aldosterone · 2014. 1. 29. · aldosterone and hypertension,ug per day in response to sodium...

ALDOSTERONESECRETIONAND PRIMARYAND MALIGNANTHYPERTENSION*

By JOHN H. LARAGH, STANLEYULICK, VLODZIMIERZ JANUSZEWICZ,QUENTIN B. DEMING, WILLIAM G. KELLY AND

SEYMOURLIEBERMAN

(From the Departments of Medicine, of Obstetrics and Gynecology and of Biochemistry, Collegeof Physicians and Surgeons, Columbia University, The Presbyterian Hospital,

and the Columbia University Research Service, GoldwaterMemorial Hospital, New York N. Y.)

(Submitted for publication November 9, 1959; accepted March 24, 1960)

After the synthesis of desoxycorticosterone(DOC), it became apparent that this cortico-steroid, the physiological effects of which are con-cerned primarily with sodium and potassium me-tabolism, can produce a state of hypertension bothin animals and in man (1, 2). The induced hy-pertension is dependent upon the administrationof adequate amounts of dietary sodium, whereasthe hypertensive state, produced by administra-tion of glucocorticoids such as cortisone, differsin that it is independent of the dietary sodiumcontent (3).

More recently, following the chemical and bio-logical characterization of the mineralocorticoidhormone, aldosterone (4), a disease state associ-ated with primary hypersecretion of this hormonehas been described in man (5). Aldosterone pro-duces effects on sodium and potassium metabolismsimilar to those of desoxycorticosterone, and theclinical syndrome of primary aldosteronism re-sembles the disease state produced by chronic ad-ministration of DOCto dogs (6). Arterial hy-pertension has been a consistent finding in pa-tients with primary hyperaldosteronism.

A number of other observations have suggesteda relationship between the dietary sodium intakeand the blood pressure level of patients with pri-mary (benign essential) hypertension. The bene-ficial effects of sodium deprivation, and of variousnatriuretic agents in certain patients with hyper-tension, is well known. In addition, other stud-ies have suggested that abnormalities of intracel-lular sodium and potassium content may occur inpatients with arterial hypertension (7). Genest,Koiw, Nowaczynski and Lebouef (8) have re-

* This work was supported by a grant from the UnitedStates Public Health Service (H-1275), the Fleitas Fund,and by Mr. Daniel G. Arnstein.

ported that the urinary excretion of aldosteronewas significantly increased in 55 per cent of theirpatients with hypertension of diverse etiologies.The increased levels of urinary aldosterone werenot correlated with any abnormality of sodium orpotassium metabolism, nor did the increased val-ues appear to be specifically associated with anyparticular type of hypertensive disease.

It has been recognized that the measurement ofurinary excretion of unchanged hormone may notaccurately reflect significant changes in adrenalsecretion of aldosterone. During the past severalyears a method has been devised which providesan estimate of the amount of aldosterone which isactually produced by the adrenal glands (9). Thetechnique involves the injection of a trace amountof tritiated aldosterone and the determination ofthe specific activity of a urinary metabolite of al-dosterone in the subsequent 24 hour urine. Thedifference between the specific activity of theinjected hormone and that of the urinary metabo-lite is considered to be a measure of the endoge-nous production of aldosterone and, as such, per-mits the estimation of the daily secretion rate.In the present report, this technique has been ap-plied to the study of patients with arterial hyper-tension. In the course of these studies an efforthas been made to correlate abnormalities in al-dosterone secretion with abnormalities in sodiumand potassium metabolism and, when possible,with changes in the morbid anatomy of the adrenalgland itself. The results have been compared withvalues obtained from normal subjects and frompatients with known primary aldosteronism.

METHODSAND MATERIALS

Patient selection. All of the patients studied werehospitalized. A complete history and physical examina-

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LARAGH, ULICK, JANUSZEWICZ, DEMING, KELLY AND LIEBERMAN

tion, routine laboratory tests, plasma and urinary elec-trolytes, intravenous pyelography and measurement ofcatecholamine excretion were obtained in all patients.None of the patients included in the group had evidenceof congestive heart failure. Frequently, the dietary in-take of sodium was stabilized by means of a constant dietprepared by the metabolic ward kitchen, and serial con-trol observations were then made while the patients wereon the metabolic ward. These detailed studies will bereported at a later date. Some of the patients were hos-pitalized at the Goldwater Memorial Hospital, ColumbiaDivision. All of the latter group had been in the hos-pital for considerable periods of time, and in severalinstances, daily blood pressure measurements for sev-eral years, as well as frequent determinations of plasmaand urinary electrolytes, were available.

Classification of hypertensive patienits. After effortsto exclude primary renal or adrenal disease the remain-ing hypertensive group selected for study was subdi-vided. The patients with elevated blood pressures butwith no evidence of renal insufficiency or of arteritiswere classified as "primary hypertension" (often called,"benign essential" hypertension). The patients withhigh blood pressure and evidence of renal or retinal com-plications were classified as "advanced hypertension" or"primary hypertension with complications." The cri-terion for renal complications was the presence of eitherproteinuria or a blood urea nitrogen greater than 30 mgper 100 ml or both. Retinal complications refer to thepresence of retinal hemorrhages (Grade III retinopathyaccording to the standard classification). Patients withunequivocal papilledema were classified as the acceleratedform or "malignant" hypertension. It was recognizedthat this classification, although useful, was arbitrary, andthat diverse etiologies could exist within these categories.For comparative purposes a group of patients with pri-mary aldosteronism was also studied. Diagnosis in thesepatients was made on the basis of 1) hypokalemic alka-losis, 2) hypertension, and 3) the finding of an adrenaltumor at operation or at postmortem.

The metabolic ward techniques and the methods usedfor measurement of plasma and urinary electrolyteshave been reported previously (10). Blood pressureswere measured with a standard cuff-type mercurymanometer.

The d-aldosterone employed in this study was tritiatedby the Wilzbach procedure (11) in the laboratories ofthe New England Nuclear Corporation. It was thenpurified to constant specific activity by paper chromatog-raphy. The paper used in the final chromatogram waswashed in a Soxhlet apparatus with ethanol for 1 weekprior to use. The aldosterone was eluted from thischromatogram with ethanol, and the eluate was filteredthrough a fine sintered glass filter. This solution wasdiluted with sterile water to make a 10 per cent ethanolsolution for intravenous inj ection.

Urine was collected for 24 hours after the injectionof tritiated aldosterone and hydrolyzed with a-glucuroni-dase at pH 5.0 for 3 days at 370 C. An extract of thehydrolyzed urine was prepared with ethyl acetate. The

tetrahydro-metabolite of aldosterone was isolated fromthe extract by paper chromatography, and acetylatedwith C14-labeled acetic anhydride of known specific ac-tivity. The triacetate of the metabolite then was chro-matographed first on paper and next on a partition col-umn. The H3/C14 ratios in the fractions from the par-tition column were determined by liquid scintillationcounting with a Packard Tri-Carb scintillation counterusing the discriminator ratio method of Okita, Kabara,Richardson and LeRoy (12). Constancy of the ratios inthe area of the tritium peak is indicative of radiochemicalpurity. The aldosterone secretion rate in microgramsper day can be shown to equal

counts per minute of aldosterone injectedspecific activity of the metabolite in 24 hour urine'

(counts per minute per microgram)

H3/C14 times the specific activity of the C`4-acetic anhy-dride equals the specific activity of the aldosterone me-tabolite. It is evident that the H3/C14 ratio is a meas-ure of the specific activity of the metabolite. This tech-nique has been previously outlined (9) and will be de-scribed in detail in a manuscript which is in preparation.

