotopederivative technique (3).
Plasma was extracted withmethylene chloride and the extract dried
and acetylatedwith a 10 per cent solution of tritium-labeled acetic
an-hydride in benzene. Measured amounts of authentic al-dosterone
diacetate-C1' and corticosterone monoacetate-C14were added and the
double labeled steroids separated andpurified by paper
chromatography. After two chroma-tographies, the samples were
treated with 0.5 per centchromic acid in glacial acetic acid. A
final chromatog-raphy was used to separate the aldosterone and
corti-costerone acetates from other labeled materials. Thetritium
and carbon-14 content of the purified steroids wasdetermined with a
liquid scintillation spectrometer. Theratio of tritium to carbon-14
approached a constant valueafter the third chromatography. The
quantities of aldo-sterone and corticosterone present in the sample
of plasma
1783
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J. 0. DAVIS, B. KLIMAN, N. A. YANKOPOULOS,AND R. E. PETERSON
were calculated from the amount of carbon-14 lost dur-ing
chromatography, the yield of tritium radioactivityand the specific
activity of the tritium-labeled acetic an-hydride. Recoveries for
aldosterone yielded values of 95to 100 per cent. Porter-Silber
reacting chromagens inadrenal vein plasma were measured by a
modification (4)of the method of Silber and Porter (5). Studies
(6)have demonstrated that 60 to 70 per cent of these chro-magens is
hydrocortisone and 10 to 20 per cent is 11-desoxyhydrocortisone
(Compound S). The rates of se-cretion of adrenal steroids were
calculated from the con-centrations in adrenal vein plasma 2 and
the rate ofadrenal plasma flow. Preliminary data on equilibrationof
aldosterone with whole dog blood for one hr. at 37° C.showed that
45 per cent of the aldosterone was recoveredfrom the red blood
cells. From this value the concen-tration of aldosterone in whole
blood can be calculatedfrom the formula: lsg. per cent of
aldosterone in wholeblood =,ug. per cent of aldosterone in plasma
(1 - he-matocrit + hematocrit X 0.818), where 0.818 is the
ratio
DOG3ALDOSTERONE .03SECRETION .02 *
0.CORTICOSTERONE I ISECRETION 3.0 ----l - T -T
ADRENALBLOODFLOW
-NSL/MIN. 2
130ARTERIALPRESSURE 100| Imm. Hg 701PLASMAVOLUME 04(%d)IVC
PRESSURE 175MM. WATER 75S-mm.WATERI' tCONSTRICTIONTHORACIC IVC
CONSTRICTION REMOVED
l0 60 120 80 240 300 360
MINUTES
FIG. 1. EFFECTS OF ACUTE CONSTRICTION OF THETHORACICINFERIOR
VENA CAVA (IVC) ON ALDOSTERONEAND CORTICOSTERONE SECRETION IN
ADRENAL VEINPLASMA
Associated measurements of adrenal blood flow, ar-terial
pressure, plasma volume and IVC pressure arepresented. Arrows
pointing upward indicate tighteningof constricting ligature whereas
release of ligature isrepresented by arrows pointing downward. The
dottedlines show the average values for three control
de-terminations.
2This calculation neglects the very low concentrationof
aldosterone in peripheral plasma which measurementsshow to be less
than 1 per cent of that in adrenal veinplasma.
of aldosterone in red blood cells to that in plasma. He-moglobin
was measured as oxyhemoglobin (7). Changesin plasma volume were
calculated from the formula:
PV2 Hgb1 X - Hct2PV1 Hgb2 1 - Hct1
Plasma sodium and potassium were determined by flamephotometry.
Total plasma osmolality was measuredwith a freezing point apparatus
designed by Bowman,Trantham and Caulfield (8).
