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Aldosterone secretion rate and electrolyte balance studies on three patients with hypertension
Aldosterone Secretion Rate and Electrolyte Balance Studies on Three Patients with Hypertension Influence of Guanethidine, Hydralazine and Methyclothiazide By MOHINDER P. SAMBHI, ELEANOR H. VENNINC AND JOHN C. BECK The influence of 3 antihypertensive agents, guanethidine, hydralazine and a thiazide derivative was studied upon aldosterone secretion in 3 patients with hypertension maintained on a controlled dietary intake. Sodium restriction and administration each methyclothiazide alone did not cause an increase in aldosterone secretion rate. Aldosterone production rose when the 2 procedures were combined and the severe symptoms
necessitated oral potassium supplements. The antihypertensive response secondary to administration of guanethidine and hydralazine did not increase aldosterone secretion, in fact a questionable fall was noticed. It is suggested that aldosterone response to sodium restriction and intravascular volume changes in certain hypertensive patients may quantatively differ from that of the normal subject.
STUDIES were designed to investigate the influence of commonly employed antihypertensive agents on aldosterone secretion in patients with hypertension maintained on controlled fluid and electrolyte intake. Guanethidine, hydralazine and a thiazide derivative were chosen each as a representative example of the variegated mechanisms of antihypertensive action. Guanethidine, an adrenergic nerve blocking agent, leads to a depletion of tissue catecholamines including heart and blood vessels and its hvpotensive action is associated with a reduction in cardiac output and myoacts both at central and peripheral sites cardial contractility. l Hydralazine to produce its antihypertensive action and is known to cause an increase in systemic blood flow distributed mainly to the renal and splanchnic area.:! The mechanism of the antihypertensive effect accompanying the saluretic and kaluretic action of thiazide derivatives is disputed. It is generally agreed, however, that their initial hypotensive effect is mediated through a reduction in plasma volume.3 It was hoped that the results of these studies would permit certain observations to be made on the regulatory mechanisms for aldosterone secretion in hypertensive subjects. The results may in addition aid in assessing the validity of a secretion rate of aldosterone determined while a patient may be receiving such form of therapy.
T
HE
ME~ODS The patients were studied on the Investigative ward of the klcGil1 University Clinic, Royal Victoria Hospital, Montreal, under standard metabolic ward conditions. The caloric, From the McGill Unir;ersily Clinic, Royal Victoria Hospital, and the Department of Investigative Medicine, McGill University, Montreal, Quebec, Canadu. Supported by grants from the LT. S. Public Health Service Grant No. H-2716, and the Medical Research Council of Canada Grant No. M-631 and Grant No. CG-4 to Dr. J. S. L. Broume. Received for publication Nov. 21, 196.3. 212 ~IETABOLISM
VOL. 13, No. 3 (MARCH),
1964
213
ALDOSTERONE AND ELECTROLYTE BALANCE fluid
and
electrolyte
intake
was
controlled.
Urinary
concentrations were determined by flame photometry, The electrolyte balance was calculated on the
and
basis
serum of
sodium
and
and
24-hour
intake
potassium urinary
excretion. Fecal excretion was not measured. Aldosterone secretion rates were determined by the isotope dilution technic of Ulick et al., using 7 Hs-d-aldosterone of high specific activity. Determinations were made on 24-hourly urine collections. The amounts of radioactivity injected and recovered are listed in table 1. Details of the methods and control values on normal subjects have been previously reported.4 CASE MATERIAL AND REXULTS Hypertensive tients
(Cases
bilateral from
renal
overt
cardiovascular 1 and 2); artery
renal
disease
was
in the third patient
stenosis.
insufficiency
All
patients,
and
azotemia.
of
the essential
(Case at the
3)
variety
it accompanied
time
of
study,
in 2 paproved were
free
Case NO. 1-A. W. 48, F.: Hypertensive disease in this patient was known to have been present for 12 years. The patient had been moderately obese for 15 years. One year prior to admission, complaints of precordial pain radiating to the arm, dyspnea on exertion and ankle swelling in the evening were recorded. The patient had complained of parietal headaches and ‘dizzy spells’ of several years’ duration. At the time of admission the patient was having menopausal symptoms (hot flushes 4-12 times per day). No medication for these symptoms was given during the time of study. Intravenous pyelogram and urinalysis revealed no abnormal findings. There was radiologic evidence of left ventricular hypertrophy. Electrocardiogram was interpreted to be within normal limits. Funduscopy revealed jection of regitine and tetraethylammonium nosis of essential hypertension.
