Effect of aging on plasma renin and aldosterone in normal man

Kidney International, Vol. 8, (1975), p. 325—333

Effect of aging on plasma renin and aldosterone in normal man PETER WEIDMANN, SYLVIANNE DE MYTTENAERE-BURSZTEIN, MORTON H. MAXWELL

and JosE DE LIMA Nephrology and Hypertension Service, Department of Medicine, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, California

Effect of aging on plasma renin and aldosterone in normal man. The influence of aging on the renin-angiotensin-aldosterone system was evaluated by comparing young (20 to 30 yr) with elderly (62 to

sential hypertension has been diagnosed more commonly in older than young adults [1—4], and the syndrome of hyporeninemic hypoaldosteronism has been described almost exclusively in patients older than 50

70 yr) healthy subjects. Despite comparable body sodium-fluid balance in the two age groups, serum renin concentration, plasma renin activity and aldosterone concentrations were lower in the elderly. The age-related decreases in circulating renin and aldosterone concentrations were slight while subjects were supine and receiving normal sodium intake; when upright and during sodium depletion, they were more pronounced. Inverse renin-blood pressure interrelations were noted during two of four study conditions involving normal sodium intake or mild sodium depletion (r =

yr of age [5]. The possibility that aging may influence renin and

aldosterone metabolism has been considered previously, but the available data on the relationship between age and the function of the renin-angiotensin-aldosterone system in normotensive healthy adults are limited and conflicting [2, 4, 6, 7]. The present study was undertaken to further investigate this question by comparing plasma renin and aldosterone concentrations under basal conditions and during stimulation

—0.44 and —0.47, respectively), but not during progressive sodium depletion. Plasma renin levels were decreased in the elderly regard-

less of the presence or absence of an inverse relationship with blood pressure. Aldosterone and cortisol responses to corticotropin infusion were unaltered in the elderly. It is concluded that aging may cause a decrease in circulating renin, with parallel lowering of plasma aldosterone concentrations.

with upright posture, sodium/volume depletion or corticotropin infusion in young and elderly healthy

Effet du vieillissement sur les concentrations de refine et l'aldostérone chez l'homme normal. L'influence du vieillissement sur Ic système rCnine-angiotensine-aldostérone a été dvaluée par Ia corn-

subjects.

paraison de sujets normaux jeunes (20 a 30 ans) et de sujets âgés (62 a 70 ans). Malgré un bilan hydro-sodique comparable dans les deux groupes d'áges, Ia concentration sérique de refine, l'activité refine du plasma et Ia concentration d'aldostérone sont inférieurs chez les sujets ages. La diminution liée a l'age de Ia refine et de l'aldostérone circulantes est minime quand les sujets sont couches et ont un ap-

Methods

Two groups of normal volunteers were studied. One group included six women and six men, ranging in age

port de sodium normal; elle est plus prononcée en orthostatisme

from 20 to 30 yr. The other group consisted of four

et au cours de Ia déplétion en sodium. Des relations inverses

women and three men, ranging in age from 62 to 70 yr.

rénine-pression artérielle ont été observées dans deux des quatre situations expérimentales associant un apport normal de sodium ou une déplétion de sodium modérée (r = -0,44 et r = —0,47, respec-

None of the participants had significant physical abnormalities and each was found to have a blood pressure of less than 140/90 mm Hg, normal concentrations of plasma creatinine and electrolytes and blood urea nitrogen, and normal urine values before entering the study. None were taking drugs.

tivement). Ces relations n'ont pas été observées au cours de Ia

depletion progressive en sodium. La refine est diminuee chez les suindépendamment de Ia presence ou de l'absence d'une relajets tion inverse avec Ia pression artérielle. Les reponses du cortisol et de l'aldostérone a Ia corticotrophine ne sont pas modiflées chez Ic sujet age. II est conclu que Ic vieillissement peut entrainer une diminution de Ia refine circulante avec une diminution parallèle des concentrations d'aldosterone.

