prolonged infusions angiotensin norepinephrine blood pressure ... · tension; 2) aldosterone should...

Journal of Clinical InvestigationVol. 44, No. 7, 1965

Prolonged Infusions of Angiotensin II and Norepinephrineand Blood Pressure, Electrolyte Balance, and Aldos-

terone and Cortisol Secretion in Normal Manand in Cirrhosis with Ascites *

RICHARD P. AMES,t ABRAHAMJ. BORKOWSKI,4 ALFRED M. SICINSKI,§ AND

JOHN H. LARAGH||(From the Department of Medicine, College of Physicians & Surgeons, Columbia University

and the Presbyterian Hospital, New York, N. Y.)

A series of renal-adrenal interactions involvingthe pressor peptide angiotensin may control so-dium balance and blood pressure in normal man(1). Evidence for this is derived from numerousexperiments in man (2-4) and animals (5-17).We propose a mechanism whereby the kidney,when its perfusion is threatened, releases renin.Renin liberates angiotensin from a specific circu-lating globulin. Angiotensin, in turn, stimulatesthe secretion of aldosterone by the adrenal cortex.Angiotensin and aldosterone, by increasing ar-terial pressure and renal sodium retention, helprestore renal perfusion, thus compensating thesystem.

Although it has been demonstrated repeatedlythat infused angiotensin stimulates the secretion ofaldosterone and causes renal retention of sodium,we do not know if the release of endogenous angio-tensin is normally associated with the release ofaldosterone. Most of our speculation concerningangiotensin as a trophic hormone for aldosteroneis derived from studies of the pathological hyper-secretion of aldosterone. Angiotensin is impli-cated in disorders such as malignant hypertension(1, 2) and the edematous states of cirrhosis,nephrosis, and heart failure (18) because they areusually associated with-renal damage and hyper-tension or abnormal renal electrolyte behavior.

* Submitted for publication August 19, 1964; acceptedMarch 18, 1965. This work was supported by grantsH-1275 and H-5741 from .the U. S. Public Health Serv-ice and by the Fleitas Fund.

t Fellow of the New York Heart Association.t Fellow of the Polachek Foundation.§ Fellow of the Rockefeller Foundation.11 Address requests for reprints to Dr. John H. Laragh,

Dept. of Medicine, College of Physicians & Surgeons,Columbia University, New York, N. Y. 10032.

If angiotensin plays a major role in the control of

aldosterone secretion, 1) it should stimulate aldos-terone secretion in nonpressor or mildly pressordoses since most examples of secondary aldos-teronism are not accompanied by arterial hyper-tension; 2) aldosterone should be stimulated se-

lectively since hyperaldosteronism is not usuallyaccompanied by increased cortisol secretion; and3) aldosterone stimulation should continue as

long as hyperangiotensinemia obtains because thepathological secretion of aldosterone is persistent.

At present we have not shown that angiotensinmeets these requirements. In fact, the literatureprovides both positive and negative opinions foreach proposal (1, 3, 16-22). Wehave examinedthe influences of prolonged infusions of angiotensinon arterial pressure, on the selectivity and per-sistence of the stimulation of aldosterone, and on

electrolyte balance. These observations were com-

pared with similar studies using the pressor agentnorepinephrine. Our subjects were normal vol-unteers and patients with cirrhosis and ascites, a

disease involving a typical form of secondaryaldosteronism.

Methods

We studied seven normal volunteers and eleven pa-tients with cirrhosis. The diagnosis of cirrhosis was de-termined from pertinent findings of the history andphysical and laboratory examinations. It was confirmedhistologically in seven patients. Ten of the patients withcirrhosis had ascites; one had completed a spontaneousdiuresis. Because this latter patient (no. 3) was in clini-cal remission and had corrected the abnormalities of elec-trolyte and aldosterone metabolism usually associated withascites formation, she was grouped with the normal sub-jects. One hypertensive patient with uncomplicated dis-ease of 12 years known duration was also studied. In

all instances full explanation of the nature of the study

1171

AMES, BORKOWSKI,SICINSKI, AND LARAGH

was given, and the full cooperation of the subjects was

obtained.The studies were conducted on the metabolism ward

where all subjects received a constant daily diet ofknown electrolyte content. All subjects received thecontrol diet for at least 6 days before study. Normalpatients were maintained on either normal or low sodiumdiets, the electrolyte composition of which is given inTable I.

All subjects received infusions of angiotensin andnorepinephrine in 5% dextrose solution at a rate of ap-

proximately 0.5 ml per minute, held constant by a Bow-man pump. Sphygmomanometric blood pressures were

recorded at 1-hour intervals during the day and 2-hourintervals at night. Wehave defined pressor infusions as

an elevation to 150/100; nonpressor is a minimal eleva-tion in both systolic and diastolic pressure. Throughoutthe study patients were permitted limited ambulation andlavatory privileges, since infusions were made througha 12-foot tube. Metabolic ward technics and the proce-dures for the routine analysis of plasma and urinary elec-trolytes have been described elsewhere (2). Many ofour basal aldosterone secretory rates were obtained by24-hour infusions of 5% dextrose without added pressor

agent.Aldosterone secretory rates were determined by an

isotope dilution technic. 7 or 1, 2, tritium-labeled aldos-terone was obtained from the U. S. Public Health Serv-ice (SA, 20 and 100 ptc per /Ag). Each batch was checkedfor purity and stability at monthly intervals by a) addition

TABLE I

Effect of 8- to 24-hour infusions of angiotensin or norepinephrine on sodium balance andaldosterone and cortisol secretion in normal-subjects

Urinary sodium Aldosterone CortisolBlood pressurel excretion secretion secretion

Subjects and conditions* Dose Control Exp. Control Exp. Control Exp. Control Exp.

sAg/min mmHg mEq/day pEqlday mg/dayNormal subjects-Angiotensin

Diet, 70-100 mEqsodium, 120 mEqpotassium

1 1.7 124/73 157/98 60 15 135 452 18.8 15.62 0.43 122/80 140/91 65 38 226 1,300 26.5 273 0.56 105/60 124/77 70 7.0 151 650 22.9 24.341 1.8 104/55 141/86 60 8.3 184 556 20 41.55 1.7 108/65 150/102 82 67 189 958 18 27

Diet, 70 mEqsodium, 190 mEqpotassium5 1.4 102/65 165/105 83 151 170 1,0395 1.9 110/70 177/106 75 276 19 34