narrowed arterioles. Response to intravenous inchloride were consistent with the clinical diag-
The study period of 33 days was divided into 5 parts as follows (fig. 1): Study Period I (I to 5 duy5): The patient was given a constant diet containing 75 mEq. of sodium and 100 mEq. of potassium with 1,800 ml. of fluid per 24 hours. The body weight stabilized at 185 pounds. The aldosterone secretion rate determined at the end of this 5 day period was Study Period II (5 to 11 thiazide (Duretic, Abbott) first 3 days followed by a
253 pg. per 24 hours. cloys): The same diet as in Study I was continued. Methylclo5 mg. daily was given orally. Sodium loss occurred for the small retention. Negative balance of potassium continued for the entire period of 5 days. Serum potassium levels decreased from 4.1 mEq. per L. to 3.4 mEq. per L.; serum sodium levels were unchanged. There was a loss of 5 pounds in body weight (from 185 to 180 pounds). Blood pressure dropped from an average of MO/IO0 to 150/100 mm. Hg. Aldosterone secretion rate determined at the end of the 5 day period
was practically unchanged ( 222 pg. per 24 hours). Study Period 111 (II to 26 days): Eight days were allowed for reequilibration while the same diet was continued. Initial retention of sodium and continued retention of potassium occurred. Body weight returned to the original level. On the twentieth day of the study a low sodium diet containing 10 mEq. of sodium and 100 mEq. of potassium per day was begun. Sodium loss and potassium retention followed. Serum concentration of potassium remained essentially unchanged, while that of sodium showed a slight upward trend. Average blood pressure level and body weight declined to 150/90 mm. Hg. and 179 pounds, respectively. Aldosterone secretion rate at the end of the 5 day period was essentialy unchanged (248 pg.@%-hours). Study Pmiod IV (26 to 33 days): The 10 mEq. sodium diet was continued and methyclothiazide 5 mg. daily was added. During the first 3 days of the study further loss of urinary sodium and potassium resulted in a fall in serum concentration of the electrolytes (Na from
1 2
1 2
E. F.
M. M.
1,460 1,780
1,740 1.480
24 hr.
V0hlume
urine
292,858 285,398
258,616 257,542
323,629 324,721 334,364 325,381
Counts per bfin. of HJAldostmone Injected _____
44.1 46.0
37.4 31.4
45.8 42.7 46.1 39.3
Recovered in 24 hr. Urinary Extract
70 64
66 60
71 70 67 80
--1
8.700 11.030
9,972 17.000
10.480 12.100
10.002 18.000
11.240 13.440 12.370 7.310
0
H,‘: Ctr Ratios on Final Purification of Metabolite on Celite Column
Rate
11.030 13.170 12.370 7.010
Secretion
of Total Radioactivity in Urinary Extract Recovered ss TetrabydroMetabolite of Aldosterone
$,
of Aldosterone
% of InjectedDose
Table L-Determinations
10.700 10.700
9.705 18.100
11.180 13.250 12.020 7.020
1
256 162
290 202
253 222 248 440
Secretion Rate in tig./24 hr.
c
ALDOSTJIRONE AND ELECTROLYTE
215
BALANCE
MEAN 0J? and RANGE
meq/L
135J
I
No INTAKE 7~,_____!_____________-________-, 60
I
45
Na BALANCE
I
.i:; Ki 450
.,..:.,..,:::’ ‘I:.:;,.:>: /* / :iiyi> :;.. /‘I , ,...‘: I’, /
meq/V
I
--•_-_--
-
-
-
’
‘- ‘;\LDOSTERON / SECRETION
400
350
300
J.250
pg/Mhr
meq/ L.
Ibs IS5 I75 i
BODY --4__i WTI CHLOROTHIAZIDE DAYS
I
3
S
7
9
II
13
15
I7
IS
21
23
m 25
27
I 29
31
33
Fig. I.--Case 1. Infiuence of thiazide therapy and sodium restriction on aldosterone secretion in a patient with essential hypertension. The daily mean and range of 4-hourly sphygm omanometric readings are recorded at the top, The days of 7-Hs-d-aldosterone injections are shown as vertical broken lines across the figure. 142 to 139 mEq. and K from 4 to 3.1 mEq. per L.). The patient at this time complained of severe and generalized prostration necessitating oral potassium supplements. Following the oral supplements, sodium loss ceased and a positive balance of potassium resulted, raising the serum K concentration to 4.4 mEq. per L. Body weight during this period showed a further decline to the lowest figure of the study ( 171 pounds). Aldosterone secretiop rate at the end of the 5 day period showed a rise to 440 pg. per 24-hours. Case No. 2-E. F. 56, F.: Hypertensive disease had been documented for 16 years.
216
SAMBHI,
60TIME
hrs
8
100
80 meq/V.
IO
9 ---,
---,
’
I
‘___I
1
II
12
I
2
,3*
,4*
5
6
7
8
9
VENNING
AND
BECK
II 124
W
; No--_INTAKE_i
4. t
20
-
20
0
40 I 60J f-5 gm
I.0
per
0.5
24hr
CREATININE
0:
l-----
y
300 __-_---
- -____
-- __---_
- _---
ALDOSTERONE
250
I 200 pg/24
hr
GUANETHEDINE IO DAYS
I
2 3 4 C”““““‘“,“.“‘.,
5
6
7
8
9
IO
25
II
12 13 14 I5
37.5
mg
16 17 I8
q. 8h
IS 20 21 22
Fig. S.-Case 2. Influence of guanethidine therapy on aldosterone secretion and electrolyte balance in a patient with severe essential hypertension. The pretreatment blood pressure level is indicated by starting lines from the mm. Hg scale at the top left corner of the figure. Half-hourly recordings of systolic and diastolic blood pressure in the recumbent and standing position are depicted for a period of 16 hours, on the day before repeat determination of aldosterone secretion rate. The vertical arrows at the top indicate the time of oral guanetbidine administration. Daily values for 24 hours urinary creatinine showed a greater than usual variation.
