Journal of Clinical InvestigationVol. 44, No. 9, 1965

Metabolism of Aldosterone in Several Experimental Situationswith Altered Aldosterone Secretion *

JAMES0. DAVIS,t MICHAELJ. OLICHNEY, TORREYC. BROWN,ANDPETERF.BINNION t WITH THE SURGICALASSISTANCEOF ALFREDCASPER

(From the Section on Experimental Cardiovascular Disease, Laboratory of Kidney and Electro-lyte Metabolism, National Heart Institute, Bethesda, Md.)

In an earlier study (1), the rate of metabolismof aldosterone was found to be decreased in dogswith chronic passive congestion of the liver sec-ondary to thoracic inferior vena caval constriction.After hepatectomy of these animals and of normaldogs, the metabolism of aldosterone was almostabolished. It was suggested that the decreasedaldosterone metabolism during liver congestionmight be secondary to decreased hepatic blood flowand associated hepatic anoxia. More recently,Tait and his colleagues (2, 3) have provided evi-dence that the rate of hepatic blood flow is one ofthe primary determinants of the rate of aldosteronemetabolism.

The present observations were undertaken toexamine the metabolism of aldosterone in severalexperimental situations in which altered aldos-terone secretion occurs and in which there areknown or suspected alterations in liver blood flow.The primary objectives were twofold: 1) to de-fine the distribution, metabolic clearance rate(MCR), and hepatic extraction of aldosterone,and 2) to determine the contribution of altered al-dosterone metabolism to the peripheral plasmalevel of aldosterone. Aldosterone metabolism wasstudied following acute hemorrhage, in dogs de-pleted of sodium, and in dogs with chronic ex-perimental heart failure. Observations were madein both low and high output failure because hepaticblood flow is reduced in the former and, presum-ably, normal or elevated in the latter situation.Since exercise greatly reduces the blood flowthrough the liver in patients with heart failure (4),observations were made before and during ex-

* Submitted for publication January 4, 1965; acceptedMay 12, 1965.

t Address requests for reprints to Dr. James 0. Davis,Building 3, Room204, National Heart Institute, Bethesda,Md. 20014.

t Ontario Heart Foundation research fellow.

hausting exercise in dogs with low output heartfailure. The metabolism of aldosterone was alsostudied in hypophysectomized dogs; in this situa-tion there is a low rather than a high rate of al-dosterone secretion, and hepatic blood flow isprobably reduced. Finally, the hepatic extractionof aldosterone was measured in several experi-mental situations.

Methods

The rate of metabolism of aldosterone was studied byobserving the rate of disappearance of 1,2-H'-d-aldos-terone from peripheral plasma; single iv injections of12 X 10' cpm of 1,2-H3-d-aldosterone with a SA of 100Acc per ug were made. The efficiency of the liquid scintil-lation spectrometer was approximately 25%b. Peripheralvenous blood samples of 20 ml were drawn at 5, 10, 15,20, 30, 45, 60, 75, and 90 minutes, and plasma was ana-lyzed for true H3-d-aldosterone. The dogs weighed from17 to 22 kg.

To study the effects of hemorrhage, 30 ml of arterialblood per kg body weight was removed over a 5- to 15-minute period in nine dogs anesthetized with Na pento-barbital. As soon as the arterial pressure had stabilized,tritiated aldosterone was injected, and peripheral venousblood samples were obtained. Arterial pressure was meas-ured continuously throughout the experiment by meansof a Statham strain gauge and a Sanborn recording sys-tem. As a control experiment, the disappearance oftritiated aldosterone was studied in a series of sevennormal dogs anesthetized similarly.

Sodium depletion was produced in seven normal dogsby feeding a diet containing less than 2 mEq per day ofNa and by administration of 2 ml of Mercuhydrin in-tramuscularly on 4 successive days. The average negativeNa balance for the 4 days in the group of seven dogs was161 mEq. The disappearance of H'-d-aldosterone wasstudied in these conscious Na-depleted animals, and thedata were compared with results obtained in normal con-scious dogs on a Na intake of 60 mEqper day.