6 0.21 90/64 108/80 17 20 234 4396 0.21 94/65 98/66 4.8 2.2 358 7716 2.1 88/58 143/93 1.7 6.8 383 7767 0.16 110/75 113/72 9.5 3.3 472 4637 0.34 105/70 125/80 6.2 4.6 215 4647t 1.9 110/65 150/98 4.9 2.9 323 6677 2.2 116/60 145/100 8.0 26 520 1,0837t 2.6 114/80 137/96 1.2 3.3 487 698

Normal subjects-NorepinephrineDiet, 70-100 mEqsodium, 120 mEqpotassium

1 13.9 124/73 150/85 50 115 166 207 18.8 23.85 7.0 115/70 165/94 66 120 151 18 19.38 7.0 118/75 139/82 108 125 9.5§ 13§


6 11.1 94/65 138/88 11 60 358 1827 25.6 116/60 162/87 2.8 337t 26.7 110/65 163/88 13 14 413 4527t 29.4 105/70 170/90 4.4 1.7 520 566

* An interval of several days separated the repeated studies of Subjects 5 to 7. Five and two weeks of the constantregimen elapsed before the final studies of Subjects 6 and 7.

t Blood pressure measurements are 24-hour means.Infusion less than 24 hours.

I Excretory rate.

1172

ANGIOTENSIN, ALDOSTERONE,SODIUMBALANCE, AND BLOODPRESSURE

TABLE II

Effect of 8- to 24-hour infusions of angiotensin or norepinephrine on sodium balance, andaldosterone and cortisol secretion in patients with cirrhosis and ascites

Urinary sodium Aldosterone CortisolBlood pressure excretion secretion secretion

Patients and conditions Dose Control Exp. Control Exp. Control Exp. Control Exp.

g/mmin mmHg mEq/day ;sEq/day mg/day

Diet, 7-18 mEqsodium, 120 mEqpotassium10* 1.011* 1.212 0.4712 2.413* 19.013* 2.413* (postshunt) 6.814* 5.3-14 4.915 0.1215 6.716* 2.416* 8.316* 12.117 3.618 0.618 7.118* 17.319 4.6

Same diet + dexamethasone, 3 mg daily12*18*

Diet, 12 mEqsodium, 190 mEqpotassium,and dexamethasone, 3 mg daily

17

2.7 97/65 155/894.0 124/75 165/85

4.7 116/75 146/85Norepinephrine

1.3 2700.2 2.8

2.7

325131

536 <1 1366 <1 0.7

2.8 723 1,058


10*1213*151516*17*1819

* Infusion less than 24 hours.t Excretory rate.

of unlabeled carrier hormone and demonstration of con-

stant specific activity after column or paper chromatog-raphy in at least two systems and b) demonstration of a

single peak with a radioactive scanner. When sampleswere found to be impure, the entire batch was purifiedor rejected. At the beginning of each study 1 or 2 ,uc ofthe labeled hormone dissolved in 5 to 10 ml of 10%o etha-

nol was given intravenously. The subsequent 24-hoururine collection was incubated at pH 1 for 24 hours.Aldosterone liberated by this procedure was identifiedand eluted from a toluene-propylene-glycol paper chro-matogram. The sample was then acetylated with C1'-

acetic anhydride to form aldosterone diacetate. Afteranother paper chromatogram the doubly labeled aldos-terone diacetate was finally purified by elution from a

Celite column chromatogram. From the H5/C1' ratio ofthe purified sample the specific activity of the urinaryaldosterone that had been released by acid hydrolysis was

determined. From this, the 24-hour adrenal secretoryrate was calculated, employing conventional isotope dilu-tion equations. Twenty-four hour excretory rates of theacid-labile conjugate of aldosterone were also measured.A known amount of labeled hormone was added directlyto the urine after acid hydrolysis but before extraction.

Angiotensin

120/60110/6590/6098/65

100/6095/6596/66

115/80115/80120/70124/60110/70100/70100/60134/76110/60105/55104/6090/60

120/65150/80110/70135/88152/84114/69147/82125/95150/90120/70182/92127/85142/90142/94140/79130/65166/79168/98102/71

0.338

1.81.00.63.80.7

252.50.10.60.10.20.32.00.40.42.00.5

0.345

8.190

116.1

1802.1

870.3

3342.8

3764

6.00.6

170501

0.4

1,560157177

1,098941967

8585

360

1,0272,2432,443

583309121122

1,368108367965772928

439582797

1,8661,8462,7801,119

35892

117

5.4 12.2

8.1 13.5

6 41

14.833.022.212.939.433.3

8.319.714.3

120/6598/6698/60

120/60120/75110/72116/60104/6090/60

160/80146/90145/78149/63187/76132/80148/73168/72143/94

0.3 0.50.3 3.00.7 0.50.4 3.60.3 540.6 73.0 50.7 390.8 4

1,560850781

1,0851,9642,2431,013

219176t

1,368487465

1,0892,165

649695178118t

6 11.5

1173


TABLE III

Prolonged angiotensin infusion: increasing pressor sensitivity of normal subjects on a normal salt intake;reduced sensitivity after sodium depletion; tachyphylaxis in cirrhosis

No. Average blood pressure levels Cumulative sodium Rate of administrationof Dura- balance during

studies tion Control First day Final day infusions First day Final day

days mmHg mEq Ag/minAngiotensin

Normal 4 6-11 110/66 140/90 150/90 +3 to +178t 0.43-1.8 0.13-1.5(Normal diet) (9)* (+132) (1.1) (0.73)

Normal 1 2 108/68 145/100 155/100 -73 2.2 3.6(Prolonged sodium

depleted)

Cirrhosis 9 2-6 107/66 145/85 145/80 0 to -880 2.4-7.1 3.3-20.7(3) (-216) (4.9) (8.4)

NorepinephrineNormal 3 3-4 118/72 155/85 160/90 -68 to -162 7.0-13.9 12.1-20.0(Normal diet) (4) (-101) (9.3) (16.4)

Normal 1 2 116/60 160/85 165/85 -53 25.6 30.1(Prolonged sodium

depleted)

Cirrhosis 5 2-4 107/63 165/80 170/85 - 2 to - 94 12.9 -39.4 12.2 -46.4(3) (-39) (26.2) (29.4)

* Numbers in parentheses = average.t The peak positive sodium balances were higher owing to escape (see text).