ALDOSTERONE
A strong familial
AND
ELECTROLYTE
tendency
217
BALANCE
to high blood pressure
and a past history
of an aneurysm
of the
ascending aorta and mild diabetes mellitus were recorded. Funduscopy showed arteriolar narrowing. Electrocardiographic evidence of an enlarged left ventricle was present. Intravenous pyelograms revealed the right kidney to be smaller than the left by 8 to 10 mm. Retrograde aortogram failed to reveal abnormal findings. Hypertension was considered to be of the essential type (fig. 2 ) . The patient was given a diet containing 100 mEq. of sodium and potassium each. The aldosterone secretion rate determined on the fifth day was 290 pg. per 24 hours. With the same diet continuing, increasing dosage of guanethidine was given orally as shown in fig. 2. A pronounced antihypertensive effect was achieved; the average blood pressure dropped from 260/120 to 140/90 mm. Hg. The patient retained both sodium and potassium while receiving the drug. A repeat determination of the aldosterone secretion rate after 2 weeks at the peak of the hypotensive effect of guanethidine was 202 pg. per 24 hours. No appreciable change occurred in the body weight during the period of study. Case No. 3-M. M. 71, M.: Hypertension was discovered 4 years prior to admission. Differential renal function studies and radiographic examination including intravenous and retrograde pyelogram, translumbar aortogram and a renal arteriogram had suggested the existence of bilateral renal artery stenosis. This was confirmed at subsequently. The patient died of disseminated carcinomatosis (fig. 3). The patient received a constant diet containing 100 mEq. of Na and K each. later the aldosterone secretion rate was found to be 256 pg. per 24 hours. In the
strongly autopsy A week follow-
ing week hydralazine, 25 mg. three times a day, was given. The efforts to achieve more than a modest hypotensive response were limited by the appearance of symptoms attributable to postural hypotension. Body weight remained essentially unchanged. Retention of sodium and potassium occurred as shown in figure 3. The aldosterone secretion rate on the sixth day of therapy was 162 pg. per 24 hours. COMMENTS
The influence of the pharmacologic agents used upon aldosterone secretion must be interpreted only under the circumstances of the present studies. It is not possible to conclude whether or not the slight to moderate fall in aldosterone secretion following guanethidine and hydralazine administration is signifiicant. It can be stated, however, that in these cases the result of antihypertensive action and the consequent reduction in renal perfusion pressure was not accompanied by increased aldosterone secretion. Similar results were reported by Laragh et al.fi using hexamethonium and alpha methyl DOPA. These findings are not in accord with the lines of experimental evidence which suggests that a reduction in renal perfusion pressure tends to increase the granularity of the juxtaglomerular cells, stimulates the release of a renal pressor material and thereby may cause an increase in aldosterone secretion.6-8 It should be mentioned, however, that certain opposing influences upon aldosterone secretion as a consequence of the hypotensive action such as the observed sodium retention may at least, in part, account for the failure of aldosterone to rise in these cases. The sodium retention associated with the antihypertensive effect may represent inhibition of the exaggerated naturesis characteristic of the hypertensive kidney.g The influence upon aldosterone secretion of changes in renal vascular flow and resistance which are likely to be caused bv hydralazine and guanethidine remains to be determinedal The physiologic role of atria1 stretch receptors”
218
SAMBHI,
mm”p
,:
6Od
100-r
SO-
AND
BECK
-- __ Mfi~~a;;y , ,i j , i _- _-- - - No INTAKE ~------~-----______________-__-_-_
someq/V
VENNING
Na
.j;::;.;., .:::.: $$
BALANCE
40+ zo-
r 300
O20-
- 250
ALDOSTERONE
170
Ibs
1
BODY
AF’RESOLINE
I
2
hr
WT
160 J
DAYS
pg/24
3
4
5
6
7
6
9
IO
II
25mg
I2
13
t.i.d.
14 IS
16
,
Fig. S.-Case 3. The influence of hydralazine administration on aldosterone secretion and electrolyte balance in a patient with hypertension and bilateral renal artery stenosis.
that may conceivably be influenced by changes in myocardial contractility is not established.lz In patient A. W., sodium lass, a positive potassium balance and a lowering of systemic blood pressure as such did not correlate with changes in aldosterone secretion, The compelling necessity to replete potassiumin the last 2 days of the study was unfortunate and discounted the possibility of differentiating between the influence of an increase in serum potassium level and an intensified sodium loss. Laragh et a1.r:’ reported a similar case in whom
ALDOSTERONE
AND
ELECTROLYTE
219
BALANCE
changes in body weight were not recorded and aldosterone rise was ascribed to the induced increase in serum potassium level. Experimental evidence supporting this possibility has been presented by Davis et all4 and BlairWest et all5 Nevertheless, the effect of intensified sodium loss, further reduction in body weight and consequences thereof, cannot be precluded in our patient. The possible influence of a critical reduction in plasma volume or intracellular shifts of electrolyte concentrations cannot be ruled out. Acute administration of chlorothiazide to hypertensive patients was shown to cause elevation in urinary aldosterone by Venning et al.16 It is well accepted that the initial hypertensive response to sodium restriction as well as to thiazide administration is mediated through a reduction in plasma volume.17 This patient (Case No. l), however, did not respond to either stimulus with a rise in aldosterone secretion. It has not been established and the present studies lend support to the doubt whether or not all patients with hypertension are equally sensitive in terms of aldosterone response to sodium depletion and changes in intravascular volume as are normal subjects. Fries has advanced an attractive hypothesis that intravascular volume receptors of a patient with hypertension may be set for a state of plethora requiring a greater than usual contraction to act as a stimulus while being oversensitive to the strech of smaller increments .ls This may explain the lack of aldosterone rise in patient No. 1 and the questionable fall in aldosterone correlating with sodium retention observed in patients No. 2 and 3. Davis et al. suggest that the stimulus to aldosterone production from sodium restiction as well as a reduction in plasma volume is mediated through reninangiotensin system.R~12~14 Available evidence favors the view that sodium restriction in normal subjects and animals leads to an increase in plasma angiotensin.lg,“O The response in hypertensive patients has not been defined. It is tempting to relate these considerations to the well-known clinical observations that sodium restriction leads to an antihypertensive response in a proportion of hypertensive patients while a parallel effect is not seen in normal subjects.21 ACKNOWLEDGMENT We are
grateful to Professor J. S. L. Browne for advice and encouragement in carrying out this work. REFERENCES 1. Butterfield, J. L., and Richardson, J. pp. 179-191. A.: The acute effects of guanethidine on myocardial contracticity and catecholamine levels. Proc. Sot. Exp. Biol. Med. 106:25%262, 1961. 2. Fries, E. D., Rose, J. C., Higgins, T. F., Finnerty, F. A., Jr., Kelly, R. T., and Partenope, E. A.: The hemodynamic effects of hypotensive drugs in man. Circulation 8: 199-204, 1953. 3. -: Mechanism of hypotensive action of saluretics. In Reubi, F. S., Bock, K. D., Cottier, P. T., (Eds.): Essential Hypertension-An International Symposium.