All studies were done while the subjects were receiving a defined daily intake of either 120 mEq of sodium

and 60 mEq of potassium ("normal sodium intake") or 10 mEq of sodium and 60 mEq of potassium ("restricted sodium intake"). Body weight, urinary sodium and potassium excretion, and creatinine clearance were measured daily throughout the study. Blood pressure; serum renin concentration; plasma renin activity; and aldosterone, sodium and potassium concentrations were determined in each subject in both the supine and upright positions (each position for one

Diminished levels of circulating renin occur in several pathologic states, but the factors responsible for this have not been fully elucidated. The incidence of at least two hyporeninemic disorders appears to increase with advancing age. More specifically, low-renin esReceived for publication March 4, 1975; and in revised form June 24, 1975. © 1975, by the International Society of Nephrology.

325

Weidmann et a!

326

hour): a) after three days of normal sodium intake (in the young subjects this was done twice); b) after three days of restricted sodium intake; c) after six days of restricted sodium intake; and d) after seven days of restricted sodium intake and oral administration of furosemide, approximately 1.2 mg/kg of body wt, at 5

Haber et al using 8-hydroxyquinoline and dimercaprol as protective agents [9]; each sample was measured at

two incubation conditions, i.e., at pH 7.4 and 5.7. Plasma aldosterone was measured by the radioimmunoassay method of Ito et al [10] and plasma cortisol by competitive protein binding [11]. Plasma volume was measured with '251-human serum albumin; the radioactivity level of peripheral venous blood volume was used to calculate whole blood volume by assuming the following: whole blood volume = measured volume X

PM on the seventh day of sodium restriction. Following three days of normal sodium intake and six and seven days of sodium depletion, measurements of plasma and blood volume were also performed. This part of the study extended over ten days. Eight young and all seven elderly subjects participated in a second part,

100 — hematocrit

in which the response to a two-hour infusion of a synthetic adrenocorticotropic hormone (Cortrosyn, Organon Inc.) at a rate of 0.1 mg/hr (approximately

[ 100—0.91 x hematocrit

A paired data I test was used for statistical comparison of measurements obtained from the young or

10 USP U of ACTH) was studied following three days of normal sodium intake: blood pressure; serum renin concentration and plasma renin activity; and aldosterone, cortisol, sodium and potassium concentrations were measured before (8 AM) and after one and two hours of ACTH infusion.

elderly group before and during the various study con-

ditions; an unpaired data I test was applied for comparison of the two age groups. In our previous studies, absolute plasma renin and aldosterone concentrations were always found to be abnormally distributed, with an approximately normal distribution following logarithmic transformation of these values [12, 13]. This was systematically reexamined and found to be also

Blood pressure was determined with a standard sphygmomanometer and pressure cuff, with the first Korotkoff sound being recorded as systolic pressure and the fifth sound as diastolic pressure. Supine and upright measurements were always obtained after the subjects had remained in these positions for one hour. Three values were recorded and averaged. Mean pressure was calculated as the sum of diastolic pressure and one-third of the pulse pressure. Plasma sodium and potassium concentrations were measured with a flame photometer (Instrumentation Laboratory). Serum renin concentration was determined by radioimmunoassay, using a modification of the method of Gould, Skeggs and Kahn [8]. Plasma renin activity was determined by the radioimmunoassay method of

true in the present study. Therefore, natural logarithms of the serum renin concentration, plasma renin activity and aldosterone values were utilized for all statistical calculations involving a t test or linear regression analysis. Results

Fluid and electrolyte status, and glomerularfiltralion rate (Table 1 and Fig. 1). Plasma sodium concentrations measured before and during different degrees

of sodium depletion were comparable in the young and elderly subjects (Table 1).

Table I. Plasma sodium and potassium concentrations and plasma and blood volumes in 12 young and 7 elderly subjects during normal sodium intake and after sodium depletion (mean SD)

Normal Naa Young

Plasma sodium, mEq/liter 140.5 Supine 140.1 Upright Plasma potassium, mEq/lizer 4.15 Supine 4.34 Upright Plasma volumed,ml/cm 14.4 Blood volume0, mi/cm 24.4