Plait of study. Because aldosterone secretion variesconsiderably with the dietary sodium intake (9), an ef-fort was made to stabilize the dietary sodium content forat least 5 days prior to study. With this precaution andin the absence of any demonstrable renal or adrenal in-sufficiency it was felt that the 24 hour urinary sodiumlevel represented a reasonably good index of sodium me-tabolism at the time the aldosterone production was meas-ured. In 17 subjects in whom a metabolic balance wasnot feasible the urinary sodium content was checked forseveral days before and after the administration of al-dosterone. If these values were not grossly reduced(below 20 mEq per day), if the patients exhibited noother signs of fluid retentioni, and if there was no his-tory of recent sodium deprivation, a state of sodiumretention was considered unlikely. However, in most(20 of 27) of these patients a complete metabolicbalance was carried out. In no instance did the pa-tients receive diuretic agents for at least 3 weeks priorto study.

RESULTS

The results are summarized in Table I and inFigure 1.

Normal subjects. In Figure 1 the results ob-tained in eight normal subjects on unselected dietsare presented graphically. The aldosterone se-cretion rate ranged from 150 to 330 ,ug per day inthese eight subjects. The corresponding 24 hoururinary sodium outputs ranged from 82 to 254mEq per day. With the same techniques em-ployed as in the present study, it has been shownpreviously that normal subjects studied increasedtheir aldosterone secretory rate to about 1,000

1 092

ALDOSTERONEAND HYPERTENSION

,ug per day in response to sodium deprivation, andthat the feeding of large amounts of sodium re-duced the rate to as low as 50 ,ug per day (9).

Primary hypertension. In eight subjects withprimary hypertension the adrenal secretory rateof aldosterone ranged from 180 to 330 pg per day.These values are within the normal range. Inthis group, there were no abnormalities in eitherplasma or urinary electrolytes suggestive of aldo-steronism. All but one of these subjects (no. 2)were without medication. Prior to the study, twoof the subjects (nos. 2 and 7) had had at least onecerebral thrombosis with recovery. There was noevidence of renal failure nor of any other compli-cations in the subjects included in this group.

Unilateral renal disease. Patients 9 and 10manifested the clinical picture of advanced hyper-tension which was presumably the result of uni-lateral renal disease. In Patient 9 the diagnosishad been established by demonstration of anoma-lous right renal arteries on aortography and wasconfirmed by surgical removal of the abnormalright kidney and a subsequent sharp fall in bloodpressure which has now been sustained for a year.A filling defect in one kidney was clearly demon-strated by pyelography in Patient 10 three yearsafter the onset of severe hypertension. This pa-tient was considered a poor surgical risk, andnephrectomy was not performed. Aldosterone se-cretory rates of Patients 9 and 10 were within the

TABLE I

Aldosterone secretory rates and related clinical and morphological findings in hypertensive patients

Degreeand dur-ation of

Age hyper- Urinet PlasmatPatient no. and and tension Aldosterone

diagnosis* sex B.P.t Study date secretion rate Na K Cl Na K C02 Cl Urea Pathology and remarks

mg/sgIday mEq/day mEqIL 100 ml

Primary 55 250/140 2/24/58 180 35 72 45 137 4.3 23 100 15hypertension F 10 yrs

200/1202.Primary 60 200/130 3/19/58 330 47 40 54 143 4.5 30 98 18 On hydralazine and re-

hypertension M 16 yrs serpine; had had multi-135/85 ple "strokes"

3Primary 40 250/120 7/9/58 180 196 81 133 138 4.3 25 102 15

hypertension M 10 yrs190/120

4Primary S3 190/122 3/12/59 320 138 49 134 3.8 25 103 22

hypertension M 9 yrs180/110

SPrimary 38 220/110 4/11/59 320 59 63 138 4.5 25 100 17

hypertension F 6 yrs190/110

6Primary 17 240/140 9/2/58 250 34 43 96 138 4.2 25 100 15


7Primary 50 180/120 4/2/59 190 103 81 114 134 4.7 24 107 12 Had one small "stroke'

hypertension F 6 yrs and diabetes170/110

8Primary 55 220/110 5/15/59 330 101 152 144 4.2 28 99 18


9Unilateral 12 270/240 9/14/58 200 66 45 57 140 4.3 25 105 16 Anomalous right renal

renal disease M 11 yrs (Before arteries; Grade I fundi225/150 nephrectomy) (had sympathectomy

in 1947) 155/110 post-nephrectomy.

10Unilateral 58 198/113 4/16/59 340 188 76 194 130 3.1 27 97 25 On chlorothiazide, reser-

renal disease M 3 yrs pine and hydralazine195/110

* Patient 12 was studied through the courtesy of Dr. Robert D. Gittler; Patient 13, courtesy of Dr. Marion Isaacs of the Veterans Administra-tion Hospital, First Avenue at 24th Street; Patient 14, courtesy of Dr. H. Chase of Brooklyn Jewish Hospital. Patients 20 and 26 were studiedthrough the kind cooperation of Dr. Milford Fulop of the Albert Einstein College of Medicine. Patient 27 has been previously reported in detail(14).

t At time of study.

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AgePatient no. and and

diagnosis* sex

11Primary 65

aldosteronism F

12Primary 42

aldosteronism F

13Primary 43

aldosteronism M

14Primary 47

aldosteronism F

15Primary 1 7

aldosteronism F

16Primary 63

hypertension Mwith complica-tions

17Primary 56

hypertension Fwith complica-tions

18Primary 56

hypertenision Mwith complica-tions

19Primary 58

hypertension Mwith complica-tions

20Primary 43

hypertension Fwith complica-tions

21Primary 47

hypertension Mwith coinplica-tions

22Primary 51

hypertension Mwith comnplica-tions

23Primary 33

hyp)ertension FwVitl cornplica-tions

TABLE i-Continued


e hyper- Urinet Plasmatd tension Aldosteronec B.P.t Study date secretion rate Na K Cl Na K C02 Cl Urea Pathology and remarks

200/13535 yrs

180/110

205/11015 yrs

180/110

240/12010 yrs

220/120

180/11010 yrs

180/110

250/1505 yrs

190/130

240/11012 yrs

155/75

220/12512 yrs

145/80

155/1007 yrs

155/105

170/1004 yrs

170/100

250/1403 yrs

250/140

170/110

240/13018 yrs

190/100

210/1206 yrs

1 60/lt)0

22(/11204 yrs

19)7/110

5/11/58

7/15/58

7/7/58

9/5/58

2/9/59

3/3/59

3/19/58

3/19/58

4/16/59

4/16/59

6/16/58

9/20/58

7/27/59

7/30/59

7/15/59

pg/day

650

510

1,350

585

1,000

1,690(After right

adrenalectomy)

450

600

960

510

1,170

350(Postop.)