Berlin,
Springer,
1960,
4. Sambhi, M. P., Levitan, B. A., Beck, J. C., and Venning, E. H.: The rate of aldosterone secretion in hypertensive patients with demonstrable renal artery stenosis. Metabolism 12:498X%,1963. 5. Laragh, J. H., Kelly, W. G., and LieberHypotensive agents and man, S.: substances. pressor The effect of nor-epinephrine Epinephrine, and Angiotensin II, and others on the secretory rate of Aldosterone in man. J.A.M.A. 174:2&l-240, 1960. 6. Hartroft, P. M.: Studies on renal juxta-
220
SAMBHI,
glomerular cells III. The effects of experimental renal disease and hyprrtension in the rat. J. Exp. Med. 105: 501, 508. 1957. 7. To&n, L.: Interrelationship of elcctrolytes, juxtaglomenrlar cells and hyprrtension. Physiol. Rev. 40: 280-312, 1960. 8. Davis, J. 0.. Hartcroft, P. \,I., Titus, E. O., Carpenter, C. C. J., Ayers, C. R., and Spiegel, H. E.: The role of renin-angiotmsin system in the control of aldosteronr secretion. J. Clin. Invest. 4 1: 378-379, 1962. 9. Cot&r, I’. T.: Renal hrmodynamics, water and electrolyte excretion in essential hypertension. In. Reuhi, F. S.. Dock, K. D., Cottier, I’. T.. (Eds. ) : Essential Hypertension. An Intemational Symposium. Berlin, Springer, pp. 66-91. 10. Muller, A. F., Moret, I’., Meqevand, R., Patty, J., and Manning, E. L.: Regulation de l’aldosterone. Helvet. hled. Acta 29:535-542, 1962. 11. Paintal, A. S., Jr.: A study of right and left atria1 receptors. J. Physiol. 126: S9Fj-6168, 1953. 12. Davis, J. 0.: A critical evaluation of the role of receptors in the control of aldosterone secretion and sodium Friedberg, (Ed. ) : excretion. In Heart, Kidney and Electrolyte. New York, Grune and Stratton, 1962, pp. 243-262. 13. Laragh, J. H., Ulick, S., Hanusqewicz, V.. Kelly, W. C., and Lieberman, S.: Eleotrolyte metabolism and aldosterone secretion in Benign and malig-
irant hypertension. 259-272, 1960.
VENNING
AND BECK
Ann. Int. Med. 53:
14. I>avis, J. O., Urquhart, J.. and Higgins, J. T.: The effects of alterations of plasma sodium and potassiun~ concentration on aldostcrone secretion. J. Clin. Invest. 42:597-609, 1963, 1.5. Blair-West, J. R., Coghlan, J. P., I>enton, I>. A.. Goding, J. R., hlunro, J. .I., Peterson, R. E., and Wintour, hl.: Hrmloral stimulation of adrenal cortical secretion. J, 1606-1627. 1962.
Clin.
Invest.
41:
16. \‘enning. E. H.. I~yrtnfruth. I., 110s setor, J. B., md Beck. J. C.: Effect of cl~olorothiazidc upon aldostrronc~ cxxcretion ;intl sodium and potassimn lralancr in e\sential hypertension. J Lab. & Clin. Med. 60:79-85, 1962. 17. Duston. H. I’.: IXct and I1iuretics iti the treatment of hypertensive carditrvascular disease. J .A.M.A. 172:20522656, 1960. 1X. Fries, E. I>. : Heruodynamic changes in hypertt nsion. hl. Clin. North America ,15:239-24.5. 1961. 19. Barbour. B. H.. Casper, A., and Bartter. F. C.: The roltr of salt in thr interaction of steroidogenesis and angiotensin. (abstract) Clin. Res. 10: 398. 196”. 20.
Launay. XI., Bouchcr, R.. and Geneat, J.: I’( rsonal communication.
21. Grollman, A.: Therapeutic aspects of salt restriction. In Reubi, F. C., Bock, K. I).. Cottier, P. T., (Eds.): Essential Hypertension-An International Symposium. Berlin, Springer. 1960, pp. 166-178.