Chronic congestive heart failure of the low outputtype was produced by a combination of tricuspid insuffi-ciency and pulmonic stenosis (5, 6). Pulmonic stenosiswas achieved by an adjustable ligature that was placedaround the main pulmonary artery and tightened under

1433

DAVIS, OLICHNEY, BROWN,AND BINNION

local anesthesia (6). All five animals showed evidenceof right heart failure including an elevated venous pres-sure, tachycardia, hepatomegaly, almost complete renalNa retention, and ascites. In an earlier study (1) itwas found that tritiated aldosterone equilibrated slowlybetween plasma and ascitic fluid. Therefore, for the pres-ent observations in experimental heart failure, asciteswas removed as completely as possible immediately be-fore injection of tritiated aldosterone. The disappear-ance of HW-d-aldosterone was measured in resting con-scious animals and again several days later during ex-hausting exercise. The dogs were run up 20 to 25 stepsof stairs; venous pressure was measured before and dur-ing exercise in two of the three dogs.

High output heart failure was produced in two dogsby placing a large aortic-caval fistula about 1 inch be-low the kidneys (7). The animals were placed on dailyNa balance studies and observed closely for signs ofheart failure. At the onset of heart failure, Na retentionwas almost complete. Both animals died from heartfailure and pulmonary edema within 3 days after themeasurements of aldosterone metabolism were made.Pulmonary edema was evident by the large amount offrothy fluid that exuded from the trachea.

Hypophysectomy was performed by the oral approach,and the rate of metabolism of aldosterone was measuredin four conscious animals after 6 weeks.

Extraction of aldosterone by the liver was determinedby measuring the concentrations of H'-d-aldosterone inperipheral and hepatic venous plasma. The first experi-ments were carried out in five dogs anesthetized with Napentobarbital; the chest and abdomen were opened, anda catheter was passed from the external jugular vein intoone of the hepatic veins. H'-d-aldosterone (12 X 106 cpm)was injected intravenously, and samples of blood wereobtained simultaneously from a peripheral and a hepaticvein after 15, 20, and 30 minutes. Because of the rapiddeterioration that occurred in these anesthetized animalswith both the chest and abdomen open, hepatic extractionratios were also measured in a group of eight consciousdogs. In these animals, a catheter was placed in a he-patic vein under sterile conditions several days before theexperiment. It should be pointed out that this techniquehas certain advantages. The abdomen was opened, and acatheter was placed in one of the hepatic veins fromthe left lobe of the liver; the catheter tip was placed im-mediately beneath the surface of the most superficial he-patic vein in the region. Consequently, there was a sub-stantial distance between the catheter tip and the inferiorvena cava, and the possibility for reflux of blood was verysmall. Three additional dogs with chronic indwellinghepatic venous catheters were anesthetized before acutehemorrhage, and measurements of the hepatic extractionratio of aldosterone were made under anesthesia.

The concentration of HW-d-aldosterone was measuredin peripheral venous plasma by a slight modification (1)of the double isotope derivative assay (8), and two ad-ditional changes were made for the present study. First,the samples were run through a third chromatography; acyclohexane (100 parts), benzene (50 parts), methanol

(100 parts), and water (25 parts) system was used, andthe chromatogram was developed for 10 hours. Second,aldosterone-4-C' was added directly to plasma ratherthan addition of aldosterone diacetate-C1' after acetyla-tion as performed previously (1).