130

240

mEq/day mEq/L 100 mnl

54 30 138 2.0 44 89 20 Right adrenal adenoma,left adrenal atrophy;arteriolar nephrosclero-sis moderately ad-vanced

58 54 45 141 2.5 37 107 15 Left 2.5 cm adrenal cor-tical adenoma removed;no polyuria

160 71 140 2.3 24 110 15 Adrenal adenoma 1 inchyellow; microscopic notunusual; C02 neverhigh; B.P. 160 to 180/110 postop.; K normal;GFRslightly low

37 70 140 2.6 38 90 18 No polyuria; 3.5 cmtumor removed fromright adrenal

43 74 144 2.5 31 107 19 Right adrenal gland re-mov-ed (normal gland);

64 68 148 3.2 33 101 14 left gland had tumor1.5 cm removed later(7/1/59)

102 44 70 143 3.5 28 103 50 Hydralazine fundi gradeIII; proteinuria; de-creased urea clearance;stroke 1949

48 29 55 141 3.4 35 91 45 Hydralazine and reser-pine; fundi grade IIIfor 5 yrs; died inuremia

87 61 103 138 3.7 28 100 37 One kidney nonfunction-ing for 1 yr by pyelo-gram calcified pineal;had stroke 2 yrs agoand thrombosis of ret-tinal artery

115 57 133 130 4.4 25 101 31 Hydralazine and hydro-chlorothiazide; pro-teinuria grade III ret-inopathy

80 51 61 138 3.5 31 96 18 Bilateral grade III retino-pathy; normal glands atexploration; left glandlremoved; postop. cor-

150 75 163 138 4.5 26 100 18 rection of slight plasmaalkalosis; persisted hy-pertension 8 mos laterof 180/110

99 44 138 4.0 26.3 104 36 Mild diabetes

85 49 142 3.9 27.7 100 17 Hemorrhages in fundinoted 1954, albuminu-ria +

575 137 57 140 5.0 26 1(13 25 Malar rasli 1954 andarthralgia, at times+++ albuminuria, L.E. prep. negative

1094

m.Pfy/


TABLE i-Continued


Age hyper- tIrinet Plasma-tPatient no. and and tension Aldosterone

diagnosis* sex B.P.J Study date secretion rate Na K Cl Na K C02 Cl Urea Pathology and remarks

56 250/150 4/28/58M 20 yrs

240/150 6/9/58

mEqlday mEq/L

130 67 122 138 3.6 30

69 60 40 135 3.5 35

36 62 30 138 3.2 35

800 26 56 42 133 3.5 30

mg/100 ml

99 53 Mecamylamine and re-serpine

92 27 Not helped by bilateraladrenalectomy in 2

92 41 stages; terminal ure-mia; adrenal glandsshowed nodular hyper-plasia but normalweight, proteinuria + +

92 35 Reserpine

1,020 47 66 139 3.7 28 99 58 Bilateral adrenal corticalhyperplasia at post-mortem

600 35 45 40 131 3.9 25

860 53 79 72 135 3.7 26

1,220 101 54 55 132 3.6 30

2,180 43 66 140 4.1 271,650 8.5 50 138 4.4 311,450 122 55 133 2.9 27

2,730 51 113 91 141 3.2 28

1,600 67 54 75 125 3.8 32

740 36 20 33 133 3.1 28

190 141 47 92 135 4.2 22

105 30 Hydralazine and reser-pine; was alkalotic attimes; was severely ma-lignant prior to drugtherapy (4 yrs ago)

95 71 Adrenal glands over-weight and hyperplasticat postmortem

92 37 Hydralazine and me-camylamine

95 45 Adrenal glands normal99 54 weight; possibly hyper-

100 40 plasia

101 47 Microscopic adrenal hy-perplasia (nodular)

76 81 Had sympathectomy8/56; adrenals "nor-mal" at operation

93 15 Normal aortogram

102 20 Hydralazine, had sym-pathectomy 1 yr priorto test with consider-able benefit

1,500 25 35 140 3.2 32 101 22 Polyuria 2 to 3 L for12 yrs

10,000 42 76 126 3.9 27 79

700 94 101 135 3.5 30 89

78 Plasma bicarbonate ashigh as 40 mEq/L, K aslow as 2.1; glandsgrossly normal at postbut hyperplastic micro-scopically

25 Many retinal hemor-rhages; + + albuminu-ria

normal range, 200 andtively.

Primary aldosteronisn

340 ,tg per day, respec- secretory rate was significantly increased abovenormal values, ranging from 510 to 1,690 ,ug per

P. Patients 11-15 repre- day. These elevated aldosterone values weresent examples of proven primary aldosteronism found in the face of relatively high values for uri-(Conn's syndrome). In these patients the adrenal nary sodium excretion. All of these patients ex-

1095

57 240/149F 12 yrs

160/110

9/13/58

,ug/day

520

600

760(Postop.

first stage)

24Malignant

hypertension25Malignant

hypertension

26Malignant

hypertension

27Malignant

hypertension

28Malignant

hypertension

29Malignant

hypertension

30Malignant

hypertension

31Malignant

hypertension

32Malignant

hypertension

33Malignant

hypertension

34Malignant

hypertension

35Malignant

hypertension

36Malignant

hypertension

37Malignant

hypertension

38Malignant

hypertension

46 250/150F 9 yrs

215/130

55 240/160.M 2 mos

250/150

59 170/100M 4 yrs

165/100

48 280/160M 3 yrs

230/130

53 220/130M 4 yrs

160/110

42 250/160F 5 yrs

240/150

44 250/150F 15 yrs

200/100

23 260/150F 5 yrs

240/150

7 300/150F 5 yrs

250/140

39 260/140F 4 yrs

230/130

53 250/149M 14 yrs

240/140

46 250/160F 12 yrs

220/160

27 240/140M 6 mos

240/140

3/19/58

4/21/58

4/16/59

4/21/59

5/15/59

3/21/593/26/594/8/59

10/8/58

9/28/58

8/30/58

9/18/58

6/30/59

7/3/59

7/25/59


4aa 2500wILU)

4

D 20000U

z

z 15000

w

U) 0ooo

z0

NORMALSUBJECTS

V

H

I-I500 -I

00

4

mEq/day200

50

501

10,0001II

UnilateralRenal1

Disease

PrimaryAldosteron ism

due toAdrenal Tumor

I

II I1

Primary(Essential)

IHypertension

I IE||

II 11111111

I

Lq mIoil 0 9 0 ,I 0 nommi MINE

AdvancedHypertension

MalignantHypertension

FIG. 1. ADRENAL SECRETION RATES OF ALDOSTERONE(IN MICROGRAMISPER 24 HOURS) FOR 8 NORMALSUBJECTS,8 PATIENTS WITH PRIMIARY HYPERTENSION, 8 PATIENTS WITH PRIMARY HYPERTENSION WITH COMPLICATIONS ("AD-VANCED" HYPERTENSION), AND 15 PATIENTS WITH MALIGNANT HYPERTENSION. For comparative purposes 2 pa-tients with unilateral renal disease and 5 patients with primary aldosteronism are presented. The urinary sodiumcontent of the corresponding 24 hour urine collection is also shown. There is no evident hypersecretion of aldo-sterone in primary hypertension. In malignant hypertension marked hypersecretion of aldosterone was found andthe values were often higher than those encountered in patients with primary aldosteronism. The patients withmalignant hypertension resembled those with primary aldosteronism in that the hypersecretion was not associatedwith grossly reduced sodium excretion.