Low Nab x 3 days

Elderly

Young

2.0 0.8

139.6

1.5

139.0

139.0

1.7

138.8

0.23

4.12 4.25

0.24

4.04

0.34 3.3 5.5

4.20

0.38 2.5

4.6

15.3 25.1

— —

Elderly

Low Nab >< 6 days

Young

Low Nab x 7 days + FC

Young

Elderly

Elderly

2.4 3.4

136.6

3.0

139.4

2.2

139.0

1.4

137.1

3.1

139.9

2.1

138.1

1.7

139.4 139.5

0.30 0.16

4.07

4.31

0.40

3.75

0.36e

4.34

4.48

3.92 0.24

4.21 0.l9

31g

13.0 22.0

3.8

23.1

0.19e 4.04 0.29 0.17e 4.12 0.25 — 13.5 2.5 — 22.5 52g

aNormal Na = sodium intake of 120 mEq/day. bLow Na = sodium intake of 10 mEq/day. CF = orally administered furosemide, approximately 1.2 mg/kg of body wt.

dEight of the 12 young subjects were studied. esignificant difference (P < 0.05) between supine and upright position. 1Significant difference (P < 0.05) between young and elderly. Significant difference (P < 0.05) vs. values during normal sodium intake.

14.4 24.0

50g

1.7 1.7

l.7g

139.0

1.3

138.3

1.0

3.90

0.27e

13.9 + 25g

50g

Effect of aging on renin and aldosterone Norma] sodium intake

—; 160

Furosenilde Sodium restriction

I

•Young T

0 Elderly

80LI L III Ii Ii ii 80

i

iii

iLEIIIi IJLFF

120

60 0

4 I

2 3 4 5 6 7 8 9 10

J'<0.05 :P<00l

Days

Fig. 1. Body weight, urinary electrolyte values and creatinine clearance before and during progressive sodium depletion in young and elderly healthy subjects.

During normal sodium intake, mean plasma potassium concentrations were also similar in the two age groups. However, following progressive sodium depletion plasma potassium values were slightly higher in the elderly than in the young subjects (P < 0.05). Fur-

thermore, the change from the supine to the upright position caused an increase in plasma potassium in the majority of studies (53 out of 76), with significant postural increments of mean potassium concentration under some of the study conditions involving sodium depletion. Plasma and blood volumes were comparable in the two age groups. Sodium depletion caused consistent significant decreases in these volumes (P < 0.05), with a mean fall of 5 to 7% following six days of low sodium diet alone, and a decrease of 8 to 10% following the addition of furosemide (Table 1). Following three days of equilibration on the initial diet containing 120 mEq of sodium and 60 mEq of potassium per day, mean body weight was stable and urinary excretion of sodium and potassium was similar in both groups (Fig. 1). Sodium depletion caused comparable weight losses in the young and elderly groups, amounting to 1.62 0.55 (± SD) kg (—2.5% of body wt) and 1.65 0.85 kg (—2.4% of body wt), respective-

ly, after six days of dietary sodium restriction, and 2.41

0.79 and 2.06

1.15 kg, respectively, following

327

the addition of orally administered furosemide. Sodium excretion decreased progressively during low sodium intake, with statistically similar excretion rates in the young and elderly, except for a slightly higher value in the elderly group after six days of sodium de-

pletion; the administration of furosemide led to an acute increase in the sodium excretion on the last study day. Mean potassium excretion during sodium depletion tended to be slightly lower in the elderly as compared to the young subjects. Mean baseline creatinine clearance was 108.0 7.9 ml/min in the young and 84.1 20.4 ml in the elderly subjects (P < 0.05), and there were no consistent changes in these values during sodium depletion (Fig. 1). Serum renin concentration, plasma renin activity and plasma aldosterone concentration (Table 2, Fig. 2). On a normal sodium intake and with the subjects in the supine position, plasma renin and aldosterone concentrations tended to be lower in the elderly than in the young group, although these age-related differences were significant only for serum renin concentration and plasma renin activity measured at incubation pH 7.4 (P < 0.05). More specifically, the young and elderly subjects had mean renin concentrations of 17.7 1.9 ng/ml/16 hr, respec2.5 (± SEM) and 11.9 tively; mean renin activity levels at incubation pH 7.4 of 248 39 and 165 29 ng/100 ml/3 hr, respectively; mean renin activity levels at pH 5.7 of 342 61 and 238