Recovery experiments utilizing these procedures indicatean experimental error of less than ± 5% for both methods.By this method normal subjects on unrestricted diets ex-hibit secretory rates of from 75 to 250 lsg per day and ex-cretory rates of from 7 to 25 ,ug per day. Full details ofthese modifications of an earlier method (2) will be re-ported elsewhere (23). Secretory rates of hydrocortisonewere determined by the isotope dilution method of Roma-noff and co-workers (24) employing tritium-labeled cor-tisol. The normal range for elderly people is 12 to 23 mgper day by this method; for younger people, 16 to 31 mgper day.

Results

Infusions of pressor agents were classified aseither brief (8 to 24 hours duration) or prolonged.Results of all the 8- to 24-hour infusion studies arepresented in Tables I and II. Prolonged infusionsvaried in duration but were never less than 2 days.Data from the prolonged infusions are summarizedin Table III. Twelve balance studies of eight sub-jects who received prolonged infusions are pre-sented in Figures 1 to 5.

Effects on arterial blood pressure

Normal subjects; normal sodium. As in otherreports, angiotensin was about ten times morepotent (by weight) than norepinephrine in pro-ducing a given rise in arterial pressure. In gen-eral, it had a greater effect on the diastolic pressurethan did norepinephrine (25). During prolonged

infusions all four subjects became increasinglysensitive to the pressor effects of angiotensin asthe drug concurrently produced sodium and waterretention (Table III, Figures 1 and 2). Thusblood pressure was maintained with progressivelydiminishing doses of angiotensin. An increase inpotassium intake did not modify the pressor re-sponse of one normal subject (no. 5).

In sharp contrast, norepinephrine producedlittle or no sodium retention, and increasing ratherthan decreasing doses of pressor agent were re-quired to maintain the pressor response of threenormal subjects (Table III, Figure 3).

Normal subjects; low sodium. The state ofsodium depletion in these subjects was progressive,as indicated by serially lower rates of sodium ex-cretion together with increased rates of aldoster-one secretion in control periods. Eight infusionsof angiotensin and four of norepinephrine revealedgraded declines in pressor sensitivity as sodiumdepletion progressed.

After several weeks of sodium deprivation, Pa-tient no. 7 developed a rather impressive reductionin pressor sensitivity. His initial dose requirementfor angiotensin was increased from 1.9 Asg perminute to 2.6 ,ug per minute, and for norepineph-rine was elevated to 29.4 Mug per minute. After2 months of continued rigid sodium deprivation inthis man, no additional reduced pressor respon-

1174

1175ANGIOTENSIN, ALDOSTERONE,SODIUM BALANCE, AND BLOODPRESSURE

I5mEq SODIUMDIET

54 Wad200

BLOODPRESSURE100i-mmHg

O-

IOOmEq SODIUM DIET

Pt ELI.36 WO

0.5

ANGIOTENSIN 0.3DOSE,ug/min.

O .1 _

O

SERUMNo+ K+

200 ,{145-5URINARY *No---_i

SODIUM 12 0 Not] 135 3

40 Intake

ALDOSTERONEM SECRETION EXCRETION

1000-100

600-j60

2001-20jugm/day

[I

30CORTISOL 20SECRETIONmgm/day IC°

TIME in DAYS

FIG. 1. PROLONGEDANGIOTENSIN INFUSION IN NORMAL SUBJECTS. AL-DOSTERONESECRETION, PRESSOR SENSITIVITY, SODIUM RETENTION, AND "ES-

CAPE." Subject A. S. had been on a low sodium diet for several weeks be-fore the study began. E. H. had been on a normal sodium intake for aboutthe same period. In the salt-depleted subject, pressor sensitivity to angio-tensin did not change during a 6-day infusion. It continued to stimulateincreased aldosterone secretion, but there were no significant changes inelectrolyte balance. In contrast, in the subject receiving a normal salt dietangiotensin produced a positive sodium balance. With this, a markedly in-creased pressor sensitivity developed so that at the end of an 11-day periodrelatively minute doses of angiotensin were required to maintain the mildpressor response. "Escape" from sodium retention began on day 5. Asher angiotensin dosage was reduced, aldosterone secretion diminished fallingalmost back to the control levels. These data suggest a normal homeostaticinteraction between the state of salt balance and the pressor and the aldos-terone stimulating effects of angiotensin.

siveness to either agent appeared, but dosages ofboth agents required further increases on thesecond day of each 2-day infusion study (TableIII).

Patients with cirrhosis and ascites. On the av-erage these patients had a fourfold reduction inpressor sensitivity to angiotensin (Table II andIII). This reduction was greater than the similar

AMES, BORKOWSKI,SICINSKI, ANDLARAGH

Pt R. R Pt. Jr37 w// 39 W0

200

BLOODPRESSURfta\mrn'4g

4

A NGIOTENSINDOSE 2jug/min. SERUM

Nor K

120 H140 4.1

URINARY 63SODIUM 60

mEq/day

ALDOSTERONE* SECRETION EXCRETION l

500 1501200 120900-90600 460

3004u30

jug /day

40r

CORTISOL 30

SECRETION 20 |mg/day 1_

TIME in DAYS

FIG. 2. PROLONGEDANGIOTENSIN INFUSION IN NORMAL

SUBJECTS ON A NORMALSODIUM INTAKE. In R. P., a

mildly pressor dose of angiotensin induced a marked andselective increase in adrenal cortical secretion of aldos-terone together with a moderate degree of sodium re-

tention for 4 days. Because of increasing pressor sen-

sitivity to angiotensin, dosage was reduced, and aldos-terone secretion returned toward control levels. "Es-cape" from more renal sodium retention occurred hereas levels of the sodium-retaining substances, angiotensinand aldosterone, declined, but at this point blood pressure

remained mildly elevated. In subject J. E. angiotensinproduced persistent hypersecretion of aldosterone, and atthis high dosage level it also stimulated cortisol secre-

tion. As in the other normal subjects, sensitivity toangiotensin increased as sodium retention progressed. Inthis particular study it was not clear why sodium re-

tention did not begin until day 3.

depression seen in sodium-depleted normals. Withmore prolonged infusions these cirrhotic patientshad tachyphylaxis to the pressor effects of angio-tensin so that progressively increasing dosageswere necessary to maintain the pressor response.

