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

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

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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-

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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

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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

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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).

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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.

REFERENCES

1. Davis, J. O., Pechet, M. M., Ball, W. C., Jr., andGoodkind, M. J. Increased aldosterone secretionin dogs with right-sided congestive heart failureand in dogs with thoracic inferior vena cava con-striction. J. clin. Invest. 1957, 36, 689.

2. Davis, J. O., Goodkind, M. J., Pechet, M. M., andBall, W. C., Jr. Increased excretion of aldosteronein urine from dogs with right-sided congestiveheart failure and from dogs with thoracic in-ferior vena cava constriction. Amer. J. Physiol.1956, 187, 45.

3. Kliman, B., and Peterson, R. E. Isotope deriva-tive assay of aldosterone in biological extracts(abstract). Fed. Proc. 1958, 17, 255.

4. Peterson, R. E., Karrer, A., and Guerra, S. L. Evalu-ation of Silber-Porter procedure for determinationof plasma hydrocortisone. Analyt. Chem. 1957,29, 144.

5. Silber, R. H., and Porter, C. C. The determination of17, 21-dihydroxy-20-ketosteroids in urine andplasma. J. biol. Chem. 1954, 210, 923.

6. Peterson, R. E. Unpublished observations.7. Evelyn, K. A. A stabilized photoelectric colorimeter

with light filters. J. biol. Chem. 1936, 115, 63.8. Bowman, R. L., Trantham, H. V., and Caulfield, P.

A. An instrument and method for rapid, dependabledetermination of freezing-point depression. J. Lab.clin. Med. 1954, 43, 310.

9. Ball, W. C., Jr., and Davis, J. 0. Failure of chronicadrenal venous congestion to produce sodium re-tention and increased aldosterone excretion in thedog. Amer. J. Physiol. 1957, 191, 339.

10. Singer, B. Aldosterone in the adrenal vein blood ofnephrotic rats. Endocrinology 1957, 60, 420.

11. Hamilton, C. E., Brown, W. J., Jr., and Hague, E. E.Comparison of adrenal morphology in dogs underdietary and circulatory handicap (abstract). Amer.J. Physiol. 1956, 187, 603.

12. Deane, H. W., and Barger, A. C. Histophysiologyof the adrenal cortex in dogs with mild and se-vere cardiac damage. Endocrinology 1957, 61,758.

13. Driscol, T. E., Maultsby, M. M., Farrell, G. L., andBerne, R. M. Aldosterone secretion in experi-mental congestive heart failure. Amer. J. Physiol.1957, 191, 140.

14. Farrell, G. L., Rosnagle, R. S., and Rauschkolb,E. W. Increased aldosterone secretion in re-sponse to blood loss. Circulat. Res. 1956, 4, 606.

15. Epstein, F. H. Renal excretion of sodium and theconcept of a volume receptor. Yale J. Biol. Med.1956, 29, 282.

16. Farber, S. J., Becker, W. H., and Eichna, L. W.Electrolyte and water excretions and renal hemo-dynamics during induced congestion of the superiorand inferior vena cava of man. . clin. Invest.1953, 32, 1145.

17. Ball, W. C., Jr., Davis, J. O., and Goodkind, M. 3.Ascites formation without sodium intake in dogswith thoracic inferior vena cava constriction andin dogs with right-sided congestive heart failure.Amer. J. Physiol. 1957, 188, 578.

18. Davis, J. O., Howell, D. S., and Southworth, J. L.Mechanisms of fluid and electrolyte retention inexperimental preparations in dogs. Circulat. Res.1953, 1, 260.

19. Davis, J. O., Howell, D. S., and Hyatt, R. E. So-dium excretion in adrenalectomized dogs withchronic cardiac failure produced by pulmonaryartery constriction. Amer. J. Physiol. 1955, 183,263.

20. Liddle, G. W., Cornfield, J., Casper, A. G. T., andBartter, F. C. The physiological basis for amethod of assaying aldosterone in extracts of hu-man urine. J. clin. Invest. 1955, 34, 1410.

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21. Luetscher, J. A., Jr., and Johnson, B. B. Observa-tions on the sodium-retaining corticoid (aldo-sterone) in the urine of children and adults in re-lation to sodium balance and edema. J. clin. In-vest. 1954, 33, 1441.

22. Davis, J. O., and Howell, D. S. Comparative effectsof ACTH, cortisone and DCA on renal function,electrolyte excretion and water exchange in nor-mal dogs. Endocrinology 1953, 52, 245.

23. Gaudino, M., and Levitt, M. F. Influence of theadrenal cortex on body water distribution and re-nal function. J. clin. Invest. 1949, 28, 1487.

24. Davis, J. O., Goodlind, M. J., and Ball, W. C., Jr.Functional changes during high output failure pro-duced by daily hemorrhage in dogs with pul-monic stenosis. Circulat. Res. 1957, 5, 388.

25. Davis, J. O., and Howell, D. S. Mechanisms offluid and electrolyte retention in experimentalpreparations in dogs. II. With thoracic inferiorvena cava constriction. Circulat. Res. 1953, 1, 171.

26. Davis, J. O., Hyatt, R. E., and Howell, D. S.Right-sided congestive heart failure in dogs pro-

duced by controlled progressive constriction of thepulmonary artery. Circulat. Res. 1955, 3, 252.

27. Johnson, R. D., and Conn, J. W. Aldosterone, anti-diuretic hormone and congestive heart failure.Mod. Conc. cardiov. Dis. 1958, 27, 431.

28. Davis, J. O., and Ball, W. C., Jr. Effects of a bodycast on aldosterone and sodium excretion in dogswith experimental ascites. Amer. J. Physiol. 1958,192, 538.

29. Bartter, F. C. Aldosterone. Geneva Symposium,June, 1957. London, J. and A. Churchill, 1957.

30. Eisenberg, S. The effect of congestive heart failureon blood volume as determined by radio-chromium-tagged red cells. Circulation 1954, 10, 902.

31. Funkhouser, R. K., Pritchard, W. H., and Littell,A. S. Changes in relationship of blood volume toweight in congestive heart failure. Circulation1957, 16, 548.

32. Eisenberg, S. The blood volume in patients withLaennec's cirrhosis as determined by radio-chro-mium-tagged red cells. Clin. Res. Proc. 1955, 3,143.

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