Results

Analysis of data. The data from the disappear-ance curves for H3-d-aldosterone for each of thegroups of animals were averaged to yield a com-posite set of values (Figures 1 to 7). The valueswere plotted on semilogarithmic coordinate paper.Two exponential terms could be resolved for thedisappearance curve from each group of animals.Accordingly, following tracer kinetic theory (9),a two compartmental model was proposed (1) tocharacterize the distribution and metabolism of al-dosterone. The characteristics of a two compart-mental model and the equations for calculation ofthe turnover rates and the volumes of distributionhave been described previously (1). The datafrom a disappearance curve are not sufficient topermit solution of the values of all the kij or turn-over rates from the j th to the ith compartment.However, with certain assumptions about the k1j,it is possible to calculate all other turnover rates.Two reasonable assumptions were made and twomodels resulted: 1) k02 = 0, which means thatlosses or degradation of aldosterone take placefrom compartment 1 only (model I); and 2)kol = 0, which requires that losses or degradationof aldosterone occur from compartment 2 only(model II).

Estimates of the volumes of distribution andturnover rates were made. The experimental val-ues were plotted, and the disappearance curveswere drawn by hand in an attempt to approximateideal curves. From these curves, the y intercepts(a1, and a12) and the slopes (a1 and 2) for thefast and slow components were calculated. Byuse of the equations that describe a two compart-mental model (1), the rate constants were calcu-lated for models I and II. The volume of distri-bution for compartment I (S1) is the same forboth models. S1 was calculated from the equa-tion, S, = (total counts per minute injected X 100ml)/(a,, + a12), and S2 = (k21 SI)/k22, and S2differs for each model because the ki; differ formodels I and II.

The observed data from the disappearance

1434

METABOLISMOF ALDOSTERONE

curves were fitted to sums of exponentials by aleast squares method with a digital computer pro-gram (10). The fitted values and the resultantdata for all, a12, a1, and a2 were obtained. By useof a digital computer, the initial estimates of S1, S2,and the fractional turnover rates were used to de-termine the definitive values and the standard er-rors for these functions. From the computer datafor the volume of distribution and the turnoverrate, the rate of plasma clearance in milliliters perminute or the MCRwas calculated for each model.On the basis of tracer kinetic theory, the values forthe MCRfor each model should be equal.

From the available data, the assumed two com-partmental model is acceptable to explain the me-tabolism of aldosterone in the situations studied.There are no systematic deviations between cal-culated and observed values for the plasma con-centrations of aldosterone, and, in general, thestandard errors of the volumes of distribution andthe fractional turnover rates are small.

The results presented in Table I were obtainedfrom the fitted data and computer analysis.

Effects of acute hemorrhage on the distributionand metabolism of aldosterone. Since acute hem-orrhage of 30 ml of blood per kg of body weightresults in hypotension, blood pressure was re-corded continuously throughout the experiment.The data show that a striking fall in arterial pres-sure occurred immediately following removal ofblood (Figure 1). Within 30 minutes arterialpressure had increased, and a relatively stable

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FIG. 2. DISAPPEARANCECURVES OF H3-D-ALDOSTERONEIN NORMALANESTHETIZED DOGS AND IN DOGS SUBJECTEDTO ACUTE HEMORRHAGE. Open symbols represent experi-mental values; solid symbols are fitted data. Where onlysolid symbols are plotted, the experimental and fitted datacoincide.

state was achieved. Thereafter, only a slight pro-gressive decline in arterial pressure occurred. Thedisappearance curve for H3-d-aldosterone is pre-sented in the upper part of Figure 1 to show itsrelationship to blood pressure. There are twoexponential components to the disappearancecurve, and the findings give no indication that anunstable state was present.