RESULTS
Experiment I. Effects of acute constriction ofthe thoracic
inferior vena cava (Dogs 1 through4)The secretion of aldosterone in
adrenal vein
plasma increased within 30 minutes and reachedlevels two- to
fourfold greater than the averagecontrol rates of 0.008 to 0.024
ug. per minute(Figures 1 and 2). In contrast, corticosterone(see
Figure 1) and Porter-Silber reacting steroidoutput decreased in
three of the four dogs. Thisdecline in steroid secretion was
associated with adecrease in adrenal blood flow. Release of
theligature after approximately three hours failed toinfluence
aldosterone secretion; adrenal bloodflow, corticosterone secretion,
and Porter-Silbersteroid output remained unchanged or
increasedtoward the control values.
The increase in aldosterone secretion was as-sociated with an
elevation in inferior vena cavalpressure of 8 to 13 cm. of water, a
reduction inarterial pressure of 10 to 55 mm. Hg and a de-crease in
plasma volume of 36 to 65 per cent. Noconsistent changes in the
concentrations of plasmasodium or potassium were observed and
plasmaosmolality was not detectably altered. Removalof the
constriction was followed immediately bycomplete or nearly complete
restoration of cardio-vascular hemodynamic function but plasma
volumeincreased only slightly (4 to 20 per cent) duringa recovery
period of one and one-half hours.
Experiment II. Effects of acute constriction ofthe abdominal
inferior vena cavc above the ad-renolumbar veins (Dogs 5 through
8)
Constriction of the abdominal inferior venacava resulted in
increased aldosterone output intwo of the four animals (Dogs 6 and
7). Theresponse occurred (see Figure 3) only in the
1784
-
ALDOSTERONESECRETION AND ACUTE CAVAL CONSTRICTION
presence of marked caval constriction and in as-sociation with
large sustained increments (greaterthan 14 cm. of water) in venous
pressure. InDog 6, the initial constriction with a
resultantelevation in venous pressure of 16 to 20 cm. ofwater
failed to stimulate aldosterone secretion,but, later in the
experiment, further constrictionof the vena cava with an additional
increment invenous pressure of 4 to 6 cm. of water was ac-companied
by a progressive elevation in aldo-sterone secretion from 0.05 to
0.16 Mg. per minute.When the rise in venous pressure after
abdominalcaval constriction was not sustained at a highlevel,
aldosterone secretion remained unchangedor decreased (see Figure
4). These findings arein contrast to the results observed
followingthoracic caval constriction in which aldosteroneoutput was
consistently elevated with a rise invenous pressure of less than 13
cm. water. Thechanges in corticosterone and Porter-Silber re-
z
i
A -0
I-w
ULA)
z0
-
J. 0. DAVIS, B. KLIMAN, N. A. YANKOPOULOS,AND R. E. PETERSON
Experiment III. The effects of thoracic cavalconstriction during
infusion of dextran (Dogs9 through 11)
Following constriction of the thoracic inferiorvena cava,
dextran was given intravenously at arate estimated by calculation
from Experiment Ito maintain or to increase plasma volume. Inall
three dogs, the increase in aldosterone secre-tion was similar to
that observed in ExperimentI (see Figure 5). This occurred in spite
of in-crements in plasma volume of 44, 80 and 330per cent. The
changes in cardiovascular functionwere similar in magnitude to
those observed inExperiment I; arterial pressure remained
un-changed or fell while venous pressure increased.Adrenal blood
flow fell progressively throughoutthe experiment (Dog 9, Figure 5)
or fell duringthe first two hours with a return toward or to
thecontrol levels during the last one to two hours ofthe experiment
in the other two animals. Noconsistent alterations in plasma
sodium, potas-sium or total osmolality were detected.
.0.ALDOSTERONESECRETIONAg. / MIN. .0
.0
CORTICOSTERONEI.SECRETION I,AS/ MIN. 0.
ADRENALBLOODFLOWumL / MIN.
PLASMAVOLUME(Oi) 100
50
ARTERIAL 130PRESSURE 100mm. HN
70275
IVC PRESSURE 175mm. WATER
75
15 DOG5
'3 - -t--------ltT
I,,I- 4
5F Ft ,- T
0 60 120 180 240 300 360MINUTES
FIG. 4. FAILURE OF ALDOSTERONESECRETIONTO INCREASEFOLLOWINGACUTE
ABDOMINAL IVC CONSTRICTIONSee Figure 1 for description of
symbols.