Tachyphylaxis was consistently observed in thesix cirrhotic patients receiving 2.4 pg per minuteor more. In dosages below this level it did notoccur in two cirrhotic patients. Pressor sensi-tivity to norepinephrine was not reduced to a

similar extent nor was tachyphylaxis observed.

Effects on the rates of aldosterone secretion andexcretion

Normal subjects; normal sodium. Infusion ofangiotensin uniformly increased aldosterone se-

cretion by 202 to 511% of the control rates witha mean of + 360%o. Prolonged infusion of angio-tensin in four subjects (Patients no. 2 to 5) forfrom 2 to 11 days always produced a sustainedrise in aldosterone secretion. In three of theseangiotensin dosage was progressively reduced as

pressor sensitivity increased. Even with these

Pt f#P

34WO200

BLOODPRESSURE 100mmHg

Pt J.r.39iW 0

VI 1 .X20w

NOR-EPINEPHRI NEDOSE 10Aigm~min. _ SERUMl

O No+ 045 6

200 0 1405O+URINARY rt;oa 135 4SODIUM 100 t*mEq/day

SECRETION EXCRETION300 30

ALDO-STERONE

jugm/day 200-2010

4040

CORTISOL _SECRETION 20 _mgm/dayi

65 -

WEIGHT 64--Lkg 64

63 L 1 1 iA

68 -

66 -

64 _1 1 1 1 I

TIM E in DAYS

FIG. 3. RESPONSE TO NOREPINEPHRINE IN NORMAL

SUBJECTS. In normal subjects on a diet containing 70mEq of sodium, prolonged infusion of norepinephrine inpressor dosage was not associated with tachyphylaxis insubject E. P., but in subject J. E. graded increases indoses were required. In both studies, a mild natriuresiswas produced followed by a period of salt retention.The transient natriuresis was accompanied by a rela-tively greater increase in urinary volume. In both stud-ies these effects may have accounted for the mild hyper-natremia and weight loss. There were no significanteffects on aldosterone or cortisol secretion in subjectE. P. In subject J. E. norepinephrine produced a rise inboth cortisol and aldosterone secretion, possibly sug-

gesting that a release of ACTHhad occurred.

1176

ANGIOTENSIN, ALDOSTERONE,SODIUM BALANCE, AND BLOODPRESSURE

INFUSIONRATEAo/mm

BLOODPRESSURE

mmHg

URINE

No*mEq/doy

ANGIO. NOREPI. ANGIO. NOREPI.

135 250mg 1669

Hg Ny*o-dwril

too

0 s

200 _60

20so40 INTAKE

6003L4

ALDOSTERONE

SECRETORYL

pg/day 0L

DAYS

FIG. 4. PROLONGEDANGIOTENSIN AND NOREPINEPHRINE INFUSIONS IN APATIENT WITH CIRRHOSIS AND ASCITES. Infusions of angiotensin and nor-

epinephrine at comparatively smaller doses failed to affect the arterial pres-sure, the electrolyte balance, or the already high aldosterone secretion. Thepatient exhibited complete unresponsiveness to a mercurial diuretic and hy-drochlorothiazide. Infusion of angiotensin at a larger dosage produced mildincreases in blood pressure, a remarkable natriuresis, and clearing of edemafluid. Larger doses of norepinephrine that produced similar increases inblood pressure produced a smaller and more transient natriuresis. Thenatriuresis and diuresis produced by angiotensin were not the result of sup-

pression of the high aldosterone secretion.

diminishing dosages aldosterone secretion ratestended to remain above the control values (Fig-ures 1 and 2). Aldosterone secretion or excretionrates usually returned to control levels whenmeasured 2 to 3 days after cessation of an infu-sion.

In contrast, norepinephrine infusions producedno consistent changes in aldosterone secretion dur-ing either three brief or three more prolonged in-fusion studies (Table I, Figure 3).

Normal subjects; low sodium. A significantstimulating effect of angiotensin on aldosterone se-cretion was apparent after prior sodium depletionin seven of the eight brief infusion studies (TableI). The already elevated control values wereaugmented by from 43 to 116%o (mean + 97%o).Both before and after sodium depletion fairlysimilar dosages of angiotensin were given, andsimilar absolute rates of aldosterone secretion

were attained. Therefore, after sodium depletionthe increment in aldosterone secretion appeared tobe blunted in proportion to the degree of under-lying increase in endogenous aldosterone secre-tion. Mean angiotensin-induced increments inaldosterone secretion rates were + 650 ,ug per daybefore sodium depletion and only + 350 ug perday after depletion (Table I). After severalweeks of sodium deprivation, aldosterone waspersistently augmented in Subject no. 7 duringa 6-day infusion study (A.S., Figure 1).

Patients with cirrhosis and ascites. It is clearthat angiotensin did not increase aldosterone se-cretion in cirrhosis to anywhere near the extentobserved in normal subjects. Secretion was gen-erally already elevated to some extent, and ingeneral, the lower the initial rate of aldosteronesecretion the higher the increment in secretion.However, these increases resulted from doses of

1177


SOmEqSODIUMDIET SmEq SODIUMDIET

Pt RA.54 W9

200 _BLOODPRESSURE l 00

mmHg

1.5

ANGIOTENSIN 1.0DOSE

.&gm/min _0.5 SERUM

250 4Na K4

135 14 .0

[1~v 25 13.6 NA

50

N SECRETION..EXCRETION

ALDO-

STERONE 1000

jugm/day600 60 :'

200 .2

CORTISOL 30-

SECRETION 2%_mgm/day 10 _

66

WEIGHT 64kg

62

TIME In DAYS

FIG. 5. PROLONGEDANGIOTENSIN INFUSION IN UN-

COMPLICATED ESSENTIAL HYPERTENSION. Unlike normalsubjects angiotensin infusion produced natriuresis anddiuresis on the first day of the infusion whether or notsodium depletion had been imposed. In both studiesaldosterone continued to be increased above normal con-

trol levels for as long as the infusion was applied. Angi-otensin stimulated aldosterone secretion without alsocausing an increase in cortisol secretion. In a later study,with norepinephrine, aldosterone secretion was not af-fected. Pressor sensitivity to angiotensin was reducedafter sodium depletion. Unlike normal subjects prolongedinfusion of angiotensin was associated with neither sodiumretention nor increasing pressor sensitivity.

angiotensin far in excess of those given to normalsubjects. At the dose level commonly employedfor normal subjects we saw little or no effect.