The disappearance curves for H3-d-aldosteronein normal, anesthetized dogs and in the anesthe-tized, acutely bled animals are presented in Figure2. The slow component of the disappearance curveis considerably more flat in the animals subjectedto hemorrhage than in the normal dogs. The bio-logical half-life (to) of aldosterone from the slowcomponent is longer (56 minutes) for the hemor-rhaged than for the normal dogs (31 minutes).Neither S1 nor S2 was altered appreciably by hemor-rhage (see comparison between normal anesthe-tized and bled dogs in Table I), but the fractionalturnover rates (k01 for model I and k02 for modelII) were decreased (Table I). The metabolic clear-ance rate was reduced 45 %o by hemorrhage. Stud-ies of hepatic extraction of aldosterone demon-strated that extraction was almost complete inboth normal and bled dogs, and no difference be-tween the two groups was discernible (Table II).Hepatic extraction ratios of 100%o represent he-

143 5

DAVIS, OLICHNEY, BROWN,AND BINNION

EKa

4-<I

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MINUTES

75 90

FIG. 3. DISAPPEARANCECURVES OF H'-D-ALDOSTERONEFOR NORMALCONSCIOUSDOGSAND CONscIous NA-DEPLETEDDOGS. Net Na loss was 161 mEq. See Figure 2 forsymbols.

patic vein samples in which the counts per minuteper milliliter were not above the backgroundcounts.

Aldosterone metabolism and distribution in so-

dium-depleted dogs. The disappearance curves of

H3-d-aldosterone for the group of Na-depleteddogs and a group of normal conscious animals arepresented in Figure 3. The two curves are in-distinguishable. The tj of the slow componentis 30 minutes for the normal dogs and 26 minutesfor the Na-depleted dogs. It is of interest thatthe curve for the normal conscious dogs is almostidentical to that observed earlier (1) for anothergroup of normal conscious animals in which thetj was 27 minutes.

Analysis of the data in terms of a two com-partmental model revealed a 41% drop in the vol-ume of distribution (S1) of compartment 1 and afall of 35%o for S2 (Table I). Thus, the fractionalturnover rates k01 and k02 were increased, but themetabolic clearance rate of aldosterone was not sig-nificantly altered by Na depletion.

The hepatic extraction ratios for aldosteroneranged from 80 to 98% for the anesthetized Na-depleted dogs and from 88 to 100% for consciousNa-depleted animals (Table II). These valueswere essentially the same as the normal extractionratios.

Distribution and metabolism of aldosterone in

TABLE I

Distribution and metabolism of H3-d-aldosterone*

Model I Model II

Dogs Si koi MCR S2 ko2 MCR tj

L fraction of ml/min L fraction of ml/min minpool/min pool/min

Normal (conscious) 18.67 0.0385 718 23.59 0.0304 717 30±0.89t ±0.0018 ±3.94 4±0.0050

Normal (anesthetized) 12.31 0.0676 832 27.38 0.0304 832 31±4.61 ±0.0179 ±3.18 ±0.0035

After acute blood loss 13.02 0.0348 453 24.04 0.0188 451 56(anesthetized) ±+1.47 ±0.0039 ±41.44 ±0.0011

Sodium depleted (conscious) 10.98 0.0567 622 15.37 0.0405 622 26± 1.67 ±0.0080 ± 1.20 ±-0.0029

Low output heart failure 12.15 0.0266 323 26.26 0.0123 322 68(conscious) ±t2.04 ±0.0072 ± 12.31 i0.0058

High output heart failure 6.96 0.1019 709 24.79 0.0282 699 31(conscious) i2.29 ±0.0311 ± 1.42 ±0.0016

Hypophysectomized group I 10.84 0.0361 391 26.24 0.0149 390 60(conscious) ± 2.05 ±0.0080 ±8.71 ±0.0049

Hypophysectomized group II 12.31 0.0437 537 33.23 0.0163 451 44(conscious) ± 1.34 ±-0.0060 ±:9.13 ±0.0045

* Si and S2 = volume of distribution for the two compartments; ko, and ko2 = turnover rates; MCR= metabolicclearance rate.

t Standard error.