hibited hypokalemia and all but one had an ele-vated plasma bicarbonate level. All of these pa-tients had adrenal adenomas. In Patient 11 thetumor was found at autopsy after a negativelaparotomy. In Patients 12-15 the symptomatol-ogy was relieved by surgical removal of an adrenaladenoma. Patient 15, a girl, aged 17, exhibitedsevere hypertension with papilledema. This pa-tient was improved after a two-stage total adrenal-ectomy. An adenoma of the right adrenal glandwas found, but all of the adrenal tissue appearedhyperplastic on microscopic study. The signifi-cance of the adenoma is thus questionable. Pre-cise classification of this patient is, therefore, diffi-cult, since, as will be seen, she could also have beenclassified as malignant hypertension with adrenalhyperplasia.

Primary hypertension with complications (Pa-

tients 16-23). The patients included in this grouphad had their hypertensive disease for periods offrom 3 to 18 years. Three of these eight patientswere on antihypertensive medications as indicated(Table I) at the time of the study. Five of the pa-tients included in this group had significant ni-trogen retention (nos. 16-19 and 21) and sevenhad retinal hemorrhages (nos. 16, 17, 19-23).The aldosterone secretion rates ranged from 130to 1,170 ,ug per day in these patients. In five ofthese eight the values were above 500 ,ug per dayand appeared significantly elevated above normal.As in the patients with primary aldosteronism,the increased aldosterone production was observedin the presence of relatively high urine sodiumlevels (Figure 1). The plasma bicarbonate levelswere 28 mEq per L or higher in four of thesepatients, and in all but one plasma potassium levels

1096


were less than 4 mEqper L. With one exception(Patient 19) the increased aldosterone secretoryrates were found in the patients with relativelyhigh plasma bicarbonate levels. In five of theeight patients in this group the blood urea nitro-gen exceeded 30 mg per 100 ml. However, theelevated aldosterone production did not appear tobe constantly associated with this nitrogen re-tention.

Patient 20 was subjected to laparotomy, and,when no tumor was found, a left adrenalectomywas carried out. The gland was grossly normalbut microscopically revealed some nodularity andfocal hyperplasia. It is of interest that followingthis procedure there was a sustained (9 months'observation) fall in blood pressure to levels of170/110 and complete clearing of retinal hemor-rhages. After the unilateral adrenalectomy thealdosterone secretion rate was also markedly re-duced from 1,170 ug per day to a value withinthe normal range of 352 ,ug per day. The se-quence of events raised the possibility that hyper-secretion of aldosterone might have been a factorin accelerating this patient's hypertensive disease.

Malignant hypertension (Patients 24-38). Fif-teen patients with malignant hypertension char-acterized by papilledema were studied. Theknown duration of the hypertension in this groupranged from 2 months to 20 years. However,the duration of the papilledema in these cases isdifficult to determine. In most instances, it ap-peared to be a relatively recent development asthe disease state progressed from the benign tothe so-called accelerated form.

The adrenal secretion rate of aldosterone inthese patients with malignant hypertension rangedfrom 190 to 10,000 ug per day. All of the valueswere markedly elevated above normal except forthat of Patient 35. The range for the remaining14 patients was from 520 to 10,000 ug per day.Patient 35 differs perhaps from the rest of thegroup in that at the time of study she was con-siderably improved following sympathectomy.Furthermore, more recently, papilledema has sub-sided, and this patient appears to be free of the"malignant" state. Another sympathectomizedpatient in the group (no. 33) exhibited an ele-vated secretion rate, but in this patient the opera-tion was not associated with clinical improvement.

In this group of patients with malignant hy-

pertension, significant nitrogen retention was pres-ent in 9 of the 15 (blood urea nitrogen over 30mg per 100 ml). Despite this evidence of renalinsufficiency, in 6 of the 15 the plasma bicarbonatevalues were 30 mEq per L or higher, and in 9of the 15 the values were 28 mEqper L or higher.These values appear particularly impressive be-cause they were often encountered in the pres-ence of nitrogen retention, which is character-istically associated with retention of fixed anionsand an associated reduction in the plasma bi-carbonate concentration. Perhaps even morestriking was the fact that in 13 of the 15 patientsin this group the plasma potassium values werefound to be less than 4.0 mEqper L, and in 10 of15 were less than 3.8 mEq per L. Again, in theface of renal insufficiency, the tendency to hypo-kalemic alkalosis in these patients is noteworthyand perhaps affords supporting evidence suggest-ing the presence of hyperaldosteronism.

The markedly increased aldosterone secretion inthis group of patients was found, as in the patientswith Conn's syndrome, to occur in the presence ofrelatively high urinary sodium levels and was,therefore, clearly not associated with a state ofprogressive sodium retention. Although the uri-nary Na levels were never grossly reduced (range,25 to 113 mEq per day), they were somewhatlower than those in the other patients (see Figure1). There was no evidence of significant positivesodium balance in any of these patients and thelowered excretions were the result of lower in-take. The increased aldosterone secretion ap-pears to be far in excess of what one would nor-mally find in association with such levels of uri-nary sodium excretion.

Relation of aldosterone secretion to blood pres-sure level. No correlation was evident betweenthe degree of elevation of blood pressure and thedegree of elevation in the aldosterone secretoryrate in this series of patients. Many of the pa-tients with primary hypertension manifested bloodpressure elevations which were as high or higherthan those observed in the patients with primaryhypertension with complications, or in the pa-tients with malignant hypertension.

Relation of aldosterone secretion rate to renalinsufficiency. The patients with advanced or withmalignant hypertension often exhibited significantnitrogen retention (13 of 23 with blood urea ni-

1097


trogen above 30 mg per 100 ml). Yet, it is diffi-cult to relate the increased aldosterone secretionspecifically to this renal failure since a number ofthe patients (7 of 23) had elevated aldosteronesecretion rates with a normal blood urea nitrogen.

It has been shown that patients with sodium-losing renal disease may excrete large amountsof aldosterone. Presumably this is a secondarymechanism in an attempt to conserve sodium.Also, these patients may continue to excrete in-creased amounts of aldosterone long after sodiumrepletion, a phenomenon which has been termed"secondary primary aldosteronism" (13). It isconceivable that certain of the patients reportedhere had antecedent or subtle forms of sodium-losing renal insufficiency, but, insofar as is pos-sible, metabolic balance studies appear to have ex-cluded this possibility at the time of the study inPatients 11-15, 20, 21, 23-28, 31, 34 and 35.These patients all had urinary sodium values ofless than 10 mEq per day after dietary depriva-tion. Patient 13 with primary aldosteronism andPatient 32 with malignant hypertension, mani-fested slight impairment of renal sodium conser-vation on low sodium intakes (urine sodium didnot fall below 20 mEq per day). Yet, even inthese two patients, there was no evidence that theimpairment of renal function had preceded thehypersecretion of aldosterone. Therefore, whileit is theoretically possible that impaired renal so-dium conservation couldI have preceded and pro-voked secondary hypersecretioni of aldosterone inthese hypertensive subjects, the available datado not establish that this was the sequence ofevents.