Mohinder P. Sambhi, M.D., B.S., MSc., Research Associate, Department of Medicine, University of Southern California School of Medicine, Los Angeles, Calif. Eleanor H. Venning, B.A., MSc., Ph.D., F.R.S.C., Professcw, Department of Experimental Medicin,e, McGill University; Director, Endocrine Laboratories, Royal Victoria Hospital, Montreal, Canada John C. Beck, M.D., C.M., MSc., F.R.C.P. (C), F.A.C.P., Chief, Endocrine-Metabolic Unit, Royal Victoria Hospital, Associate Professor uf Medicine, McGill University, Montreal, Ca?Ul&
necessitated oral potassium supplements. The antihypertensive response secondary to administration of guanethidine and hydralazine did not increase aldosterone secretion, in fact a questionable fall was noticed. It is suggested that aldosterone response to sodium restriction and intravascular volume changes in certain hypertensive patients may quantatively differ from that of the normal subject.
STUDIES were designed to investigate the influence of commonly employed antihypertensive agents on aldosterone secretion in patients with hypertension maintained on controlled fluid and electrolyte intake. Guanethidine, hydralazine and a thiazide derivative were chosen each as a representative example of the variegated mechanisms of antihypertensive action. Guanethidine, an adrenergic nerve blocking agent, leads to a depletion of tissue catecholamines including heart and blood vessels and its hvpotensive action is associated with a reduction in cardiac output and myoacts both at central and peripheral sites cardial contractility. l Hydralazine to produce its antihypertensive action and is known to cause an increase in systemic blood flow distributed mainly to the renal and splanchnic area.:! The mechanism of the antihypertensive effect accompanying the saluretic and kaluretic action of thiazide derivatives is disputed. It is generally agreed, however, that their initial hypotensive effect is mediated through a reduction in plasma volume.3 It was hoped that the results of these studies would permit certain observations to be made on the regulatory mechanisms for aldosterone secretion in hypertensive subjects. The results may in addition aid in assessing the validity of a secretion rate of aldosterone determined while a patient may be receiving such form of therapy.
T
HE
ME~ODS The patients were studied on the Investigative ward of the klcGil1 University Clinic, Royal Victoria Hospital, Montreal, under standard metabolic ward conditions. The caloric, From the McGill Unir;ersily Clinic, Royal Victoria Hospital, and the Department of Investigative Medicine, McGill University, Montreal, Quebec, Canadu. Supported by grants from the LT. S. Public Health Service Grant No. H-2716, and the Medical Research Council of Canada Grant No. M-631 and Grant No. CG-4 to Dr. J. S. L. Broume. Received for publication Nov. 21, 196.3. 212 ~IETABOLISM
VOL. 13, No. 3 (MARCH),
1964
213
ALDOSTERONE AND ELECTROLYTE BALANCE fluid
and
electrolyte
intake
was
controlled.
Urinary
concentrations were determined by flame photometry, The electrolyte balance was calculated on the
and
basis
serum of
sodium
and
and
24-hour
intake
potassium urinary
excretion. Fecal excretion was not measured. Aldosterone secretion rates were determined by the isotope dilution technic of Ulick et al., using 7 Hs-d-aldosterone of high specific activity. Determinations were made on 24-hourly urine collections. The amounts of radioactivity injected and recovered are listed in table 1. Details of the methods and control values on normal subjects have been previously reported.4 CASE MATERIAL AND REXULTS Hypertensive tients
(Cases
bilateral from
renal
overt
cardiovascular 1 and 2); artery
renal
disease
was
in the third patient
stenosis.
insufficiency
All
patients,
and
azotemia.
of
the essential
(Case at the
3)
variety
it accompanied
time
of
study,
in 2 paproved were
free
Case NO. 1-A. W. 48, F.: Hypertensive disease in this patient was known to have been present for 12 years. The patient had been moderately obese for 15 years. One year prior to admission, complaints of precordial pain radiating to the arm, dyspnea on exertion and ankle swelling in the evening were recorded. The patient had complained of parietal headaches and ‘dizzy spells’ of several years’ duration. At the time of admission the patient was having menopausal symptoms (hot flushes 4-12 times per day). No medication for these symptoms was given during the time of study. Intravenous pyelogram and urinalysis revealed no abnormal findings. There was radiologic evidence of left ventricular hypertrophy. Electrocardiogram was interpreted to be within normal limits. Funduscopy revealed jection of regitine and tetraethylammonium nosis of essential hypertension.