Several diverse effects should be noted. Twopatients (no. 12 and no. 16) showed increases inaldosterone in control periods while being main-tained on low sodium diets and subsequent to diu-resis induced by angiotensin. Two patients (no.11 and no. 18), who did not show secondary al-dosteronism in connection with cirrhosis, also did

not show any increases in aldosterone secretionwith angiotensin. This is the first time we haveever observed the failure of angiotensin to in-crease low secretory rates of aldosterone. Whendexamethasone was given to two patients to sup-press ACTH release, angiotensin augmented al-dosterone secretion without modifying their neg-ligible rates of cortisol secretion.

Equipressor amounts of norepinephrine reducedaldosterone secretion in six infusions and had nosignificant effect in three infusions (Table II,Figure 6).

Effects on cortisol secretion (Tables I and II, Fig-ures 1 to 3, 5, and 7)

Angiotensin did not produce any uniform orstriking effects on cortisol secretion in normalsubjects. Figure 2 shows that one subject showeda 100% increase after prolonged infusion. How-ever, two other subjects experienced no effect(Figures 1 and 2).

Norepinephrine did not stimulate cortisol se-cretion in four infusion studies of normal subjectson normal sodium intake (Table I and Figure 3).

In cirrhosis, the comparatively large doses ofangiotensin that were administered produced im-pressive increases in cortisol secretion withoutany great increases in aldosterone secretion (Ta-ble II). A similar pattern obtained in one cir-rhotic patient given norepinephrine.

Effects on plasma electrolytes and sodium and po-tassium balance

Normal subjects; normal sodium. Except forSubject no. 5, brief infusions of angiotensin alwaysproduced renal retention of sodium. Prolongedinfusions from 6 to 11 days also produced mod-erate sodium and water retention in all four sub-jects. The positive sodium balance during pro-longed infusions ranged from 90 to 265 mEq (av-erage maximum: 200 mEq). This retention wasaccompanied by a weight gain of 1 to 2.5 kg, butedema was never clinically detectable. These pa-tients showed the so-called "escape" from renalretention, when, after 3 to 5 days of sodium re-tention, there was a tendency to excrete more so-dium. At the termination of the infusions thepositive sodium balances ranged from 3 to 178mEqwith a mean of + 132 mEq.

1178

ANGIOTENSIN, ALDOSTERONE,SODIUM BALANCE, AND BLOODPRESSURE

ANGIOTENSIN

40

30

20

10 :r,nlJLnn11L I] .DO.1+200 -

la 1501-UNAV loo -

E _

- 25 _

NOREPINEPHFRNE

Il

S1;4j

IKKAIt W

50_

-looPATIENT NUMBER 17 10

334 500

416 54 107

U--. U-

19 11 16 14 12 13 IS

- -- - I I

Hr.I?= OsS I I

FIG. 6. NATRIURESIS IN PATIENTS WITH CIRRHOSIS AND ASCITES. Patient numbers corre-

spond to those of Table II. The patients are arranged according to increasing urinary sodiumexcretion during an 8- to 24-hour angiotensin infusion. Natriuresis with angiotensin is corre-

lated with increases in diastolic arterial pressure. Similar pressure increments due to norepi-nephrine did not produce a significant natriuresis. When angiotensin infusions were accom-

panied by a marked further increase in aldosterone secretion, natriuresis generally did notappear. Patients 12 to 14, 16, and 18 had repeated angiotensin infusions. Each was separatedby an interval of several days.

These four subjects showed a tendency to hy-ponatremia. Plasma sodium levels declined by an

average of 5 mEqper L. They also developed a

negative potassium balance. Cumulative lossranged from 14 to 70 mEq with an average lossof 36 mEq. A slight tendency to hypokalemiawas observed with an average fall of 0.5 mEqper

L. Plasma bicarbonate levels remained below30 mEqper L throughout. Three of these studiesare presented in Figures 1 and 2.

Brief infusions of norepinephrine, unlike angio-tensin, produced variable effects on electrolyte ex-

cretion. With prolonged infusions of 2 to 4 daysthree subjects showed a slight natriuresis and a

more marked diuresis in the first 1 to 3 days.This was followed by mild sodium retention and a

return to sodium balance but at a slightly lowerweight. In these three studies the plasma sodiumlevels rose from 4.5 to 6.6 mEqper L with a mean

of 5.5 mEq per L. Perhaps this is because nor-

epinephrine produced a relatively greater increasein water excretion. Upon cessation of infusionrenal retention of salt and water was observeduntil weight returned to control values. Potas-

sium balance did not change appreciably duringnorepinephrine infusion. It remained slightlypositive, averaging + 18 mEq per L. Two ofthese norepinephrine studies are presented inFigure 3.

Normal subjects; low sodium. In seven ofeight brief infusions angiotensin did not usuallymodify the low rate of sodium excretion. Onepatient (no. 7) did show a slight sodium diuresis.However, this subject (A.S., Figure 1) exhibitedno change in fluid and electrolyte balance during6 days of mildly pressor infusion. After 2 monthsof salt deprivation, he received a higher somewhatmore pressor dosage (2.2 ,ug per minute). Thistime a mild natriuresis occurred on the first dayfollowed by a decrease in pressor response, (TableI, no. 7, and Table III). Brief infusions of nor-

epinephrine in four sodium-depleted subjectscaused no change in three and a mild natriuresisin one (Table I). In one subject a 2-day infu-sion of norepinephrine continued to produce mildnatriuresis with slightly declining pressor sensi-tivity (Table III).

Patients with cirrhosis and ascites. In ten pa-

DIASTOLJCPRESSUREINCREMENT

mmHg

%CHANGEOFALDOSTERONE

SECRETORF

1.179

n n-LL


tients 22 brief infusions of angiotensin resulted inten instances of natriuresis in which there was anaverage increase in sodium excretion of 183 mEqper day (range, 37 to 501 mEq per day). Ingeneral, occurrence and degree of natriuresisseemed related to both the degree of pressor re-sponse and the amount of angiotensin adminis-tered. Nine prolonged infusions were conductedin six patients. Four of the nine had natriuresis.This natriuresis tended to diminish, even whendosages were increased to maintain the pressorresponse. However, in one patient (no. 18) na-triuresis resulted in complete diuresis of edemafluid and a 6-kg weight loss in 3 days. Twoother patients showed a considerable reduction inascites (Figure 4). Natriuresis in two subjectswas accompanied by significant hyponatremia.Negative potassium balance accompanied natriure-sis (increments of 20 to 80 mEqper day) duringseven studies of four patients.