47 ng/l00 ml/3 hr, respectively; and mean

aldosterone values of 4.2 0.5 and 3.1 0.4 ng/100 ml, respectively (Table 2). Upright posture and sodium depletion caused consistent significant increases in circulating renin and al-

dosterone concentrations in both age groups (P < 0.001). However, during each of the seven study conditions in which these stimuli were used, the mean

values achieved were almost always significantly lower in the elderly than in the young group (P < 0.05) (Table 2, Fig. 2). There was no correlation between postural increases in circulating renin or aldosterone concentrations and associated changes in blood pressure or plasma potassium values in either the young or elderly subjects. However, aldosterone responses to upright posture correlated significantly with the associated increases in plasma renin (r = 0.52; P < 0.01) without significant improvement of this correlation when the associated changes in potassium were introduced as a sec-

ond independent variable (r =

0.53;

P < 0.01).

Regarding volume-renin interrelations, there was no correlation between the absolute values of plasma or blood volumes and plasma renin activity; however, the increases in plasma renin following volume depletion correlated (F < 0.05) with the associated decreases in

Weidmann et al

328

Table 2. Serum renin concentration and plasma renin activity and aldosterone concentrations in young and elderly healthy subjects during

normal sodium intake and after sodium depletion (mean

SCM)

Renin

Sodium intake Body mEq/24 hr position Supine

120 x 3 days

10 x 3 days

10 x 6 days lOx 7 days +

Upright

furosemide 120 x 3 days

tO x 3 days

lOx 6days 10 x 7 days + furosemide

Age group°"

N

Y

32

E

14

Y

12

E

7

Y E

12

35.3 21.9 44.3

7

Y E Y E Y E Y E Y E

Concentration ng/ml/16 hr

Activity (pH 7.4)

Activity (pH 5.7)

ng/100 ml/3 hr

ng/100 ml/3 hr 342 6l

2.5c

248 39C

l.9c 4.0c

165 539

4.lc

80c

5.8c

347 695

27.4

55C

434

79C

12

79.9

7

11.7

1207

47.3

l0.4c

726

24

41.1

4.lc

7

26.4

57C

12

17.7 11.9

77.6 6.8

7

47.4

12

124.3 55.1

7 12

7

11.0c 25.6c

596 287 1219 811

61c

88' 196c 152c

238 713 418 870

47

0.5 0.4

92c 66c 105e

13.8

2.7c

6.4

0.9c

574 95

0.4c

1664 307

18.1

2.5

187c

8.8

Q•9C

928

774 92c

65c

369

74C

1625 l53

+ 203e

913

235c 206

1548

141c

1807

14.2c

1132

1283 293

149.1 + 19.2e 89.3 25.4e

2365

258c 203c 330c

1555

4.2 3.1 7.1 4.8

73C 103c

Aldosterone ng/100 ml

2926

320c

1690 313c

12.6

5.6

0.8c

43.8

14.5

16.5

20.3

2.9 15.O 37C

65.4 25.9

3.8c

59.7

12.2c

ay = young.

bE

elderly.

C1 test using logarithms of variables showed significant difference between young and elderly subjects (P < 0.05).

blood volume in both young (r = —0.45) and elderly (r = —0.49) subjects. Effect of corticotropin administration (Table 3). Basal concentrations of plasma aldosterone, cortisol, sodium and potassium and renin concentration and activity were not significantly different in the two age groups. Infusion of corticotropin caused significant increases in plasma aldosterone (P < 0.001), cortisol (P < 0.001) and potassium (P < 0.05) concentrations in both the young and elderly subjects. These responses were similar in the two age groups; serum renin concentration, plasma renin activity and sodium

concentration showed no consistent changes. Also,

there was no significant correlation between the changes in plasma aldosterone and those in potassium concentration. Relationship between plasma renin activity measured at pH 7.4 and 5.7 (Fig. 3). There was an excellent correlation between the plasma renin activity values

found following incubation at pH 7.4 and those obtained at pH 5.7 (r = 0.98; P < 0.001). Angiotensin I generation at pH 5.7 exceeded the values at pH 7.4 by approximately 40% in the low and 20% in the high range of measurements.

Relationship between serum renin concentration and plasma renin activity (Fig. 4). In both age groups, serum renin concentration showed an excellent corre-

lation with plasma renin activity measured either at incubation pH 7.4 (r = 0.94) or at pH 5.7 (r = 0.93 and 0.92, respectively). There were no apparent agerelated differences in the relationship between renin concentration and activity.