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1436

METABOLISMOF ALDOSTERONE

TABLE II

Hepatic extraction ratio of H3-d-aldosterone in dogs*

Type of Dog After 15 After 20 After 30animals no. min min min

%Ex- %Ex- %Ex-traction traction traction

AnesthetizedNormal 1 93 95

2 87 81

After acute 1 97 100blood loss 2 93 84 94

3 100 100 96

Sodium 1 98 85 98depleted 2 93 86 80

Thoraciccaval 1 87 94 95constriction

ConsciousNormal 1 99 100 86

2 100 90 853 96 98 100

Sodium 1 99 100 98depleted 2 88 100 100

Thoracic 1 100 100caval 2 100 100constriction

Hypophy- 1 100 100 100sectomized

* Simultaneous hepatic and peripheral venous blood samples weredrawn at 15, 20, and 30 minutes after a single injection of 12 X 106 cpmof H3-d-aldosterone, and plasma was analyzed for true Hs-d-aldosterone.

chronic experimental heart failure. The disap-pearance curve of H3-d-aldosterone for dogs withlow output heart failure is presented for compari-son with the normal curve (Figure 4). The tj forthe slow component of the curve from the dogswith heart failure is 68 minutes, which representsa marked prolongation over the normal t1 of 30minutes. The volume of distribution S, was re-duced 35%o in the heart failure dogs, whereas S2was unchanged (Table I). The fractional turn-over rates k01 and k02 were reduced, and since S2was unaltered the reduction in k02 was muchgreater than that for k01 (Table I). The metabolicclearance rate was decreased from 718 to 322 mlper minute, a 55%o fall (Table I).

Since exercise has been found to decrease he-patic blood flow markedly in patients with heartfailure (4), three of the dogs with low outputheart failure were subjected to exhausting exer-cise (Figure 5). The venous pressure, whichranged from 180 to 190 mmwater before exercise,increased to 205 to 300 mmwater during exercise.All three animals were tachypneic and showedsigns of weakness and exhaustion during exercise.The disappearance curves of HW-d-aldosterone,

40.4

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0.1 l l I910 20 30 45 60 75 90MINUTES

FIG. 4. DISAPPEARANCECURVESFOR H'-D-ALDOSTERONEIN NORMALCONSCIOUSDOGS AND IN DOGS WITH EXPERI-

MENTALLOWOUTPUT HEART FAILURE. See Figure 2 forsymbols.

although obtained several days apart, were es-sentially the same before and during exercise.The slow component of the curve was very flat,and the long tj of 71 minutes before exercisewas not altered significantly. Calculations showedthat the metabolic clearance rate of aldosteronewas not detectably influenced by exercise.

In two dogs with high output failure secondaryto a large aortic-caval fistula, the disappearancecurve was within normal limits (Figure 6). The

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FIG. 5. FAILURE OF EXERCISE TO ALTER THE RATE OF

DISAPPEARANCEOF H8-D-ALDOSTERONEIN THREEDOGSWITH

EXPERIMENTALLOWOUTPUTHEARTFAILURE.

1437

DAVIS, OLICHNEY, BROWN,AND BINNION

tj of the slow component was 31 minutes in com-parison with the t4 of 30 minutes for normal con-scious dogs. Consequently, the MCRfor dogswith high output failure was not appreciably dif-ferent from the normal MCR(Table I). The vol-ume of distribution for compartment 1 (S,) wasmarkedly reduced, but S2 was not significantlychanged. Thus, k01 was very high, whereas kO2was unaltered.

To evaluate the influence of chronic passive con-gestion of the liver on the hepatic extraction of al-dosterone, hepatic extraction ratios were obtainedin dogs with chronic constriction of the thoracicinferior vena cava (1). Hepatic extraction of al-dosterone in these animals was virtually completedespite the marked liver congestion (Table II).This result is in contrast to the frequent finding ofa decreased hepatic extraction ratio of aldosteronein patients with heart failure (3, 11, 12). Thedifference in the extraction of aldosterone by theliver in man and in the experimental animal withheart failure may be a reflection of more severeliver damage in man because of the longer durationof the disease.