It is important to emphasize that, conceivably,as a consequence of severe renal disease themethod as employed might yield an apparentlyhigh secretory rate in the absence of true hyper-secretion of aldosterone. A basic requirementwhich must be fulfilled, if the isotope dilution tech-nique used in this study is to measure the truesecretion rate, is that the reactions involved in theconversion of radioactive hormone to radioactivemetabolite and also in excretion of the radioactivemetabolite into the urine must have gone to com-pletion within the period during which the urineis collected. In other words, regardless of theother metabolites to which the injected labeledhormone may be converted, all of the isotopically

labeled tetrahydrometabolite which is to be formedmust have been formed and excreted within thecollection period. If additional amounts of radio-active metabolite were to be excreted into subse-quent urine collections, then the conditions neces-sary for determination of the secretion rate byisotope dilution would not exist and the value ofthe secretory rate derived from such an incom-plete collection would be artificially high.

It has already been shown (14) that the frac-tion of radioactivity originating from injected C14-cortisol that appears in urine and, to a muchlesser extent, the rate at which it appears in theurine, are related to the clearance of creatinine.Normal individuals with clearances of about 125ml per minute excreted about 80 per cent of C14in the first day's urine, whereas patients with kid-ney disease and creatinine clearances of 42 to 55ml per minute excreted about 50 per cent in thefirst day, and patients with creatinine clearancesof 5 to 9 ml per minute excreted only about 3 percent in the first 24 hours. Perhaps more impor-tantly, in all of the subjects, very little additionalradioactivity appeared on the second and thirddays.

The condition set forth above does not requirethat a certain percentage of injected radioactivitymust appear in the urine. If the assumption ismade that the injected labeled molecules have thesame fate as the endogenously produced hor-mone, then if only a small fraction of injectedhormone is converted to radioactive metabolite,a similar small fraction of the endogenous hor-mone undergoes the same fate. It is only neces-sary that the collection period be long enough topermiiit complete formation and then complete ex-cretion of all the radioactive metabolite which isto be excreted.

Analysis of the dlata presented in Table II re-veals no consistent relationship between the bloodurea nitrogen and the aldosterone secretion rate.In Table II seven patients with good renal func-tion (three normal subjects and four subjects withbenign hypertension) are compared with sevenpatients with nitrogen retention. The patientswith elevated blood urea values, as a group, ex-creted less of the injected hormone as the urinarytetrahydrometabolite than did the patients withnormal renal function (average of 6.1 comparedto 12 per cent). There is overlap in the two

1098

ALDOSTERON'EANDHYPERTENSION1

TABLE II

Relationship of blood urea nitrogen concentration to excretion of labeled aldosterone

Per cent of in-jected counts

released byglucuronidasehydrolysis (24 Aldosterone

Patient Diagnosis BUN* hour urine) secretion rate

mg/100 ml pg/24 hrsB Normal 16 14.3 334F Normal 18 7.9 170G Normal 15 8.7 255

4 Primary hypertension 22 13.5 3216 Primary hypertension 15 12.0 2507 Primary hypertension 12 8.5 1908 Primary hypertension 18 12.1 330

18 Primary hypertension 37 4.7 960with complications

26 Malignant hypertension 35 3.4 80029 Malignant hypertension 71 5.3 86030 Malignant hypertension 37 4.2 1,22531 Malignant hypertension 45 4.3 2,18032 Malignant hypertension 47 11.5t 2,73037 Malignant hypertension 78 9.2 10,000

$ Blood urea nitrogen.t In this subject no radioactivity was released by enzyme hydrolysis of the urine collected on the second day after

injection.

groups; the former ranging from 7.9 to 14.3 percent; the latter, from 3.4 to 11.5 per cent. Pa-tient 37 with a blood urea nitrogen of 78 mg per100 ml had a secretory rate of 10,000 ,ug per day,whereas Patient 29 with a blood urea nitrogen of71 mg per 100 ml had a secretory rate of only 860Mug per day.

Of the patients in this group an effort was madeonly once to determine whether radioactivity wasstill being excreted after the first day. Patient 32who excreted 11.5 per cent of the injected tritiumon the first day (secretory rate = 2,730 ug) ex-creted no detectable radioactive metabolite on thesecond day. Thus, in this single study, at least,the observed high secretion rate appears to beunrelated to renal failure, because all of the radio-active metabolite destined for excretion appearedwithin the first 24 hours. While this require-ment has not actually been demonstrated in theother subjects with renal failure, the fact thatthese subjects often excreted about as much iso-tope as did the normal controls, and the fact thathigh secretion rates did not always correlate withrenal failure, tend to indicate that the observed in-creases in aldosterone secretion are not related tokidney disease but rather to a truly increasedadrenal production.

Because an abnormally prolonged excretion ofisotopically labeled metabolite in renal diseasewould produce artificially high estimates of the24 hour secretory rate, another group of ten pa-tients has been studied in which the urinary col-lection periods were extended to two or threedays, and the specific activity of labeled metabolitewas determined for each of the days of collection.These data are summarized in Table III and inFigure 2. Included in this group are three preg-nant women in the third trimester, four patientswith renal diseases other than malignant hyper-tension, one patient with uncomplicated hyper-tension (normal renal function) and three pa-tients with malignant hypertension.

Since accurate quantitation of the amount ofradioactivity in the metabolite is difficult, its spe-cific activity, derived from the ratio of H3 to C14in the triacetate of the metabolite, was determinedinstead. If the major portion of labeled metabo-lite is excreted in the first 24 hours, the H3/C14ratio for the first day should be much higher thanthat for subsequent days. The average secretionper day over a two or three day period was cal-culated from the average H3/C14 ratio over thegiven period. When the average secretion ratewas the same as the secretion rate determined for

1099


TABLE III

The effect of delayed excretion of labeled tetrahydroaldosteroneon the estimation of the aldosterone secretory rate

Estimated secretory*rate (gg/day)-

Counts per minute:Per cent of

labeled H3/C'4t of In eluateRenal status metabolite aldosterone of first Per cent

Patient and accounted tetrahydro Released by chromato- of injecteddiagnosis BUN Proteinuria Days S. R. for metabolite glucuronidase gram dose

(a) 18 0 1 310 93.6 54.7 104,000 95,000 12Lay.Primaryhypertension (b)

2Ver.Pregnancy

3Thom.Pregnancy

4Vict.Pregnancy

5Du.Nephrosis

6 (a)Tayl.Malignanthypertension (b)

7

Youn.Diabeticnephropathy

8 (a)Vel.Malignanthypertension (b)

9Kirt.Nephrosclerosis

10 (a)Chris.Sodium-losingnephritis (b)