Nine brief infusions of equipressor amounts ofnorepinephrine caused much smaller increases insodium excretion. Only three patients showedsignificant natriuresis, the average increases be-ing 33 mEqper day (range, 7 to 54 mEqper day)(Table II). Prolonged infusions lasting up to 4days produced a mild diminishing natriuresis witha maximal loss of 94 mEq in 4 days in two of thefive studies. Plasma electrolytes were not changed.The differences between norepinephrine and an-giotensin in cirrhosis are illustrated in Figure 6.

Untoward effects. During the sixth day of acontinuous angiotensin infusion a 36-year-oldnormal volunteer (no. 4) suffered a cerebralhemorrhage and expired within 24 hours. Theepisode occurred while straining at stool. Autopsyconfirmed the diagnosis, but the ruptured cerebralvessel could not be located. There was no evi-dence of gross or microscopic damage to the cere-bral vessels or pre-existing vascular injury. Theheart, kidneys, and adrenals were entirely normalhistologically. Blood pressure was 180/100 afew minutes before this accident occurred.

This man, receiving 80 mEq of sodium daily,had demonstrated sodium retention (265 mEq in5 days) and then began to "escape" with urinarysodium excretion rising from a low of 2 mEq perday on day 2 to 127 mEqper day on day 6. Pos-sibly this sodium retention predisposed to a subtlebut serial rise in pressor sensitivity, leading to an

inordinate rise in blood pressure during straining.Pressure rises from angiotensin or norepinephrinehave not heretofore been related to cerebral bleed-ing in extensive studies of animals and man.Throughout this study the infusion rate was 1.5,ug per minute, a rate well below that employed inother reports (26-34). Because of this occur-rence, this study and all other investigations withinfusions of pressor agents were terminated im-mediately.

In general, blood pressure responses occurredwithin 1 to 2 minutes after the infusion of eitheragent. Usually, patients were unaware of thechange in blood pressure; some noted occasionalpalpitation, but none had chest pain. Transientheadache was occasionally observed with pressordoses of both drugs. No serious cardiac arrhyth-mias were encountered, although there were veryoccasional extrasystoles. When infusion of eitheragent ceased, there was almost always a period ofhypotension that was more pronounced after pro-longed infusions. The fall in blood pressure wasprincipally orthostatic and lasted about 1 to 6hours. A "weaning" period was often necessaryafter some of the more prolonged infusions in cir-rhosis, lasting about several hours, but occasionallyas long as several days.

Discussion

Our experiments with prolonged infusions ofangiotensin appear to establish several facts.The prolonged aldosterone hypersecretion second-ary to the infusion of angiotensin produces slightlydifferent physiological changes than those previ-ously described for the continued administration ofaldosterone (35). Infusion of angiotensin pro-duces more immediate and impressive increases inarterial blood pressure; it produces hyponatremiainstead of hypernatremia and shows less tendencyfor potassium wastage and alkalosis. Therefore,while the administration of aldosterone duplicatesthe abnormalities found in primary aldosteronism,the effects of angiotensin infusion appear to re-semble those of aldosteronism associated withmalignant nephrosclerosis (2). Thus, angiotensinand aldosterone cannot be equated as physio-logical agents, but we have obtained considerableevidence indicating that angiotensin could operateas a trophic hormone for the stimulation of aldos-

180


terone secretion, in the mechanism outlined in theintroduction.

In normal subjects angiotensin stimulated aldos-terone secretion selectively and persistently, inlower, mildly pressor doses. Small doses of angio-tensin stimulate aldosterone secretion exclusively;at larger dose levels where aldosterone secretioncannot be further increased, cortisol stimulationoccurs (Figure 7). This pattern of adrenal corti-cal responsiveness is the opposite of that seen

with ACTH, where cortisol secretion is selectivelystimulated at lower doses and aldosterone stimu-lation occurs at higher levels after cortisol secre-

tion approaches a maximum. Although angio-tensin has a direct stimulating effect on theadrenal cortex (14-16), a subtle discharge ofACTHmay have been responsible for the occa-

sionally observed rise in cortisol secretion. Evi-dence for this was obtained in the two cirrhoticpatients in whom dexamethasone suppressionblocked the usual cortisol stimulating effect ofhigher angiotensin dosage.

As in previous reports (3, 4, 28), the dosagesof angiotensin required to stimulate aldosteronesecretion nearly always were sufficient to producesmall but definite increases in arterial blood pres-

sure. In one report in which nonpressor amountsof angiotensin were said to stimulate aldosterone,significant elevations of pressure were described(4). Weobserved stimulation of aldosterone se-

cretion with nonpressor dosages of angiotensinonly once in these experiments. Otherwise thebulk of our data indicates that dosages exceeding0.2 ug per minute of angiotensin were requiredto produce significant stimulation of aldosteronesecretion. At this level pressor effects were smallbut evident.

The stimulation of aldosterone secretion by an-

giotensin therefore appears to be closely associ-ated with its pressor action. However, pressor

agents, in general, do not stimulate aldosteronesecretion. Norepinephrine and other pressor

agents (3) produce only slight and variable ef-fects on aldosterone secretion. Moreover, thedata presented in this paper indicate that boththe pressor activity and the aldosterone stimulatingactivity of exogenous angiotensin are related tosodium balance. Wecould not demonstrate thisor any similar relationship with norepinephrine.

In this study stimulation of aldosterone secre-

tion by angiotensin continued for as long as thedrug was applied and returned to control levelswhen application ceased. In contrast, in sheepthe stimulating effect of angiotensin on aldos-terone secretion did not persist after 6 hours(16). However, a sustained stimulation for manydays in dogs receiving nonpressor infusions hasbeen reported (19). The ineffectiveness of non-pressor dosages in stimulating aldosterone secre-tion in man may perhaps be explained by a spe-cies difference. Man appears quantitatively moresensitive than animals to the pressor effects ofangiotensin (19, 36).