narrowed arterioles. Response to intravenous inchloride were consistent with the clinical diag-
The study period of 33 days was divided into 5 parts as follows (fig. 1): Study Period I (I to 5 duy5): The patient was given a constant diet containing 75 mEq. of sodium and 100 mEq. of potassium with 1,800 ml. of fluid per 24 hours. The body weight stabilized at 185 pounds. The aldosterone secretion rate determined at the end of this 5 day period was Study Period II (5 to 11 thiazide (Duretic, Abbott) first 3 days followed by a
253 pg. per 24 hours. cloys): The same diet as in Study I was continued. Methylclo5 mg. daily was given orally. Sodium loss occurred for the small retention. Negative balance of potassium continued for the entire period of 5 days. Serum potassium levels decreased from 4.1 mEq. per L. to 3.4 mEq. per L.; serum sodium levels were unchanged. There was a loss of 5 pounds in body weight (from 185 to 180 pounds). Blood pressure dropped from an average of MO/IO0 to 150/100 mm. Hg. Aldosterone secretion rate determined at the end of the 5 day period
was practically unchanged ( 222 pg. per 24 hours). Study Period 111 (II to 26 days): Eight days were allowed for reequilibration while the same diet was continued. Initial retention of sodium and continued retention of potassium occurred. Body weight returned to the original level. On the twentieth day of the study a low sodium diet containing 10 mEq. of sodium and 100 mEq. of potassium per day was begun. Sodium loss and potassium retention followed. Serum concentration of potassium remained essentially unchanged, while that of sodium showed a slight upward trend. Average blood pressure level and body weight declined to 150/90 mm. Hg. and 179 pounds, respectively. Aldosterone secretion rate at the end of the 5 day period was essentialy unchanged (248 pg.@%-hours). Study Pmiod IV (26 to 33 days): The 10 mEq. sodium diet was continued and methyclothiazide 5 mg. daily was added. During the first 3 days of the study further loss of urinary sodium and potassium resulted in a fall in serum concentration of the electrolytes (Na from
1 2
1 2
E. F.
M. M.
1,460 1,780
1,740 1.480
24 hr.
V0hlume
urine
292,858 285,398
258,616 257,542
323,629 324,721 334,364 325,381
Counts per bfin. of HJAldostmone Injected _____
44.1 46.0
37.4 31.4
45.8 42.7 46.1 39.3
Recovered in 24 hr. Urinary Extract
70 64
66 60
71 70 67 80
--1
8.700 11.030
9,972 17.000
10.480 12.100
10.002 18.000
11.240 13.440 12.370 7.310
0
H,‘: Ctr Ratios on Final Purification of Metabolite on Celite Column
Rate
11.030 13.170 12.370 7.010
Secretion
of Total Radioactivity in Urinary Extract Recovered ss TetrabydroMetabolite of Aldosterone
$,
of Aldosterone
% of InjectedDose
Table L-Determinations
10.700 10.700
9.705 18.100
11.180 13.250 12.020 7.020
1
256 162
290 202
253 222 248 440
Secretion Rate in tig./24 hr.
c
ALDOSTJIRONE AND ELECTROLYTE
215
BALANCE
MEAN 0J? and RANGE
meq/L
135J
I
No INTAKE 7~,_____!_____________-________-, 60
I
45
Na BALANCE
I
.i:; Ki 450
.,..:.,..,:::’ ‘I:.:;,.:>: /* / :iiyi> :;.. /‘I , ,...‘: I’, /
meq/V
I
--•_-_--
-
-
-
’
‘- ‘;\LDOSTERON / SECRETION
400
350
300
J.250
pg/Mhr
meq/ L.
Ibs IS5 I75 i
BODY --4__i WTI CHLOROTHIAZIDE DAYS
I
3
S
7
9
II
13
15
I7
IS
21
23
m 25
27
I 29
31
33
Fig. I.--Case 1. Infiuence of thiazide therapy and sodium restriction on aldosterone secretion in a patient with essential hypertension. The daily mean and range of 4-hourly sphygm omanometric readings are recorded at the top, The days of 7-Hs-d-aldosterone injections are shown as vertical broken lines across the figure. 142 to 139 mEq. and K from 4 to 3.1 mEq. per L.). The patient at this time complained of severe and generalized prostration necessitating oral potassium supplements. Following the oral supplements, sodium loss ceased and a positive balance of potassium resulted, raising the serum K concentration to 4.4 mEq. per L. Body weight during this period showed a further decline to the lowest figure of the study ( 171 pounds). Aldosterone secretiop rate at the end of the 5 day period showed a rise to 440 pg. per 24-hours. Case No. 2-E. F. 56, F.: Hypertensive disease had been documented for 16 years.
216
SAMBHI,
60TIME
hrs
8
100
80 meq/V.
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’
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- -____
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ALDOSTERONE
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I 200 pg/24
hr
GUANETHEDINE IO DAYS
I
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5
6
7
8
9
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IS 20 21 22
Fig. S.-Case 2. Influence of guanethidine therapy on aldosterone secretion and electrolyte balance in a patient with severe essential hypertension. The pretreatment blood pressure level is indicated by starting lines from the mm. Hg scale at the top left corner of the figure. Half-hourly recordings of systolic and diastolic blood pressure in the recumbent and standing position are depicted for a period of 16 hours, on the day before repeat determination of aldosterone secretion rate. The vertical arrows at the top indicate the time of oral guanetbidine administration. Daily values for 24 hours urinary creatinine showed a greater than usual variation.