Dunc.Malignanthypertension

18 0

12 +

2 29031 2702 2603 260

123

1.7

96.3 86.74.30.16

750lost

1 8402 710

11 ++++ 12

1,200

(a) 14 ++++ 1 3802 3503 340

(b) 14 ++++ 1 3102 2953 295

35 +

45 +

49 ++

55 +++

67 +++

89 +++

86 0

104 0

1 9252 830

1 5102 445

23

23l23

2

1

231

2

210185

740595570665490

200

1,000

1,320970

185 ++++ 1 14,6002 7,5003 6,000

21,0006,000

104,00044,000

8,500

9.5 50,000

0.3 2,500

1,5001,100

95,0007,0001,000

35,000

3,000

0.160.148.90.650.1

12.5

1.0

84.6 9.4 41,000 69,000 24.61.6 7,700 23,000 8.2

6.6 30,0001,500

89.5 22.897.2 1.0

0.36

95.2 73.43.70.084

89.8 9.71.1

87.3 16.82.4

88.1 426.2

77.0 11.695.8 2.8

0.573.7 13.5

4.7

43.2

9.7

0.1473.5 18.0

6.4

33,0009,0005,000

158,00037,00014,000

43,0008,000

16,0005,500

43,000 15.3

22,000 5.51,000 0.25

500 0.1

66,5003,000

750

16,0001,500

10,0004,500

31,0005,000

64,000 1,200

23,5006,5001,000

30,00015,000

5,000

18,0003,6001,000

13,0005,000

6.30.30.1

4.10.4

2.51.1

8.21.40.3

4.60.9

3.31.3

23,000 10,000 2.613,000 2,200 0.6

26,00014,00011,00077,00025,000

11,0006,2001,500

60,00020,000

2.61.50.45.51.8

0.59 8,000 4,000 1.00.54 10,000 3,000 0.750.30 4,000 2,000 0.50

* The secretion rate (S.R.) for Days 2 and 3 is calculated fromH3/C14 Day 1 + H3/C'4 Day 2 + - - H3/C'4 Day n

nand (S) = S.R./day.

n

Per cent of labeled metabolite accounted for is the per cent of completeness of excretion of the labeled metabolite of the

7 ++

1100


N

I-

a

112LARAGH, ULICK, JANUSZEWICZ, DEMING, KELLY AND LIEBERMAN

26.5 per cent (or, more properly, by the 16.5 percent value in excess of the normal error). How-ever, in Imlost instances, the error is less. The26.5 per cent figure was obtained in a patientwith a blood urea nitrogen of 104 mg per 100 ml(Patient 10). Thus, the rate of excretion of thelabeled metabolite by two subjects with overt re-nal insufficiency (Patients 6 and 7) did not differsignificantly from patients with normal renalfunction. Of special interest is the finding that intwo patients with malignant hypertension and azo-temia (Patients 6 and 8), both tested twice, thepercentages of labeled metabolite excreted in thefirst day were 89.8, 87.3, 77 and 74 per cent.

One comatose patient with malignant hyper-tension and terminal urenmia, who died the dayafter the last collection, has been included. Thispatient was obviously moribund. Unlike allothers, the specific activity of the metabolite didnot fall between the first and second days and fellby only 50 per cent in three days. The minimumestimated secretory rate was 6,000, but this resultis obviously invalid because no evidence for com-pleteness of excretion of metabolite could be ob-tained before death of the patient. The number ofcounts excreted was small and constituted a traceof the injected dose. In contrast, in the one pa-tient of the present series of malignant hyperten-sive subjects with a similarly high estimated se-cretory rate of 10,000 ,ug (Patient 37, Table II)both the amount and the percentage of labeledmetabolite excreted were similar to that of normalsubjects and were considerably higher than thoseobserved in Patient 11 of Table III. The possibleerror associated with this estimated 10,000 ugproduction value was not determined, but from theexperience summarized in Table III it seemslikely that the corrected value would be consider-ably elevated above the normal range.

The experience summarized in Table III andin Figure 2 illustrates that the renal excretion oflabeled tetrahydroaldosterone is inversely relatedto the excretion of urea. The data indicate thata secretion rate value in patients with azotemiamay need to be corrected by as much as about30 per cent. The data suggest that a correctionfactor based on the degree of azotemia should beapplied to each of the secretion rates given inTable I in order to obtain a more accurate secre-tory rate valuie. However, it appears from re-

examination of Table I that even if a correctionerror of about 30 or even 40 per cent is applied tothe mlalignant hypertensive patients studied, mostof the abnormally high values remain above thenormiial limits. This finding, combined with thedemiionstration of hypersecretion in a number ofthe patients who (lid not exhibit nitrogen reten-tion, suggests that the high values observed in thiscondition are not miierely the result of delayedrenal excretion of the metabolite.

Evidences for hypersecretioni of other adr-enalcortical hormiones. Four of the patients reportedin the present study were tested for their glu-cocorticoid response to an ACTH infusion. Pa-tient 11 exhibited a rise in plasimia 17-hydroxy-corticoids (Porter-Silber miiethodl) from 31.2 to51.6 Mg per 100 ml after an ACTH infusion. Pa-tient 15 responded by an increase in plasma hy-(lroxycorticoids fromii 17.6 to 41.5 ,ug per 100 ml.(This test was done after one adrenal had beenremoved.) Patient 23 exhibited a rise in plasma17-hydroxycorticoids of from 35.7 to 58.0 Mug per100 ml. These values are all considered to bewithin the upper limilit of normal. Patient 27 hasbeen previously reported in detail by Hilton,Westermann, Bergen and Crampton ( 15), andexhibited an abnormal response to the infusion ofACTH. This patient is the only patient in theseries in whom hyper-responsiveness to ACTHwas clearly present. In ten other patients of thepresent series the urinary 17-hydroxycortico-steroi(ls and 17-ketogenic steroids were measured,and all of these values were within normal limits.

Correlation of findings withi miorphologicalchanges in the adrenal tissuie. In seven of the pa-tients with malignant hypertension reported inthis study, complete postmortem examination hasbeen made. No tuimor was found in the adrenalsof any of these patients, but in four of the seventhe adrenal glands were significantly above theupper limits of normal in weight. In all sevensubjects the glands exhibited areas of focal hyper-plasia and nodularity, especially in the region ofthe glomerulosa zone. In additioni, there wasfocal increase in cellular activity and increasedlipid deposits in focal cellular areas. Pathologi-cal findings in these cases, as well as in two othersurgical specimens. will be the subject of a sepa-rate report (16).

Effect of v,ariouis pharnmacological agents. The

102


effect of various antihypertensive drugs on thesecretion rate of aldosterone is unknown. Cer-tain of the patients (10 of 33) included in thisseries were under treatment with various hypo-tensive agents, and this has been recorded inTable I. From the results obtained, these agentsdo not appear to have had any consistent or spe-cific effect on the secretion rate of aldosterone.