DISCUSSION
The present experiments demonstrate that acuteconstriction of
the inferior vena cava resulted inincreased aldosterone secretion.
The responsewas consistent following thoracic caval constric-tion
whereas aldosterone secretion increased inonly two of the four dogs
with abdominal inferiorvena cava constriction. In these two animals
theelevated venous pressure was sustained at ahigher level than in
the two dogs not showing aresponse. The two animals in which
aldosteronesecretion was unchanged or declined providecontrol data
for the dogs with thoracic inferiorvena cava constriction; the
results indicate thatother factors such as trauma and changes
inanesthesia failed to result in increased aldosteronesecretion.
Failure of aldosterone secretion to de-crease after release of the
thoracic caval ligatureis probably a reflection of the short
recoveryperiod, and consequently of inadequate time foraldosterone
output to return to the control level.
In has been shown previously (9) that chronicconstriction of the
abdominal inferior vena cavadoes not result in increased
aldosterone outputand sodium retention whereas chronic
thoraciccaval constriction produces these alterations con-sistently
(1, 2). This difference in response ap-parently is related to the
greater ease of filtrationof fluid and electrolytes from the liver
and hepaticlymphatics of the latter preparation in compari-son with
that from the congested area in dogswith abdominal caval
constriction. Edema orascites failed to occur after chronic
abdominalcaval constriction although a higher level ofvenous
pressure was present than observed fol-lowing thoracic caval
constriction. In the ab-sence of or during minimal extravascular
loss offluid and electrolytes, as in Dogs 5 and 8 of thepresent
study, the stimulus may have been in-adequate to effect an
elevation in aldosteroneproduction.
Increased aldosterone secretion has been re-ported previously
(1) for dogs with chronicheart failure or with chronic ascites
secondary tothoracic caval constriction. In recent unpub-lished
studies with the present radioisotope tech-nique for measuring
aldosterone, a markedly ele-vated rate of aldosterone secretion in
adrenalvein plasma (mean value of 0.142 jAg. per minute;
t -1-- ---- 4--- -
t
11
1786
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ALOSTERONESECRETION AND ACUTE CAVAL CONSTRICTION
N equals 8) was observed in dogs with chronicascites produced by
thoracic caval constriction.Increased secretion of aldosterone has
also beenreported in nephrotic rats with edema or ascitesby Singer
(10). Histochemical studies of theadrenal cortex from dogs with
experimental as-cites by Hamilton, Brown and Hague (11) andfrom
dogs with experimental congestive failureby Deane and Barger (12)
have provided addi-tional data indicative of increased adrenal
corticalactivity in the zona glomerulosa. There is, there-fore,
considerable evidence for increased secretionof aldosterone in
experimental states with edemaor ascites and, consequently, a
satisfactory ex-planation for the source of the excess
circulatinghormone which is excreted in urine (2). Never-theless,
evidence to the contrary has been reportedby Driscol, Maultsby,
Farrell and Berne (13).These workers were unable to detect either
in-creased secretion or increased urinary excretionof aldosterone
in dogs with apparent experimentalheart failure produced by
controlled progressivepulmonic stenosis.
The rapidity of the response in adrenal veinaldosterone output
to caval constriction in thepresent study and to hemorrhage
[Farrell, Ros-nagle and Rauschkolb (14)] provides evidencethat
alterations in aldosterone secretion may con-stitute an important
acute homeostatic mecha-nism. This possibility has been clearly
recognizedby many investigators. Epstein (15) has re-cently
suggested "the direct adrenal participationin a number of acute
renal readjustments, suchas the antinatriuresis of quiet standing,
of limbcongestion, or of hemorrhage." The dog withacute abdominal
caval constriction provides anexperimental situation comparable to
that of quietstanding and of limb congestion in man. Also,the
increments in venous pressure observed inthe present study were
similar to those of Farber,Becker and Eichna (16) following acute
cavalobstruction in man. These workers were unableto explain the
drop in sodium and water excretionon the basis of renal hemodynamic
changes aloneand they too suggested a hormonal mechanism.