ALDOSTERONE
A strong familial
AND
ELECTROLYTE
tendency
217
BALANCE
to high blood pressure
and a past history
of an aneurysm
of the
ascending aorta and mild diabetes mellitus were recorded. Funduscopy showed arteriolar narrowing. Electrocardiographic evidence of an enlarged left ventricle was present. Intravenous pyelograms revealed the right kidney to be smaller than the left by 8 to 10 mm. Retrograde aortogram failed to reveal abnormal findings. Hypertension was considered to be of the essential type (fig. 2 ) . The patient was given a diet containing 100 mEq. of sodium and potassium each. The aldosterone secretion rate determined on the fifth day was 290 pg. per 24 hours. With the same diet continuing, increasing dosage of guanethidine was given orally as shown in fig. 2. A pronounced antihypertensive effect was achieved; the average blood pressure dropped from 260/120 to 140/90 mm. Hg. The patient retained both sodium and potassium while receiving the drug. A repeat determination of the aldosterone secretion rate after 2 weeks at the peak of the hypotensive effect of guanethidine was 202 pg. per 24 hours. No appreciable change occurred in the body weight during the period of study. Case No. 3-M. M. 71, M.: Hypertension was discovered 4 years prior to admission. Differential renal function studies and radiographic examination including intravenous and retrograde pyelogram, translumbar aortogram and a renal arteriogram had suggested the existence of bilateral renal artery stenosis. This was confirmed at subsequently. The patient died of disseminated carcinomatosis (fig. 3). The patient received a constant diet containing 100 mEq. of Na and K each. later the aldosterone secretion rate was found to be 256 pg. per 24 hours. In the
strongly autopsy A week follow-
ing week hydralazine, 25 mg. three times a day, was given. The efforts to achieve more than a modest hypotensive response were limited by the appearance of symptoms attributable to postural hypotension. Body weight remained essentially unchanged. Retention of sodium and potassium occurred as shown in figure 3. The aldosterone secretion rate on the sixth day of therapy was 162 pg. per 24 hours. COMMENTS
The influence of the pharmacologic agents used upon aldosterone secretion must be interpreted only under the circumstances of the present studies. It is not possible to conclude whether or not the slight to moderate fall in aldosterone secretion following guanethidine and hydralazine administration is signifiicant. It can be stated, however, that in these cases the result of antihypertensive action and the consequent reduction in renal perfusion pressure was not accompanied by increased aldosterone secretion. Similar results were reported by Laragh et al.fi using hexamethonium and alpha methyl DOPA. These findings are not in accord with the lines of experimental evidence which suggests that a reduction in renal perfusion pressure tends to increase the granularity of the juxtaglomerular cells, stimulates the release of a renal pressor material and thereby may cause an increase in aldosterone secretion.6-8 It should be mentioned, however, that certain opposing influences upon aldosterone secretion as a consequence of the hypotensive action such as the observed sodium retention may at least, in part, account for the failure of aldosterone to rise in these cases. The sodium retention associated with the antihypertensive effect may represent inhibition of the exaggerated naturesis characteristic of the hypertensive kidney.g The influence upon aldosterone secretion of changes in renal vascular flow and resistance which are likely to be caused bv hydralazine and guanethidine remains to be determinedal The physiologic role of atria1 stretch receptors”
218
SAMBHI,
mm”p
,:
6Od
100-r
SO-
AND
BECK
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someq/V
VENNING
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BALANCE
40+ zo-
r 300
O20-
- 250
ALDOSTERONE
170
Ibs
1
BODY
AF’RESOLINE
I
2
hr
WT
160 J
DAYS
pg/24
3
4
5
6
7
6
9
IO
II
25mg
I2
13
t.i.d.
14 IS
16
,
Fig. S.-Case 3. The influence of hydralazine administration on aldosterone secretion and electrolyte balance in a patient with hypertension and bilateral renal artery stenosis.
that may conceivably be influenced by changes in myocardial contractility is not established.lz In patient A. W., sodium lass, a positive potassium balance and a lowering of systemic blood pressure as such did not correlate with changes in aldosterone secretion, The compelling necessity to replete potassiumin the last 2 days of the study was unfortunate and discounted the possibility of differentiating between the influence of an increase in serum potassium level and an intensified sodium loss. Laragh et a1.r:’ reported a similar case in whom
ALDOSTERONE
AND
ELECTROLYTE
219
BALANCE
changes in body weight were not recorded and aldosterone rise was ascribed to the induced increase in serum potassium level. Experimental evidence supporting this possibility has been presented by Davis et all4 and BlairWest et all5 Nevertheless, the effect of intensified sodium loss, further reduction in body weight and consequences thereof, cannot be precluded in our patient. The possible influence of a critical reduction in plasma volume or intracellular shifts of electrolyte concentrations cannot be ruled out. Acute administration of chlorothiazide to hypertensive patients was shown to cause elevation in urinary aldosterone by Venning et al.16 It is well accepted that the initial hypertensive response to sodium restriction as well as to thiazide administration is mediated through a reduction in plasma volume.17 This patient (Case No. l), however, did not respond to either stimulus with a rise in aldosterone secretion. It has not been established and the present studies lend support to the doubt whether or not all patients with hypertension are equally sensitive in terms of aldosterone response to sodium depletion and changes in intravascular volume as are normal subjects. Fries has advanced an attractive hypothesis that intravascular volume receptors of a patient with hypertension may be set for a state of plethora requiring a greater than usual contraction to act as a stimulus while being oversensitive to the strech of smaller increments .ls This may explain the lack of aldosterone rise in patient No. 1 and the questionable fall in aldosterone correlating with sodium retention observed in patients No. 2 and 3. Davis et al. suggest that the stimulus to aldosterone production from sodium restiction as well as a reduction in plasma volume is mediated through reninangiotensin system.R~12~14 Available evidence favors the view that sodium restriction in normal subjects and animals leads to an increase in plasma angiotensin.lg,“O The response in hypertensive patients has not been defined. It is tempting to relate these considerations to the well-known clinical observations that sodium restriction leads to an antihypertensive response in a proportion of hypertensive patients while a parallel effect is not seen in normal subjects.21 ACKNOWLEDGMENT We are
grateful to Professor J. S. L. Browne for advice and encouragement in carrying out this work. REFERENCES 1. Butterfield, J. L., and Richardson, J. pp. 179-191. A.: The acute effects of guanethidine on myocardial contracticity and catecholamine levels. Proc. Sot. Exp. Biol. Med. 106:25%262, 1961. 2. Fries, E. D., Rose, J. C., Higgins, T. F., Finnerty, F. A., Jr., Kelly, R. T., and Partenope, E. A.: The hemodynamic effects of hypotensive drugs in man. Circulation 8: 199-204, 1953. 3. -: Mechanism of hypotensive action of saluretics. In Reubi, F. S., Bock, K. D., Cottier, P. T., (Eds.): Essential Hypertension-An International Symposium.