Aldosterone metabolism and distribution in hy-pophysectomized dogs. The data from the hypo-physectomized dogs have been divided into twogroups on the basis of the completeness of hypo-physectomy. In group I (two dogs), hypophysec-tomy was complete or almost complete as indicated

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10 20 30 45 60 75 90MINUTES

FIG. 6. DISAPPEARANCECURVESFOR H8-D-ALDOSTERONEIN NORMALCONSCIOUSDOGSANDIN DOGSWITH HIGH OUT-

PUT HEART FAILURE SECONDARYTO AN AORTIC-CAVALFISTULA.

X4 ' A

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0.10 10 20 30 45 60 75 90

MINUTES

FIG. 7. DISAPPEARANCECURVESFOR H3-D-ALDOSTERONEIN NORMALCONSCIOUSDOGSAND IN DOGS6 WEEKSAFTER

HYPOPHYSECTOMY.

by markedly atrophic adrenals; the left adrenalsweighed 0.43 and 0.45 g for the two animals,whereas the left adrenals from normal dogs of thesame size weighed 0.81 ± 0.04 g SE (N = 17).In two other animals (group II), the adrenalswere only partially atrophied; the left adrenalsweighed 0.56 and 0.62 g. The t1 of the slow com-ponent of the disappearance curve from the groupI dogs was 60 (Figure 7), whereas the tj was 44minutes for the group II dogs (Table I). S, wasreduced 42%o for group I dogs and 34%o for groupII animals (Table I); S2 was not significantlyaltered in either group of dogs. k01 was unal-tered in either group, but k02 was markedly de-creased in both the completely and incompletelyhypophysectomized animals. The MCRwas de-creased 46%o in group I and 25%o in group II.The hepatic extraction of aldosterone was meas-ured in one of the hypophysectomized dogs ofgroup II (Table II), and extraction was complete.

Discussion

In the present study, the single injection methodwas used to measure the metabolism of aldosterone.This procedure has the advantage over the con-stant infusion method in that more informationcan be obtained. Not only can the rate of disap-pearance or metabolism of aldosterone be ascer-tained, but the volume of distribution and the frac-tional turnover rate can be calculated. The rate

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1438

METABOLISMOF ALDOSTERONE

of clearance of aldosterone from peripheral plasmain milliliters per minute, the MCR, can be cal-culated by multiplying the volume of distributionby the fractional turnover rate. Tait and his col-leagues (2) have demonstrated by the single in-jection and constant infusion methods that theMCRfor normal human subjects is essentiallythe same (within 10%o). In general, the presentdata show an inverse correlation between the tj ofthe slow component of the disappearance curvesand the MCR (Table I). However, when thevolume of distribution was altered markedly asduring Na depletion, this relationship was notclose.

After acute hemorrhage there was a marked re-duction in the rate of metabolism of aldosterone.Consequently, after acute blood loss decreasedmetabolism as well as increased secretion of aldos-terone leads to an elevation of the peripheralplasma level. Actual calculations of the peripheralplasma concentration of aldosterone from knownsecretion rate values in anesthetized dogs (13)and the present data on plasma clearance in anes-thetized animals show that hemorrhage increasedthe peripheral plasma level of aldosterone from0.005 to 0.0175 pg per 100 ml. The present datademonstrate, therefore, the occurrence of anotherimportant mechanism leading to hyperaldosterone-mia that promotes the retention of salt and waterfollowing acute hemorrhage. Both the renin-an-giotensin system and ACTHlead to increased al-dosterone secretion after blood loss (14), andacute hemorrhage is one of the most potent stimulifor release of antidiuretic hormone and water con-servation (15).