There appeared to be a limit to the increasesthat angiotensin can effect on aldosterone secre-tion. Aldosterone secretion rates were increasedto approximately the same absolute levels bothbefore and after sodium deprivation. The peptidetherefore had relatively less augmenting effect insodium-depleted subjects in whomaldosterone se-cretion was already elevated. Angiotensin failedcompletely to increase the often high aldosteronesecretion of patients with cirrhosis and ascites,even though the much larger doses given to thesepatients increased cortisol secretion. The partialaldosterone response of sodium-depleted normalsubjects and the total lack of response in cirrhosisand ascites point to a ceiling for adrenal responseto angiotensin. Increased endogenous angiotensinmight be the basis for the elevated aldosterone se-cretion that occurs naturally in both of thesesituations. Pre-existing angiotensinemia couldexplain the blunted aldosterone response of thesodium-depleted normal subjects. A still higherendogenous level of angiotensin in cirrhosis wouldaccount for the total failure of infused angiotensinto stimulate aldosterone secretion.

Differences between the pressor sensitivity toangiotensin and norepinephrine were observedthat seemed to be related to the different effects ofthe two agents on sodium balance. In normalsubjects, angiotensin produced sustained sodiumchloride retention. This was regularly accom-panied by a graded increase in pressor sensitivity.In contrast, norepinephrine caused either natri-uresis or no significant change in sodium balance,and pressor sensitivity tended to diminish as theinfusion proceeded. In acute experiments nor-epinephrine too causes renal sodium retention(25), but the present study indicates that an

1181


early escape from this effect occurs. Increasingvascular sensitivity to prolonged angiotensin in-fusion was also recently described in rabbits (37).This phenomenon was not related to sodiumbalance.

In general, sodium depletion diminishes pres-sor responsiveness and enhances the effectivenessof antipressor drugs. Thus, pressor sensitivity toboth angiotensin and norepinephrine was reducedsomewhat after sodium depletion of normal sub-jects and to a greater extent in cirrhosis with as-cites (Table III). These patients were particu-larly insensitive to angiotensin and tended to be-come increasingly unresponsive (i.e., to developtachyphylaxis). This phenomenon seemed quan-titatively related to the considerably greater natri-uresis induced by the peptide as compared withnorepinephrine. That sodium balance may bean important determinant of pressor sensitivity isfurther suggested by similar prolonged infusionstudies of a hypertensive subject (Figure 5).

The state of sodium metabolism, therefore,seems important in determining pressor re-sponsiveness, but the amount of angiotensin ad-ministered may also be involved. Tachyphylaxiswas observed only in the six cirrhotic patientsgiven dosages of 2.4 Mg per minute or more. How-ever, a dose of 2.8 pg per minute did not inducetachyphylaxis in a normal subject (J. E., Figure2). This possible relationship to dosage may besimilar to that reported in dogs (38) and in rab-bits (36).

Patients with cirrhosis and ascites have largeincreases in body sodium content. Yet, in pres-sor responsiveness they behaved as though se-verely sodium depleted. This finding, togetherwith the fact that the angiotensin-induced sodiumaccumulation of normal subjects actually increasedpressor sensitivity to angiotensin, suggests thatthe abnormal distribution of retained sodium inedematous patients precludes it from supportingthe action of pressor agents. Both the tendencyto transudation in cirrhosis and the lack of edemain association with angiotensin-induced sodiumaccumulation of normal subjects suggest that thesodium retention of normal subjects increasespressor sensitivity by contributing to the volumeor composition of the intravascular bed. Thedeclining pressor sensitivity of edematous sub-jects during angiotensin natriuresis may have re-

sulted from a further depletion of this intravascu-lar sodium store.

In normal subjects as angiotensin caused sodiumretention, pressor sensitivity increased to a pointwhere the pressure elevation could be maintainedby smaller dosages, which might not be expected tostimulate increased aldosterone secretion. Thisphenomenon might be relevant to the problem ofhypertension associated with unilateral renal dis-ease. In this condition one group has consistentlyfound increased angiotensin release from thedamaged kidney. Usually there was no attendantevidence of hyperaldosteronism (39). Theamounts of angiotensin released by these patientsmight conceivably suffice to maintain hypertension(after sodium retention had been induced) withoutbeing sufficient to also maintain aldosteronism.This explanation might be in accord with Tobian'shypothesis of an increased sodium content of thearterial wall in experimental hypertension (40).

If the renin-angiotensin-aldosterone system isoriented to prevent salt depletion or arterial hy-potension, the paradoxical natriuresis observedafter larger, more pressor dosages of angiotensinin cirrhosis requires an explanation. This lattereffect might result from an undue increase in ar-terial blood pressure in patients with a high en-dogenous angiotensin.1 In cirrhosis with nearlycomplete sodium retention the renal tubules andthe adrenal cortex may be already respondingmaximally to an endogenous angiotensin stimulus.Administration of exogenous angiotensin in thissituation exerts no further direct effect on therenal tubules or the adrenal cortex. The natriu-resis therefore may be caused by the systemic pres-sor effects of excesses of the drug. This mecha-nism implies that increases of circulating levels ofangiotensin and elevations of systemic blood pres-sure have opposing effects on renal sodium excre-tion. The sodium-retaining effect of lower doses

1 The indirect evidence for increased circulating angi-otensin in cirrhosis is derived from the specifically de-creased pressor sensitivity to this agent, the failure tofurther stimulate aldosterone secretion, and the presenceof avid renal sodium retention all described herein andreported elsewhere (41, 42). McManus (43) describedjuxtaglomerular cell hyperplasia in human cirrhosis.Dogs with experimental ascites also have decreased an-giotensin pressor sensitivity and increased renal andcirculating renin activity and juxtaglomerular cell hy-perplasia (44, 45).

1182


Increments_...ALDO-

CORT. STERONESEC. EXC. SEC.mg/d ,ugm/day

24 120 1200O 0 @

20 l00 1000

10 50 5001-

00 0

s0

*00

.

0

Cortisol*

,-II,' *

,' * 0

I 00O e* 1:

0 1 00 *.~~t 0

*~..I 0 0IOn~ ~ 1 lb

L o9~~ II n

0 0 0.25 0.5 1.0 1.5 2.0DOSE of ANGIOTENSIN jugm/min.