DISCUSSION

Estimation of the adrenal production rate byisotope dilution as carried out in the present studypossesses a number of inherent advantages overthe previously employed methods which havemeasured the small fraction of hormone excretedunchanged in the urine. However, it should berecognized that while the measurement of adrenalsecretory rate would seem to be a more preciseand reliable index of aldosterone activity, it too,may not always be an accurate reflection of theeffective concentration of active hormone in theblood. Possibly, blood level measurements mayprovide additional information in this regard, andultimately may even be necessary to assure properinterpretation of secretion rate studies.

The data presented suggest that a well definedbiochemical difference exists between a group ofpatients classified as benign essential hypertensionand those who manifest the clinical picture of ad-vanced or of malignant hypertensive disease.Marked increases in the secretion rate of aldo-sterone were found in all but one of the patientswith malignant hypertension and in three of eightpatients classified as "advanced" hypertension.These increased values were observed in the pres-ence of normal sodium intakes. In contrast, allof the patients with primary hypertension se-creted normal amounts of aldosterone.

Thus, malignant hypertension represents an-other syndrome which is associated with increasedsecretion of aldosterone. While this clinical stateresembles the disease produced in animals givenexcess mineralocorticoid, it clearly differs from theclinical picture of primary aldosteronism in thatevidences of vasculitis are characteristically ab-sent in the latter condition.

The frequent occurrence of hypokalemic alka-losis as manifested by either an elevated plasmabicarbonate and/or a reduced plasma potassium

concentration in patients with advanced or withmalignant hypertension appears as a somewhatunexpected finding. This tendency to alkalosismay be taken as supportive evidence of increasedaldosterone secretion. The alkalosis may haveadditional significance since it was found to occurat times in the presence of renal failure where re-tention of fixed anions ordinarily tends to lowerthe plasma bicarbonate level and thus could maskthe typical plasma abnormalities of aldosteronism.

In the patients reported here hypersecretion ofaldosterone was often found in association withdemonstrable renal insufficiency. One cannotdeny that sodium-losing renal disease could leadto secondary hypersecretion of aldosterone in pa-tients with advancing hypertensive disease. How-ever, as pointed out above, the data obtained thusfar do not tend to suggest the operation of such amechanism. (Most of the patients conserved so-dium normally.) Further study of patients withother forms of renal disease may be necessary todetermine a possible relationship between aldo-sterone secretion and renal insufficiency. Itshould be restated here that the technique em-ployed for estimation of adrenal secretion may beaffected by renal insufficiency, but the error causedby delayed excretion has not been of sufficientmagnitude to invalidate the results.

In general, the hypersecretion of aldosteronewas more impressive in the seriously ill patients(10 of the 15 patients with malignant hyperten-sion are now deceased). However, whether thealdosterone hypersecretion is a cause or a resultof the severe disease is not clear. Hypersecretionof aldosterone has not been noted in associationwith various other severe illnesses (17), but heretoo, further studies are necessary, especially inpatients with other forms of arteritis.

Prior to the present study, the association ofpotassium depletion and alkalosis with severe hy-pertension has been noted. Wyngaarden, Keiteland Isselbacher (18) reported the case of a 46year old man with malignant hypertension andsevere alkalosis whose adrenal glands were grosslynormal at postmortem. Two other cases of potas-sium depletion associated with malignant hyper-tension and high aldosterone excretion have beenreported (19, 20). In both, the authors consid-ered that the observed aldosteronism might havebeen secondary to renal damage. Both of these

1 103


patients succumbed without being helped by bi-lateral adrenalectomy, and here too, the adrenalglands were not grossly abnormal.

About 35 cases of primary aldosteronism havenow been reported (17). About 28 of these havebeen shown to be associated with an adrenal ade-noma, and two others were associated with adrenalcarcinoma (21, 22). Hypertension of varyingdegree was present in all of the cases, but in onlyone of the cases associated with an adenoma wasthe hypertension malignant (23). This patientdied without operation. In marked contrast, andof special interest in relation to the present study,is the fact that in five of the six reported cases(15, 24-28) of primary aldosteronism associatedwith bilateral adrenal cortical hyperplasia, thesyndrome of malignant hypertension with papill-edema was present. In all but one of these sixpatients subtotal adrenalectomy was carried outand was followed by improvement. The fact thatthe syndrome of malignant hypertension was sooften found in these patients labeled "primary al-dosteronism due to bilateral adrenal hyperplasia."illustrates again a fundamental difficulty in prop-erly classifying these diseases. Obviously, thesereported cases might well have been more appro-priately classified as examples of "malignant hy-pertension" rather than of "primary aldosteron-ism."

The finding of an adrenal adenoma at least sug-gests a primary adrenal disease. On the otherhand, the occurrence of bilateral adrenal hyper-plasia is in keeping with secondary rather thanwith primary adrenal disease. In other words,the two diseases may be of entirely different ori-gin. Also, they appear to be associated with dif-ferent clinical pictures-bilateral adrenal hyper-function being characteristically associated withmalignant hypertension. However, as yet, no bio-chemical differences are apparent which might aidone in distinguishing the disease state of bilateralhyperplasia from that of an adrenal adenoma.Four of the cases of bilateral hyperplasia occurredat a young age (ages 9, 10, 13 and 17) and oneother case (15) exhibited an abnormal gluco-corticoid response to ACTH. One of our patients(no. 20) resembles the patient reported by Holtenand Petersen (25) in that unilateral adrenalec-tomy in both was followed by a fall in aldosteroneand striking clinical improvement. In both pa-

tients the excised adrenal gland was histologicallyunremarkable. However, it is also possible thataldosterone hypersecretion remits spontaneously,and one of our patients (no. 34), a seven year oldgirl with malignant hypertension, has improvedconsiderably on a medical regimen.

It is difficult to determine whether the clinicalpicture of malignant hypertension is caused by theexcessive secretion of aldosterone or, alternatively,whether the hypersecretion is in some way a sec-ondary reaction to the diseased state. That hy-persecretion is a cause of the syndrome is sug-gested by the fact that the vascular lesions of ma-lignant hypertension resemble those produced inanimals given desoxycorticosterone (1). More-over, the excessive prodtuction of aldosterone inthese patients appears to be independent of thedietary sodium intake. On the other hand, cer-tain observations suggest the contrary idea, thatthe hypersecretion is secondary to the underlyinghypertensive disease. Thus, it is noteworthy thathypersecretion is absent in uncomplicated hyper-tension and becomes more and more proim-inent inassociation with dlevelopment of renal and vascu-lar comiiplications. Secondly, the fact that theclinical picture is not the same as that of primaryaldosteronism due to an adenoma suggests thatpre-existing vascular disease is necessary for aldo-sterone hypersecretion to be associated with themalignant syndrome. This concept has supportin animal studies wNherein production of renal dam-age or a unilateral nephrectomy facilitates theproduction of the state of ml-alignant hypertensionby steroid administration.

In summary, the data appear to indicate thataldosterone hypersecretion does not participate inthe pathogenesis of primary hypertensive disease.However, hypersecretion of aldosterone, perhapssuperimposed on various hypertensive states, can-not be excluded as a causal factor in the develop-ment of the malignant syndrome. Viewed in thislight, aldosterone hypersecretion may follow thehypertensive process but may possibly precedethe syndrome of malignant hypertension. Thenature of this stimulus to hypersecretion is un-known, but might be related to renal damage, be-cause, regardless of the nature of the underlyinghypertensive process, renal vascular damage is amost consistent finding in the malignant syndrome.