Relationship between circulating renin and a/dosterone concentrations (Fig. 5). All measurements except those obtained during corticotropin infusion were used for linear regression analysis. Elderly subjects tended to have a slightly lower plasma aldosterone concentration for a given renin concentration or activity, but the differences were statistically not significant. Relationship between blood pressure and circulating renin levels (Table 4). While receiving 120 mEq of sodium daily, the elderly subjects showed slightly but significantly higher supine and upright mean blood pressures (95.1 8.9 and 81.3 10.7 mm Hg, respectively; P < 0.05). During progressive sodium depletion, the elderly subjects showed a distinct tendency toward orthostatic decreases, and upright blood pressures were comparable in the two age groups. Linear regression analysis of plasma renin concentrations on mean blood pressure revealed significant (P < 0.05) inverse correlations between these variables during two of the eight study conditions, e.g., during normal sodium intake and upright posture (r = —0.44) and following three days of sodium depletion in the supine position (r = —0.47 and —0.49, respectively) (Table 4). During the remaining six study conditions, significant renin-blood pressure interrelations could not be demonstrated. Discussion

These data demonstrate that aging may influence the functional status of the renin-angiotensin-aldoster-

Effect of aging on renin and aldosterone Na intake

120 x lOx

10 x

10 x

,nEq/24 hr 3 days 3 days 6 days

7 days + F

5000

:

3000 2000

.. 1000

500

300 200

•

°

:

9)

•

•' §

•'

.

°

values [7], but others reported data indicating that plasma renin concentration [2] and renin activity [4] remain unchanged with aging. In the present study, circulating renin levels were evaluated with three dif-

o

8

o

.

30

ferent methods, namely by the determination of serum renin concentration and by measurements of plasma renin activity at incubation pH 7.4 and 5.7. Correlations between the results from the three methods were

o

50

NS P
L1 LJ YE

YE Na intake

120

,nEq/24 hr 3 days

lOx 3 days

Ii YE II

YE lOx

lOx

6 days

7 days + F

,

..

30

S

.5

• ° 5

::

o

•:

°

.. S

8

°

•

creases in circulating renin were noted with each procedure. Therefore, methodological problems would appear to play little or no role in the observed effects of aging on renin. However, our findings and those of Sambhi, Crane and Genest [7] and Hayduck eta! [14] are consistent with the possibility that age-induced decreases in plasma renin levels may become apparent would be an explanation for the data of Tuck et al [4], who reported unaltered renin responsiveness in norma! subjects ranging in age from 20 to 60 yr. The present results indicate further that aging does

not impair the aldosterone secretory response to the

stimulatory effects of exogenous corticotropin. Whether this is also true for adrenal responsiveness to angiotensin II remains to be clarified, since angiotensin infusions were not performed. It should be noted

o

3

excellent (r 0.92; P < 0.001) and age-related de-

only after the sixth decade of life. Such a pattern

S.

:

20 10

concentration. These age-related differences were gen-

erally slight while the subjects were supine and ingesting a normal sodium intake, and they were more pronounced during the stimulatory conditions of upright posture and sodium-volume depletion. Previous findings regarding renin and aldosterone metabolism in the aging human have been difficult to interpret [2, 4, 7]. Some authors noted diminished unnary aldosterone [6] or plasma renin and aldosterone

1 o°

•

329

that elderly subjects tended to have a slightly lower plasma aldosterone concentration for a given renin

i o

level. However, this difference was statistically not significant; also, the relationship between circulating renm and aldosterone concentrations does not necessari-

0.5

NS

LJ

YE

P <0.02 P < 0.02 P < 0.005 L_.J

YE

L_...J

YE

L.....J

YE

Fig. 2. Distribution of individual supine plasma renin (A) and aldosterone values (B) before and during progressive sodium deple(ion in young and elderly healthy subjects. Y = young subjects; E = elderly subjects. Values indicating statistical significance refer to difference between young and elderly subjects. Plasma renin activity values are those obtained at incubation pH 5.7.

ly reflect adrenal responsiveness to endogenous angiotensin II. When related to measurements of urinary sodium

excretion, body weight and plasma and blood volumes, plasma renin values at any degree of sodium . and fluid depletion were lower in the elderly than in the young subjects. Thus, it appears that the primary age-induced alteration in the function of the renin. angiotensin-aldosterone system may be a reduction in

renin production or release. Consequently, limited alone system. Compared to young subjects in their third decade of life, healthy elderly subjects in their seventh decade showed moderate decreases in circulating re-

nm, with a parallel reduction in plasma aldosterone

dosterone responses to upright posture or hypovolemia probably result from reduced renin-angiotensin activity rather than from a primary age-induced alteration in adrenal function.