Berlin,
Springer,
1960,
4. Sambhi, M. P., Levitan, B. A., Beck, J. C., and Venning, E. H.: The rate of aldosterone secretion in hypertensive patients with demonstrable renal artery stenosis. Metabolism 12:498X%,1963. 5. Laragh, J. H., Kelly, W. G., and LieberHypotensive agents and man, S.: substances. pressor The effect of nor-epinephrine Epinephrine, and Angiotensin II, and others on the secretory rate of Aldosterone in man. J.A.M.A. 174:2&l-240, 1960. 6. Hartroft, P. M.: Studies on renal juxta-
220
SAMBHI,
glomerular cells III. The effects of experimental renal disease and hyprrtension in the rat. J. Exp. Med. 105: 501, 508. 1957. 7. To&n, L.: Interrelationship of elcctrolytes, juxtaglomenrlar cells and hyprrtension. Physiol. Rev. 40: 280-312, 1960. 8. Davis, J. 0.. Hartcroft, P. \,I., Titus, E. O., Carpenter, C. C. J., Ayers, C. R., and Spiegel, H. E.: The role of renin-angiotmsin system in the control of aldosteronr secretion. J. Clin. Invest. 4 1: 378-379, 1962. 9. Cot&r, I’. T.: Renal hrmodynamics, water and electrolyte excretion in essential hypertension. In. Reuhi, F. S.. Dock, K. D., Cottier, I’. T.. (Eds. ) : Essential Hypertension. An Intemational Symposium. Berlin, Springer, pp. 66-91. 10. Muller, A. F., Moret, I’., Meqevand, R., Patty, J., and Manning, E. L.: Regulation de l’aldosterone. Helvet. hled. Acta 29:535-542, 1962. 11. Paintal, A. S., Jr.: A study of right and left atria1 receptors. J. Physiol. 126: S9Fj-6168, 1953. 12. Davis, J. 0.: A critical evaluation of the role of receptors in the control of aldosterone secretion and sodium Friedberg, (Ed. ) : excretion. In Heart, Kidney and Electrolyte. New York, Grune and Stratton, 1962, pp. 243-262. 13. Laragh, J. H., Ulick, S., Hanusqewicz, V.. Kelly, W. C., and Lieberman, S.: Eleotrolyte metabolism and aldosterone secretion in Benign and malig-
irant hypertension. 259-272, 1960.
VENNING
AND BECK
Ann. Int. Med. 53:
14. I>avis, J. O., Urquhart, J.. and Higgins, J. T.: The effects of alterations of plasma sodium and potassiun~ concentration on aldostcrone secretion. J. Clin. Invest. 42:597-609, 1963, 1.5. Blair-West, J. R., Coghlan, J. P., I>enton, I>. A.. Goding, J. R., hlunro, J. .I., Peterson, R. E., and Wintour, hl.: Hrmloral stimulation of adrenal cortical secretion. J, 1606-1627. 1962.
Clin.
Invest.
41:
16. \‘enning. E. H.. I~yrtnfruth. I., 110s setor, J. B., md Beck. J. C.: Effect of cl~olorothiazidc upon aldostrronc~ cxxcretion ;intl sodium and potassimn lralancr in e\sential hypertension. J Lab. & Clin. Med. 60:79-85, 1962. 17. Duston. H. I’.: IXct and I1iuretics iti the treatment of hypertensive carditrvascular disease. J .A.M.A. 172:20522656, 1960. 1X. Fries, E. I>. : Heruodynamic changes in hypertt nsion. hl. Clin. North America ,15:239-24.5. 1961. 19. Barbour. B. H.. Casper, A., and Bartter. F. C.: The roltr of salt in thr interaction of steroidogenesis and angiotensin. (abstract) Clin. Res. 10: 398. 196”. 20.
Launay. XI., Bouchcr, R.. and Geneat, J.: I’( rsonal communication.
21. Grollman, A.: Therapeutic aspects of salt restriction. In Reubi, F. C., Bock, K. I).. Cottier, P. T., (Eds.): Essential Hypertension-An International Symposium. Berlin, Springer. 1960, pp. 166-178.
Mohinder P. Sambhi, M.D., B.S., MSc., Research Associate, Department of Medicine, University of Southern California School of Medicine, Los Angeles, Calif. Eleanor H. Venning, B.A., MSc., Ph.D., F.R.S.C., Professcw, Department of Experimental Medicin,e, McGill University; Director, Endocrine Laboratories, Royal Victoria Hospital, Montreal, Canada John C. Beck, M.D., C.M., MSc., F.R.C.P. (C), F.A.C.P., Chief, Endocrine-Metabolic Unit, Royal Victoria Hospital, Associate Professor uf Medicine, McGill University, Montreal, Ca?Ul&