Some question has been raised (12, 13) as tothe importance of
aldosterone in the pathogenesisof edema and ascites. It was
suggested that in-creased aldosterone production might occur late
inthe course of edema or ascites formation and,
ALDOSTERONESECRETIONA:/MIN.
CORTICOSTERONESECRRTIONAO/lMIN.
ADRENALBLOODFLOW
'Mt/MIN.
PLASMAVOLUME(04.
ARTERIALPRESSUREmm. Hg
IVC PRESSUREmm. WATER
IIrI 1 1 1DOG9.01~~~~~~~~~~~~~
3.0-
2.0-lr
1.0
ISO
100
so
130
100
70
175
75
0 60 120 I8O 240 300 360MINUTES
FIG. 5. INcREASED ALDOSTERONESECRETIONFOLLOWINGTHORACIC IVC
CONSTRICTION DURING MAINTAINED ORINCREASEDVASCULARVOLUME
See Figure 1 for description of symbols.
therefore, contribute only as a secondary mecha-nism. The
present data demonstrate the acutenessof the response of the
adrenal cortex in the secre-tion of increased amounts of
aldosterone followingan alteration in cardiovascular function.
In-creased aldosterone secretion occurred within30 minutes
following caval constriction. Also, in-creased excretion of
aldosterone in urine has beendemonstrated during the first four
days followingeither caval constriction or pulmonic stenosis
(17).
The role of aldosterone in the formation of as-cites does not
appear to be a "permissive" one.In adrenalectomized dogs with caval
constriction(18), only 0.5 mg. per day of
desoxycorticosteroneacetate (DCA) was necessary to maintain
theanimals in sodium balance but 6 to 10 times thisamount of DCAwas
required to effect the degreeof sodium retention observed in the
presence ofthe adrenals and endogenous aldosterone. Simi-larly, it
was demonstrated that the degree of so-dium retention in dogs with
cardiac failure wasrelated to the amount of DCA given (19).
Itshould be emphasized that the effects of desoxy-
--, * ma---r-l-I 1 aIJ
1~~~~~~~~~~~~~4I 4t CNSRICTION:
THORACICIVC CONSTRICTION REMOVEDDEXTRAN 344CC.M
I_r
1787
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J. 0. DAVIS, B. KLIMAN, N. A. YANKOPOULOS,AND R. E. PETERSON
corticosterone and aldosterone on electrolyte ex-cretion by the
kidney are qualitatively identical[Liddle, Cornfield, Casper and
Bartter (20)].In addition, observations on urinary aldosteroneand
sodium excretion in both dog (2) and man byLuetscher and Johnson
(21) have demonstratedthat an inverse relation between these
functions isvery frequently present.
Failure of large amounts of DCA to producechronic sodium
retention in both normal (22) andsimple adrenalectomized animals
(23) may beexplained by the necessity of factors other thanan
excess of circulating sodium-retaining hormonefor chronic sodium
retention. The importance ofa cardiovascular factor which acts in
associationwith aldosterone to promote chronic sodium re-tention
has been emphasized (1, 2, 24). In dogswith thoracic caval
constriction (25) or with ex-perimental heart failure of either the
low output(26) or high output (24) type, this factor appearsto be
elevated venous pressure.
Three lines of evidence support the view thatvenous hypertension
initiates the sequence of eventsleading to chronic sodium retention
in dogs withexperimental ascites. First, in dogs with
chronicthoracic caval constriction and ascites, venous
hy-pertension below the constriction was usually theonly detectable
cardiovascular alteration (25).In the majority of these animals,
arterial pres-sure and cardiac output were normal. Second,in dogs
with right heart failure secondary to pul-monic stenosis and in
dogs with thoracic cavalconstriction, ascites formed during the
first oneto four days following the onset of cardiac failureor
after caval constriction in the absence of so-dium intake (17).