104


If aldosterone is important in the pathogenesisof malignant hypertension, one might ask whetherbeneficial effects are to be expected from bilateraladrenalectomy. Unfortunately, this question can-not be categorically answered since results ofadrenalectomy have been variable, and since manypatients with malignant hypertension have beenexcluded from surgery because of attendant re-nal insufficiency. One patient in our series (no.25) was subjected to bilateral adrenalectomy, butfollowing the second operation terminal uremiadeveloped. Two similar experiences have beenreported (19, 20). It is possible that a moresatisfactory answer can be obtained when patientsare operated on earlier in the malignant phase.However, in this regard it should be rememberedthat in animals, after a certain stage, hypertensionprogresses when desoxycorticosterone is no longeradministered ("metacorticoid" hypertension)(29). Another, perhaps more promising, ap-proach to the problem involves the administrationof aldosterone inhibitors. These studies are cur-rently under way in our laboratory.

The findings reported here perhaps confirmin part the work of Genest and associates (8)who reported increased urinary excretion of al-dosterone in some patients with malignant hyper-tension. However, these workers also found in-creased aldosterone excretion in milder forms ofhypertension, and this latter finding is at variancewith our data.

SUMMARY

A technique of isotope dilution which involvesthe injection of a trace dose of tritiated aldosteroneand the determination of the specific activity oflabeled tetrahydroaldosterone in the subsequent24 hour urine has been applied to the study of pa-tients with hypertensive vascular disease. Thetechnique obviates a difficulty inherent in previousstudies which have been based on measurementof the small fraction of aldosterone excreted un-changed in urine.

In eight patients with benign essential hyper-tension, the adrenal secretion rate of aldosteronewas found to be within the normal limits (180 to330 ,ug per day). The values were similar to thoseobtained in eight normal subjects maintained oncomparable normal intakes of sodium ion.

The secretion rate of aldosterone was alsowithin the normal range in two patients with hy-pertension associated with unilateral renal disease.

Five patients with proven primary aldosteron-ism due to adrenal adenoma (Conn's syndrome)exhibited significantly increased secretory ratesof from 510 to 1,690 ,ug per day.

In three of eight advanced hypertensive patientsstudied, and in all but one of 15 patients with ma-lignant hypertension, the adrenal secretion rate ofaldosterone was significantly elevated. The ab-normal values ranged upwards from 510 ,ug perday in these patients. The patients with malig-nant hypertension resembled those with primaryaldosteronism in that the hypersecretion was notassociated with grossly reduced urinary sodiumexcretion. With unexpected frequency, the pa-tients with malignant hypertension also exhibiteda tendency to hypokalemia and/or an elevatedplasma bicarbonate level, even in the presence ofrenal failure.

Delayed excretion of the labeled metabolite canbe related to the degree of nitrogen retention pres-ent and may lead to artificially high estimates ofthe 24 hour secretion rate. Nevertheless, in theexperience to date the error produced by excretoryfailure does not appear to be of sufficient magni-tude to invalidate results based on 24-hour urinecollections.

The results provide no indication that aldo-sterone hypersecretion participates in the patho-genesis of primary (benign) hypertension.

The data obtained on the patients studied estab-lish that the syndrome of malignant hypertensionis usually associated with hypersecretion of aldo-sterone. In addition to the differences in the clin-ical picture between patients with malignant hy-pertension and those with Conn's syndrome, thehypersecretion of aldosterone may differ in itsorigin. In malignant hypertension it seems to bedue to bilateral adrenal hyperfunction rather thanto an adrenal adenoma.

Hypersecretion of aldosterone in the syndromeof malignant hypertension may prove to be a sec-ondary or concomitant phenomenon. However,the results presented here make it reasonable toconsider the possibility that hypersecretion of al-dosterone plays a causal role in malignant hyper-tension.

1105


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8. Genest, J., Koiw, E., Nowaczynski, WV., and Leboeuf,G. Further studies on urinary aldosterone in hu-man arterial hypertension. Proc. Soc. exp. Biol.N. Y. 1958, 97, 676.

9. Ulick, S., Laragh, J. H., and Lieberman, S. Theisolation of a urinary metabolite of aldosteroneand its use to measure the rate of secretion ofaldosterone by the adrenal cortex of man. Trans.Ass. Amer. Phycns 1958, 71, 225.

10. Laragh, J. H. The effect of potassium chloride onhyponatremia. J. clin. Invest. 1954, 33, 807.

11. Wilzbach, K. E. Tritium-labeling by exposure oforganic compounds to tritium gas. J. Amer. chem.Soc. 1957, 79, 1013.

12. Okita, G. I., Kabara, J. J., Richardson, F., and Le-Roy, G. V. Assaying compounds containing H3and C4. Nucleonics 1957, 15, 111.

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Eds. Boston, Little, Brown & Co., 1958, pp. 155-166.

14. Rifkin, H., Solomon, S., and Lieberman, S. Role ofthe adrenal cortex in diabetic retinopathy andnephropathy. Diabetes 1958, 7, 9.

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disorders: Hyper and hypoaldosteronism. J. chron.Dis. 1960, 11, 292.

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19. FitzGerald, M. G., Fourman, P., James, A. H., andScarborough, H. Malignant hypertension, adrenalhyperplasia and depletion of potassium. Scot. Med.J. 1957, 2, 473.

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21. Foye, L. V., Jr., and Feichtmeir, T. V. Adrenalcortical carcinoma producing solely mineralo-corticoid effect. Amer. J. Med. 1955, 19, 966.

22. Brooks, R. V., McSwiney, R. R., Prunty, F. T., andWood, F. J. Potassium deficiency of renal andadrenal origin. Amer. J. Med. 1957, 23, 391.

23. Flynn, P. Adrenal cortical tumour with fulminatinghypertension. J. Irish med. Ass. 1956, 39, 77.

24. van Buchem, F. S. P., Doorenbos, H., and Elings,H. S. Primary aldosteronism due to adrenocorti-cal hyperplasia. Lancet 1956, 2, 335.

25. Holten, C., and Petersen, V. P. Malignant hyper-tension with increased secretion of aldosteroneand depletion of potassium. Lancet 1956, 2, 918.

26. Bartter, F. C., and Biglieri, E. G. Primary aldo-steronism: Clinical Staff Conference at NationalInstitutes of Health. Ann. intern. Med. 1958, 48,647.

27. Kretchmer, N., Dickinson, A., and Karl, R. Aldo-steronism in nine-year-old child (abstract). J.Dis. Child. 1957, 94, 452.

28. Mellinger, R., Therian, B., Kline, I. T., Ditzler, J.,Smith, R., and Fine, G. Primary aldosteronism.Henry Ford Hosp. Bull. 1958, 6, 1.

29. Friedman, S. M., Friedman, C. L., and Nakashima,M. Sustained hypertension following the adminis-tration of desoxycorticosterone acetate. J. exp.Med. 1951, 93, 361.

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aldosterone · 2014. 1. 29. · aldosterone and hypertension,ug per day in response to sodium...

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