Weidmann et al

330

Table 3. Effect of corticotropin administration on plasma aldosterone, cortisol, renin, potassium and sodium concentrations in young and

elderly healthy subjects (mean Cortisol cg/iOO ml

AIdosterone ng/100 ml

60"

Age group CC Young Mean

spf

120°

Cc

60'd

21.0

24.7 6.6 <0.001 <0.001

15.3

11.8

4.9

6.1

4.5

24.4 7.2 <0.001

11.4

13.9

5.9

6.4

3.8

11.5

10.3

10.7

1.6

5.3

3.3

3.1

<0.0025 <0.001

Elderly Mean

3.8

11.4

13.0

11.9

SD

2.3

4.5 <0.01

9.2 <0.01

4.1

P1

l20

SRca ng/ml/16 hr 120 e cc

18.8 10.6

<0.05

SD)

Potassium Renin

mEq/liter

PRAb (pH 7.4) ng/lOO ml/3hr 120'° Cc

PRAb (pH 5.7) ng/IOOml/3 hr 120° Cc

231 172 117

NS

96 <0.01

NS

265 231

59

NS

214

221

169

92

60"

3.93 0.13

4.16 0.33 <0.05

3.93 0.16

3.98 0.12

NS

175 149 97

308

216

Cc

NS

NS

120°

4.24 0.29 <0.05

4.26 0.34 <0.05

aSRC — serum renin concentration. bPRA = plasma renin activity. CC = control.

d60' = following administration of corticotropin for one hour. 120 = following administration corticotropin for two hours. fp P values for t tests between the control value and the one and two hour values.

Several factors could theoretically lower renin release in the elderly. An age-dependent change in sodium and water metabolism which could account for

during prolonged sodium depletion in the elderly was a consequence rather than the cause of lowered renin and aldosterone activity [5, 21, 22].

the observed differences in plasma renin concentration

Corticotropin infusion and the assumption of the

and activity [15, 16] was not apparent. Except for slightly higher levels in the elderly group following

upright position during progressive sodium depletion

progressive sodium depletion, the plasma potassium

concentrations were also similar in the young and

caused significant (P < 0.05) increases in mean plasma potassium concentration in both the young

dosterone concentrations in the elderly. It is probable

and the elderly subjects. Previous studies in man have shown that following potassium loading or depletion even small alterations in plasma potassium may induce parallel changes in plasma aldosterone concentrations [19, 20, 23, 24]. In the present study, increases in plasma aldosterone concentration following corticotropin administration or assumption of the upright

that the mild tendency toward potassium retention

posture did not correlate with the accompanying

elderly subjects. Increased plasma potassium concentrations could inhibit renin release [17], but they would also be expected to stimulate aldosterone secretion [18—20].

Therefore, potassium retention could not account for

the parallel reductions in circulating renin and a!-

L 5000 3000

5000 3000

2000

2000

1000

1000

cc

-

500

500

300 200

> 300

'::

N=l91

I-

p
cc

200

100 -

30 20 10

r= 0.98

log x = 0.940 logy + 0.638

30 50 100 200 500 1000 2000 5000 Plasma renin activity at pH 7.4, ng/1 00 ml/3 hr

Fig. 3. Relationship between measurements of plasma renin activity at incubation pH 7.4 and 5.7.

50

-

30

-

.Young Elderly 5

N 128 r0.93 P<0.00l N = 63

r = 0.92 P< 0.001

10 2030 50 100200300

Serum renin concentration, ng/ml/16 hr Fig. 4. Correlation between serum renin concentration and plasma renin activity in young and elderly healthy subjects.