Since sodium was not in-gested, a positive sodium balance could not
occur;ascitic fluid was formed by a shift of electrolytesand water
from other body fluids. Therefore, inthe dogs with pulmonic
stenosis, a full-blownclinical picture of frank congestive heart
failurewith ascites developed in the absence of a renalfactor with
its resultant positive sodium balance.Third, an analysis of the
functional changes dur-ing high output failure secondary to anemia
indogs with pulmonic stenosis (24) showed that anelevation in right
atrial pressure was closely as-sociated with sodium retention;
cardiac output,
glomerular filtration rate and renal plasma flowwere elevated in
the majority of instances.
It has been repeatedly suggested that the stim-ulus to increased
aldosterone production arises asa result of some unknown factor or
factors as-sociated with loss of fluid and electrolytes fromthe
blood stream. Johnson and Conn (27) havereferred to the effect of
venous pressure as creat-ing a "leak" of salt and water from the
circulationwith a resultant abnormal redistribution of
ex-tracellular fluid. It was reasoned (28) that if thestimulus to
increased aldosterone secretion is re-lated to loss of fluid and
electrolytes from the vas-cular bed, prevention or inhibition of
this lossshould result in decreased aldosterone output anda
natriuresis. To inhibit transudation of fluid, aplaster body cast
was applied to dogs with thoraciccaval constriction and ascites
(28); aldosteroneoutput dropped and sodium excretion increased.The
data suggest a close association between in-creased aldosterone
secretion and factors associ-ated with fluid and electrolyte loss
from the vas-cular bed.
The precise changes which accompany the acuteloss of fluid and
electrolytes from the blood streamand stimulate aldosterone
production remain ob1-scure. The mechanism does not seem to be
ef-fected by increased secretion of adrenocortico-tropic hormone
(ACTH) since corticosterone out-put was decreased following acute
thoracic cavalconstriction. The present data do not suggestthat
under these conditions the increased aldo-sterone secretion is the
result of a decreased vascu-lar volume, proposed by Bartter (29) as
thenormal stimulus for aldosterone secretion. In-travenous
administration of dextran at a ratesufficient to maintain or to
increase plasma vol-ume markedly failed to prevent the rise in
aldo-sterone secretion following thoracic caval con-striction.
Also, Farrell and associates (14)observed an increase in
aldosterone secretion fol-lowing hemorrhage in spite of an elevated
plasmavolume secondary to infused dextran. Thus, ob-servations on
the relation of aldosterone secre-tion to vascular volume in acute
animal experi-ments agree with the frequent finding of a normalor
high blood volume in patients with cardiac de-compensation (30, 31)
and during decompensatedhepatic cirrhosis (32).
1788
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ALDOSTERONESECRETION AND ACUTE CAVAL CONSTRICTION
SUMMARY
The effects of acute constriction of the thoracicinferior vena
cava (seven dogs) and of the ab-dominal inferior vena cava above
the adrenals(four dogs) on aldosterone, corticosterone
andPorter-Silber steroid secretion in adrenal veinplasma were
studied. Three of the dogs withthoracic caval constriction received
dextran intra-venously to maintain or to increase plasma vol-ume.
After three control determinations 30 min-utes apart, six to eight
measurements were madeat similar intervals during the
experimentalperiod. Following thoracic caval constrictionalone,
aldosterone secretion increased within 30minutes and reached levels
two- to fourfold greaterthan the average control rates of 0.008 to
0.024 pg.per minute; corticosterone and Porter-Silbersteroid output
remained unchanged or decreased.Plasma volume was reduced. However,
similarincreases in aldosterone secretion occurred despiteincreased
vascular volume secondary to infuseddextran in three other animals
with thoraciccaval constriction. Two of four dogs with ab-dominal
caval constriction showed increased aldo-sterone secretion; this
occurred only after markedcaval constriction and large sustained
incrementsin venous pressure. The data demonstrate in-creased
aldosterone secretion following acute con-striction of the inferior
vena cava above or belowthe hepatic veins and irrespective of
changes invascular volume.
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