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The effects of exogenous aldosterone on sweat electrolytes
346
March, 1967 T h e Journal o[ P E D I A T R I C S
The effects of exogenous aldosterone on sweat electrolytes I. Normal subjects
Six normal children and eight normal adults received exogenous aldosterone intramuscularly while being maintakned on constant sodium, potassium, and fluid intake. Both groups showed active sweat gland responses, with characteristics in many ways different [rom responses o[ the kidney. The effects were independent o[ dosage and were reversible with spironoIaetone. Sweat sodium retention during administration of aldosterone was not necessarily dependent upon a decrease in sweat rate. The re,naI response to exogenous aldosterone in children was quite different [rom that o[ adults, and may be related to age.
Richard J. Grand, M.D., Paul A. di Sant'Agnese, M.D., * Richard C. Talamo, M.D., and J. Charles Pallavieini, Ph.D. WITH
THE
TECHNICAL
ASSISTANCE
OF
Kenneth Rich BETHESDA~
MD.
S T U D I E S of acclimatization to heat a-4 and to sodium depletion a, ~, Gsuggest that the normal sweat gland in both adults and children responds to endogenous aldosterone by retaining sodium and excreting potassium, effects which can be reversed by spironolactone.2, 5 Under conditions which avoid sweating and salt loss from prolonged or re-
From the Pediatric Metabolism Branch, Natio.nal Institute o[ Arthritis and Metabolic Diseases, Bethesda, Md. Presented in part at the Third International Research Conference on Pathogenesis o/ Cystic Fibrosis, Sept. 29, 1964, Bethesda, Md. ~'Address, Pediatric Metabolism Branch, National Institute o] Arthritis and Metabolic Diseases, Bethesda, Md. 20014.
Vol. 70, No. 3, part 1, pp. 346-356
peated exposure to heat, and consequent endogenous secretion of the steroid, the effect of exogenous aldosterone can be studied without superimposed acclimatization. This requires pharmacologic agents to stimulate sweating. Few such studies are available, and only isolated features of the electrolyte response have been described. ~'s Similarly there is no information regarding the response of the juvenile kidney to exogenous aldosterone, although there are numerous reports of the renal action of this hormone in adults? -la In preparation for similar studies of patients with cystic fibrosis, 1. the present investigation was undertaken in an effort to
Volume 70 Number 3, part 1
Exogenous aldosterone and sweat electrolytes. I
elucidate the electrolyte response in pilocarpine-induced sweat of normal adults and children and in the urine of normal children, during short term intravenous and prolonged intramuscular administration of aldosterone, with and wkhout spironolactone. METHODS
Eight healthy white adult volunteers (5 males, 3 females), aged 17 to 23 years, and 6 healthy white normal children (2 males, 4 females), aged 9 to 12 years, were studied. A similar protocol was followed for both groups. Each study lasted 3 to 4 weeks. The environment was kept constant (ranging 40 to 50 per cent relative humidity and 72 to 76 ~ F.) and strenuous exercise a n d / o r exposure to heat were forbidden. Thus seasonal variations were considered insignificant. In the adult group the diet averaged 2,700 calories per 24 hours and contained 125 mEq. of sodium, 100 mEq. potassium; the total fluid volume was 2,100 c.c. In children, this diet contained 2,400 calories with 100 mEq. of sodium, 100 mEq. of potassium and a total fluid volume of 1,800 c.c. per 24 hours. Sweat was induced 2 to 4 times daily by iontophoresis of 0.2 per cent pilocarpine nitrate a5 at different sites each time on the volar surface of both forearms in an area of 38.46 cm. 2, and collected on preweighed Whatman No. 44 ashless filter paper for 45 minutes. Output of sweat was expressed as milliliters per minute per square meter of surface area. Urine for each 24 hour period was pooled. Sodium and potassium in sweat and urine were determined in a flame photometer* with lithium as internal standard. Chloride was determined with a Cotlove chloridometer. 16 The subjects were weighed daily before breakfast, after voiding, and serum electrolyte values were obtained frequently. Preliminary studies were performed on 5 of the normal adults with 2.0 mg. of d-aldosterone in 95 per cent ethanol,t given intravenously in 400 ml. of 5 per cent dextrose *National Instrument Laboratories, Rockville, Md. ~Aldosterone supplied by CIBA Pharmaceutical Company, Summit, N. J.
347
and water over an 8 hour period with a constant-infusion pump (4.2/~g per minute). In other studies, the 8 adults were given d-aldosterone in sesame oilt (1.0 mg. per 24 hours) intramuscularly in equal doses every 8 hours for 7 days. A second experiment was performed on 3 of these subjects with 2.0 mg. of aldosterone in oil per 24 hours. Three other normal subjects also received this higher dose of aldosterone; but instead of discontinuing the hormone after the seventh day (study day 14), it was continued for 5 days more (through study day 19) and spironolactone* (200 rag. orally every 12 hours) was added from study day 15 through 19, inclusive. Normal children were given the same preparation of d-aldosterone in oil intramuscularly in equal doses every 8 hours for 7 days, but at a dosage of 0.5 mg. per 10 Kg. of body weight per 24 hours (range of total dose: 1.0 to 2.25 mg., Table I). The 7 day period of aldosterone administration for both children and adults was preceded by a control period of 7 to 10 days and was followed by a similar period of at least 2 days. RESULTS
Intravenous aldosterone--normal adults. Following intravenous administration of aldosterone, the maximal renal response always preceded that of the sweat gland, but the time interval varied from subject to subject. In 4 subjects maximal fall of urinary sodium output and of the sodium-to-potassium ratio occurred 4 to 6 hours after the start of the infusion (Fig. 1). One subject showed this maximal fall 2 to 4 hours following the end of the infusion. In all cases there was a concomitant potassium diuresis. In contrast, sweat sodium concentration and the sodium-to-potassium ratio decreased maximally at the end of the infusion or shortly thereafter. Three of the 5 subjects showed a concomitant rise in sweat potassium concentration. The reduction in the concentration of sweat sodium and in the sodium-to-potassium ratio continued for as ~In the form of aldactone-A, G. D. Searle & Co., Chicago, Ill.