The degree of Na depletion used in this studyfailed to produce a detectable alteration in aldos-terone metabolism. However, the volume of dis-tribution was markedly decreased, a finding thatmay reflect a decreased plasma and extracellularfluid volume. Net Na loss was 161 mEq overthe 4 days. This same Na depletion regimen witha similar loss of Na produced a 200%o increase inaldosterone secretion in conscious dogs (16).Available data demonstrate, therefore, that in-creased secretion is the primary mechanism lead-ing to hyperaldosteronemia during this degree ofNa depletion. Calculations of the peripheralplasma concentration of aldosterone show an in-crease from the value of 0.002 pg per 100 ml for

normal conscious dogs to 0.025 pg per 100 mlduring Na depletion in conscious animals.

In chronic low output experimental heart fail-ure, both the volume of distribution and the frac-tional turnover rate were reduced. The resultwas a decrease in metabolic clearance rate of 55%,and the tj for the slow component of the disap-pearance curve was the longest observed in theseseveral experimental situations. Calculations ofthe peripheral plasma level of aldosterone fromknown values for aldosterone secretion and thepresent MCRdata show an increase from 0.002to 0.088 ug per 100 ml. The explanation for thedecreased volume of distribution is not clear.Failure of exercise to decrease further the rate ofmetabolism of aldosterone is probably a reflectionof the slow rate of degradation before exercise.It seems likely that hepatic blood flow was verylow in these animals with heart failure and thata further decrease failed to occur; the restingMCRof aldosterone for the animals before exer-cise was the lowest observed in the several situa-tions studied. These findings during the restingstate in chronic experimental low output failureagree with the results on the metabolism of aldos-terone in patients with heart failure (3, 11, 12, 17,18) in that MCRwas reduced. No data are avail-able on the effect of exercise on aldosterone metab-olism in patients with cardiac failure, and themeasurements of hepatic blood flow in patientswere made (4) on individuals with less heartfailure than these experimental animals. Sincethe MCRof aldosterone is unchanged in experi-mental high output failure, the increase in theperipheral plasma level of aldosterone is the re-sult of increased secretion of the hormone (7).

After hypophysectomy, the decrease in MCRmight be considered to provide a compensatorymechanism to help maintain the peripheralplasma level of aldosterone in the presence of de-creased aldosterone secretion. However, in spiteof this mechanism the peripheral plasma level ofaldosterone was reduced because of the relativelymore marked reduction in secretion than in MCR.

A decrease in hepatic blood flow appears to bethe primary mechanism leading to decreased aldos-terone metabolism. Since the slow component ofthe disappearance curve for aldosterone is almostflat following hepatectomy (1), the liver is theprincipal site for metabolism of aldosterone. The

1439

DAVIS, OLICHNEY, BROWN,AND BINNION

present data on the almost complete hepatic ex-traction of aldosterone and the earlier evidence(1) for negligible extrahepatic clearance of aldos-terone from plasma indicate that the system forthe metabolism of aldosterone is flow-limited. Inother words, with complete extraction of aldos-terone in one circulation of blood through the liver,a decrease in the total amount of aldosterone ex-tracted by the liver per unit of time is effected bya decrease in hepatic blood flow.

The importance of hepatic blood flow in deter-mining the rate of metabolism of aldosterone isalso indicated by the frequent association of re-duced liver blood flow with decreased MCRforaldosterone. Smythe (19) has reported a drop inhepatic blood flow from 43.4 to 20.8 ml per kg perminute following removal of 33 ml of blood per kgof body weight in anesthetized dogs. The au-thors are unaware of measurements of hepaticblood flow during Na depletion; if hepatic bloodflow was decreased in the present study, the changewas inadequate to influence aldosterone metabo-lism. There are many studies that demonstratedecreased hepatic blood flow in patients with lowoutput heart failure (4, 20), and the MCRforaldosterone is markedly reduced in both patientsand experimental animals with this type of cardiacfailure. In high output failure, data are not avail-able on the rate of hepatic blood flow. After hy-pophysectomy, a marked decrease (50 to 70%)in cardiac output occurs (21), and on this basishepatic blood flow might be expected to be low.Measurements of hepatic blood flow (personalobservations) in one of the four hypophysecto-mized animals of this study revealed a reductionin liver blood flow, and the MCRfor aldosteronewas reduced by hypophysectomy. Thus, the pres-ent alterations in aldosterone metabolism parallelthe known or suspected changes in hepatic bloodflow. In support of this relationship, Bougas andassociates (3) have recently demonstrated thatthe MCRfor aldosterone was halved by a changefrom the supine to the upright posture in man;hepatic blood flow also fell approximately 50%cwith this change in position (22).