FIG. 7. RELATIONSHIP OF ANGIOTENSIN DOSE TO ALDOSTERONEAND CORTI-

SOL SECRETION. Data are taken from all studies of the normal subjects.Angiotensin appears to stimulate aldosterone secretion maximally at dosesless than 0.5 ,ug per minute. However, even the lower of these dosages can-

not be defined as nonpressor. Although results with cortisol secretion arenot conclusive, it appears that cortisol secretion is not significantly increaseduntil large doses of angiotensin exceeding 0.5 /Ag per minute are applied.

of angiotensin has been repeatedly demonstrated(25-27). Also, elevations of arterial pressure

per se can promote natriuresis in normal animals,(4648) and more specifically in patients withcirrhosis and ascites (25, 49). Furthermore, pa-

tients with arterial hypertension (Figure 5) are

much more prone than normal subjects to natriu-resis when various pressor agents are infused(28, 30). Saline-loaded normal subjects can de-velop this natriuretic response to pressor in-fusions (50).

Operation of this interaction may provide an

explanation for the mysterious "escape" from renalsodium retention induced by angiotensin in our

normal subjects and also described in the dog(19). Sodium chloride retention of the order of+ 90 to + 265 mEqwas produced during the first3 to 5 days of angiotensin infusions in subjectsreceiving a normal sodium intake. Escape fromthis renal sodium retention may be a "pressure"natriuresis resulting from the attainment of a

critical increment in arterial pressure that over-

comes the angiotensin-aldosterone initiated so-

dium retention.

Borst and Borst-de-Geus (51) have proposedthat the "escape" phenomenon observed in normalsubjects during mineralocorticoid administrationis induced by a critical rise in arterial blood pres-

sure resulting from sodium retention. Althoughtheir hypothesis may also prove correct, no con-

sistent rise in arterial pressure was observed dur-ing this type of "escape" in a study of 17 normalsubjects (52). Furthermore, this experimentalsituation differs from our study because one

would expect endogenous renin and angiotensinto be suppressed by excess mineralocorticoid (9).

Despite a vast literature there is virtually no

information about the effects of angiotensin on thecerebral circulation. No deleterious effects havebeen heretofore described. In view of the vas-

cular accident observed in this study, additionalstudies are in order. Dickinson and Lawrence(37) have recently suggested that angiotensin is a

specific cerebral vasoconstrictor. If this is so, itcould play a role, not only in the pathogenesis ofarterial hypertension, but also in the productionof the associated encephalopathic syndromes andcerebral accidents. Because of the vascular acci-

2.5 3.0

1183

i


dent described herein infusion of all pressor agentsin man should be approached with this possibilityin mind until mechanisms can be worked out byfurther animal investigation.

Our data indicate that angiotensin is orientedto prevent sodium depletion or arterial hypoten-sion. Loss of body sodium is associated with atendency for a fall in arterial pressure; either mayelicit the secretion of renin and the elaborationof angiotensin. Angiotensin then promotes saltretention both directly and by augmenting aldos-terone secretion; as sodium stores increase, pres-sor sensitivity to angiotensin rises, leading toblood pressure elevation. Increased renin andaldosterone activity are then suppressed. If bloodpressure rises excessively "pressure natriuresis"occurs, returning the sodium stores and bloodpressure toward normal.

SummaryTo obtain more information about a possible

angiotensin-aldosterone interaction for regulationof sodium balance and arterial blood pressure, theeffects of prolonged infusions of angiotensin andnorepinephrine on blood pressure, electrolyte bal-ance, and adrenal secretion rates of aldosteroneand cortisol were studied in normal subjects andin a representative form of secondary hyperal-dosteronism.

In normal subjects, norepinephrine in pressordosage for 2 to 4 days usually produced transientnatriuresis and diuresis associated with diminish-ing pressor responsiveness. In patients with cir-rhosis, norepinephrine at times also produced sig-nificant, although transient, natriuresis and diure-sis. Pressor responsiveness was reduced, buttachyphylaxis was not impressive.

Angiotensin produced quite different effects.In normal subjects an initial marked renal reten-tion of sodium chloride occurred, paralleled by in-creasing pressor sensitivity. After the initial 3-to 5-day period "escape" occurred with increasedrenal salt excretion and a tendency for the weightto stabilize. Angiotensin also produced promptand sustained increases in aldosterone but not incortisol secretion. In sodium-depleted normalsubjects sodium accumulation was prevented, andpressor responsiveness remained reduced.

In cirrhosis with ascites angiotensin often pro-duced a striking natriuresis with diuresis of edema.

These patients exhibited pressor unresponsivenessand tachyphylaxis to angiotensin.

The stimulating capacity of exogenous angio-tensin on aldosterone secretion was a graded one,related directly to the state of sodium balance andinversely to the pre-existing rate of aldosteronesecretion. In normal subjects angiotensin aug-mented aldosterone secretion by a mean of 360%obefore and by only 97% after sodium depletion.In cirrhosis, larger doses of angiotensin failedcompletely to increase the already high aldos-terone secretion. But these larger dosages werecapable of increasing cortisol secretion.

Our findings indicate that the state of sodiumbalance is an important determinant of vascularresponsiveness to both pressor agents. However,a direct, internally controlled relationship betweenthe vasoactivity of angiotensin and the state ofsodium balance was suggested because in normalsubjects pressor sensitivity increased with anangiotensin-induced sodium retention, and it de-creased after sodium depletion. Also the pressorunresponsiveness of cirrhosis became enhanced,and tachyphylaxis often developed after angio-tensin natriuresis.

The data imply that under a certain circum-stance, angiotensin-induced sodium retention,pressor sensitivity may increase so that hyperten-sion can be sustained by amounts of angiotensininsufficient to also stimulate aldosterone. Thispoint may be relevant to the pathogenesis ofcertain hypertensive states.

Angiotensin meets certain major criteria for analdosterone-stimulating hormone because its ac-tion on the adrenal cortex appeared selective andpersistent, and it could be demonstrated in mildlypressor dosage. Because of this and because thevasoactivity of angiotensin interacted with thestate of sodium metabolism, a mechanism has beenproposed in which angiotensin release participates,with aldosterone, in normal regulation of sodiumbalance and arterial blood pressure. The angio-tensin-induced "escape" observed in the normalsubjects and the paradoxical natriuresis observedin patients with cirrhosis might be explained interms of this proposed mechanism.

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prolonged infusions angiotensin norepinephrine blood pressure ... · tension; 2) aldosterone should...

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