Effect of aging on renin and aldosterone

changes in plasma potassium; therefore, it would appear that in normal man acute changes in plasma potassium during these conditions are of little importance for aldosterone regulation. Although only healthy subjects with a pre-study blood pressure of less than 140/90 mm Hg were included in these investigations, blood pressure during

nm deficiency [26—28].

As expected [29] mean creatinine clearance was sig-

--N=60 r0.53*

100 C)

0

0o 00

normal sodium intake and in the supine position tended to be slightly higher in the elderly than in the young group. Furthermore, significant although weak inverse renin-blood pressure interrelations were noted during two of the four study conditions involving normal sodium intake or mild sodium depletion. This is consistent with the possibility that the lowered plasma renin concentration and activity in the elderly group may have been partly related to a higher systemic pressure [25]. However, during progressive sodium depletion circulating renin and aldosterone concentrations remained suppressed in the elderly, despite a) the lack of a significant correlation between blood pressure and renin, and b) the absence of age-related differences in blood pressure when the young and elderly subjects were studied in the upright position. Thus, altered systemic pressure would not appear to be the main mechanism causing renin inhibition in the elderly. Furthermore, it is also possible that the tendencies for blood pressure to increase and for the circulating renin to decrease in the elderly may both be consequences of cardiovascular aging rather than being causally interrelated. There was no apparent relationship between postural renin responses and accompanying blood pressure changes in either the young or elderly subjects. Consequently, the tendency toward postural decreases in the salt-depleted elderly subjects was not related to re-

331

50 30 20

r = 0.60* N = 68

10

r = 0.63*

r= 0.61*

5 3 2 I

I

I

I

I

I

I

2 3 5 10 20 50 100200 500 Serum renin concentration, ng/ml/16 hr N = 60

100 C)

50

0

30

o

— Elderly

r = 0.61* Supine N = 35

/Upright

10

P

.-N=28 r = 0.68*

—Young

20 5 3 2

r = 0.57*

r = 0.88*

I

20 50 100

5001000 5000 Plasma renin activity ng/100 rnl/3 hr Fig. 5. Relationship between circulating renin and plasma aldosterone Concentrations Ifl young and elderly subjects. Heavy regression lines represent young, and thin regression lines represent elderly subjects. Asterisks denoting significance refer to the correlation coefficients between renin and aldosterone values. The equations for the regression lines showed no significant age-related differences.

nificantly lower in the elderly than in the young subjects (84 vs. 106 ml/min/l.73 m2). It appears possible that nephrosclerosis [30, 31] or other morphologic or functional alterations normally occurring in the aging kidney or both [32, 33] may lead to a reduction in renm release [34]. Whether increases in the filtration fraction of the aging kidney [35] could be related to this [36] remains to be clarified.

Table 4. Linear regress ion analysi s of plasm a renin activity or serum renin concentration on mean bloo d pressure in normal subjects during normal sodium intake or sodium depletion Correlation coefficients

Ranges of values

pRAa

N

ng/iOO m!/3 hr

S

46

U

31 19 19

60—885 185—1410 240—1285 375—3015 240—1680 435—3895 425—3825 870—5745

Condition

Normal sodium intake Low sodium intake 3 days fidays 7 days, + Fd

S U S

U

19 19

S

19

U

19

a PRA = plasma renin activity.

bSRC =

serum renin concentration.

BP = mean blood pressure. = furosemide, approximately 1.2 mg/kg of body wt. ep < ØØ5•

SRCb ng/ml/16 hr 3—33

15—75

9—62 16—136 8—78 17—320 16—170 35—274

BPC

mm Hg

In pRAa vs. BPC In SRCb vs. BP°

62—107 66—110 59—97 60—95 71—110 68—94 69—100

—0.21 —0.44e —0.47e —0.11

—0.19 —0.44e —0.49e —0.15

—0.11

64—101

—0.10

—0.09 —0.18 0.06 —0.19

—0.20 0.23

332

Weidmann et a!