Finally, it should be pointed out that decreasedaldosterone metabolism is not always associatedwith increased aldosterone secretion. The excep-tion in this study is the occurrence of a decreasedMCRin the hypophysectomized dog in which al-

dosterone secretion is markedly reduced (13).Usually, however, altered cardiovascular hemo-dynamic function with reductions in both renaland hepatic blood flow leads to hyperaldosterone-mia by the dual mechanism of hypersecretion anddecreased metabolism of aldosterone. A negativefeedback mechanism has been proposed (14, 16)to explain the regulation of aldosterone secretionand the peripheral plasma concentration of aldos-terone.

Summary

The rate of disappearance of H3-d-aldosteronefrom peripheral plasma was studied in dogs. Thedata were analyzed in terms of a two compart-mental model; the volume of distribution, frac-tional turnover rate, and metabolic clearance rate(MCR) were calculated. The tj of the slow com-ponent of the disappearance curve was prolongedand the MCRwas decreased after hemorrhage, fol-lowing hypophysectomy, and in experimental lowoutput heart failure, but aldosterone metabolismwas not detectably altered during Na depletion orin high output heart failure. Consequently, a de-creased rate of aldosterone metabolism contributedto the hyperaldosteronemia of hemorrhage and ex-perimental low output heart failure and provideda mechanism for counteracting the low secretionrate of aldosterone in experimental hypopituita-rism. Exhaustive exercise in dogs with low outputheart failure failed to produce a further decreasein the low rate of aldosterone metabolism. Aninverse relationship was observed between the tjof the slow component of the disappearance curvesand the MCR.

Measurements of the hepatic extraction of al-dosterone demonstrated almost complete removalof the hormone in one circulation of blood throughthe liver in normal dogs, following acute bloodloss, during Na depletion, after hypophysectomy,and during severe congestion of the liver sec-ondary to thoracic caval constriction. This findingsuggests that the hepatic mechanism for metabo-lism of aldosterone is flow-limited, since previousstudy has indicated negligible extrahepatic clear-ance of aldosterone from plasma. Also, there isevidence that hepatic blood flow is decreased inthe present conditions with a low rate of aldos-terone metabolism.

1440

METABOLISMOF ALDOSTERONE

Acknowledgments

We are grateful to Dr. Mones Berman for his help-ful advice in the use of the digital computer program.

References

1. Ayers, C. R., J. 0. Davis, F. Lieberman, C. C. J.Carpenter, and M. Berman. The effects of chronichepatic venous congestion on the metabolism ofd,l-aldosterone and d-aldosterone. J. clin. Invest.1962, 41, 884.

2. Tait, J. F., B. Little, S. A. S. Tait, and C. Flood.The metabolic clearance rate of aldosterone inpregnant and nonpregnant subjects estimated byboth single-injection and constant-infusion methods.J. clin. Invest. 1962, 41, 2093.

3. Bougas, J., C. Flood, B. Little, J. F. Tait, S. A. S.Tait, and R. Underwood. Dynamic aspects of al-dosterone metabolism in Symposium on Aldos-terone. Oxford, Blackwell, 1964, p. 25.

4. Donald, K. W. Hemodynamics in chronic con-gestive heart failure. J. chron. Dis. 1959, 9, 476.

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