One more factor which has to be considered as possibly contributing to age-dependent changes in renin release is the sympathetic system [37, 38]. The role of this system in the control of renin secretion is particularly important during standing and following volume depletion [26, 39—42]. Thus, limited renin release during these latter conditions in our elderly subjects could

be compatible with lowered sympathetic activity. A

previous report suggested that circulating cate-

cholamine concentrations do not decrease with ad-

vancing age [40], although no information is available

with regard to sympathetic function during upright posture or volume depletion. Regardless of the underlying mechanisms, the demonstration of decreased activity of the renin-angiotensin-aldosterone system in healthy elderly subjects may have at least two clinical implications. This alteration may facilitate the development of hyporeninemic hy-

poaldosteronism in the elderly [5, 21, 22], and it should be considered as a possible contributory factor when low renin levels have to be interpreted in older patients with essential hypertension or other clinical conditions. Acknowledgments

This investigation was presented in part at the 7th Meeting of the American Society of Nephrology, November 25—26, 1974. This study was supported by

University Medical Research Foundation. Dr. de Lima was partly supported by Fundacao Amparo a Pesquisa de Sao Paulo, Brasil, and by grant 415 IG from the Los Angeles County Heart Association. Miss Graciela Vega-Gomez and Miss Margrit Stoll provided technical assistance.

5. WEIDMANN P, REINHART

R, MAXWELL MH, ROWE P, COBURN

JW, MASSRY SG: Syndrome of hyporeninemic hypoaldosteron-

ism and hyperkalemia in renal disease. J Clin Endocrino! Metab 36:965—977, 1973 6. FLooD C, GHERONDACHE C, PINCUS G, TAIT JF, TAIT SAS, WILLOUGHBY S: The metabolism and secretion of aldosterone in elderly subjects.) C/tn Invest 46:960—966, 1967 7. SAMBHI MP, CRANE MG, GENEST J: Essential hypertension New concepts about mechanisms. Ann Intern Med 79:411—424, 1973 8. GOULD A, SKEGGS LT, KAHN JR: Measurement of renin and substrate concentrations in human serum. Lab Invest 15:1802— 18 13, 1966 9. HABER E, KOERNER T, PAGE LB, KLIMAN B, PURNODE A: Ap-

plication of a radioimmunoassay for angiotensin Ito the physiologic measurements of plasma renin activity in normal human subjects.) Clin Endocrinol Metab 29:1349—1355, 1969 tO. ITo T, Woo J, HANING R, HORTON R: A radioimmunoassay for aldosterone in human peripheral plasma including a com-

parison of alternate techniques. J C/in Endocrinol Metab 34:106—112, 1972

11. NUGENT CA, MAYES DM: Plasma corticosteroids determined

by use of corticosteroid-binding globulin and dextran-coated charcoal.) C/in Endocrinol Metab 26:1116—1122, 1966 12. WEIDMANN P, MAXWELL MH, LUPU AN, LEWII.1 AJ, MASSRY

SG: Plasma renin activity and blood pressure in terminal renal failure. N EngI J Med 285:757—762, 1971 13. WEIDMANN P, HIRSCH D, MAXWELL MH, OKUN R, SCHROTH

P: Plasma renin and blood pressure during treatment with methyldopa. Am) Cardiol 34:671—676, 1974 14. HAYDUCK K, KRAUSE DK, KAUFMANN W, HUENGES R, SCHILLMOLLER U, UNBEHAUN V: Age-dependent changes of

plasma renin concentration in humans. C/in Sd Mo! Med 45:273s—278s, 1973 15. BROWN JJ, DAVIES DL, LEVER AF, ROBERTSON uS: Influence

of sodium loading and sodium depletion on plasma-renin in man. Lancet 2:278—279, 1963 16. NEWSOME HH, BARTrER FC: Plasma renin activity in relation

to serum sodium concentration and body fluid balance. J C/in Endocrinol Metab 28:1704—1711, 1968 17. BRUNNER HR, BAER L, SEALEY JE, LEDINGHAM JOG, LARAGH

JH: The influence of potassium administration and of potas-

Reprint requests to Dr. Peter Weidmann, Renal Section, Department of Medicine, LA C-USC Medical Center, 2025 Zonal Avenue, Los Angeles, California 90033, U.S.A.

sium deprivation on plasma renin in normal and hypertensive subjects.) C/in Invest 49:2128—2138, 1970 18. DAVIS JO, URQHART J, HIGGINS iT JR: The effects of altera-

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