348
The Journal of Pediatrics March 1967
Grand et aI. d-ALDOSTERONE 2 mg lV
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Fig. 1. The effect of intravenous administration of 2.0 mg. of d-aldosterone on sweat and urinary excretion of electrolytes in a 20-year-old male.
long as 14 hours following the end of the infusion in 2 subjects. I n all subjects the concentration of sweat sodium a n d the sodium-to-potassium ratio were still diminished at a time when a r e t u r n of u r i n a r y sodium excretion toward control levels or a r e b o u n d natriuresis was taking place. Intramuscular aldosterone--normal adults. T h e responses to intramuscularly administered aldosterone in the adult subjects were quite u n i f o r m (Fig. 2). As described in the literature, a0, 18 all a d u l t subjects in the present study experienced a fall in urinary excretion of sodium within the first 24 hours after administration of aldosterone was beg~an. T h e r e was then a stepwise escape, a n d a marked r e b o u n d natriuresis when administration of aldosterone was discontinued. U r i n a r y diuresis of potassium occurred at the start of aldosterone treatment. Changes in the urinary sodium-to-potassium ratio a n d in the excretion of chloride paralleled those of sodium. I n all adults, sweat sodium values began to fall within the first 48 hours after aldo-
T a b l e I. C o m p a r i s o n of sweat electrolytes in control period a n d d u r i n g aldosterone a d m i n i s t r a t i o n Sodium
Subiect
Adults A.K. R.B. L.S. P. DF. E.G. L.F. T.P. C.N.
Sex
Age (yr.)
Dose o[ aldosterone (reg.~day)
M M F M F M F M
23 20 20 19 19 18 18 17
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
Group~. Children D.S. D.W. D.K. C.W. S.K. S.W. Group~
1V[ M F F F F
12 11 10 10 9 9
2.25 1.5 1.7 1.3 1.2 1.0
Control N* 7 7 7 7 7 7 7 7
Mean _+SEt (mEq./L. ) 49.1 _+2.92 25.2 +_1.16 33.0 _+0.59 20.1 +- 1.03 53.3 _+2.21 13.4_+0.83 30.0-+ 1.19 30.4 _+2.24
N
Mean _+SE (mEa./L.)
7 7 7 5 7 7 7 7
32.5 -+2.09 19.0 -+0.98 22.0.+ 0.96 I7.8_+1.31 44.3 + 3.29 10.4+_0.61 19.7 _+1.48 18.4 .+ 1.03
56
31.8 + 1.80
54
23.2 -+ 1.48
6 7 5 7 5 7 37
10.1 -+0.65 9.7 -+0.75 15.3 .+ 1.14 15.9.+0.74 12.3 -+0.42 12.1 + 1.47 12.5 + 0.54
7 7 5 7 5 7 38
8.4 + 0.79 7.9_+0.81 11.3 +-2.04 13.0 + 1.83 11.1 .+ 1.40 8.0 .+ 1.46 9.8 +-0.63
*Number of days on which observations were made. The daily average for each subject was used. ~Standard error of mean. :~Total of observations from all subjects.
Aldosterone
Volume 730 Number 3, part 1
E x o g e n o u s a l d o s t e r o n e a n d s w e a t electrolytes. I
Fig. 4 depicts a typical study combining the high dose of atdosterone with the later a d d i t i o n of spironolactone. T h e results were indistinguishable f r o m those o b t a i n e d b y completely discontinuing a d m i n i s t r a t i o n of aldosterone. W i t h i n the first 24 hours of spironolactone administration, a sodium diuresis occurred, a n d the u r i n a r y sodium-topotassium ratio increased markedly. W i t h i n 48 hours there was a rise in the concentration of sweat sodium a n d in the sodium-to-potassium rati% a n d a fall in the concentration of sweat potassium. Body weight also decreased rapidly. I n t r a m u s c u l a r a l d o s t e r o n e - - n o r m a l children. T h e sweat electrolyte response in all 6 n o r m a l c h i l d r e n was similar to t h a t of n o r m a l adults. T h e lag phase at the start of h o r m o n e a d m i n i s t r a t i o n a n d the recovery p e r i o d a t t h e end were m o r e p r o l o n g e d (Fig. 5). I n d e e d , aidosterone seemed to have little effect on the sweat glands of these children in the first 48 hours. T h e r e a f t e r , sweat sodium c o n c e n t r a t i o n declined, stayed low d u r i n g the t r e a t m e n t period, a n d rose after-
sterone t r e a t m e n t was b e g u n (Fig. 2 ) ; in 2 of them, the d r o p occurred within the initial 24 hours. T h e concentration of sweat sodium decreased progressively a n d r e m a i n e d low as long as the h o r m o n e was a d m i n i s t e r e d ; it rose slowly t o w a r d control values after administration of aldosterone was discontinued. T h e concentration of sweat chloride a n d the sodium-to-potassium ratio changed similarly. T h e concentration of sweat potassium showed no consistent p a t t e r n in i n d i v i d u a l subjects. Body weight rose in 4 subjects while they were receiving aldosterone (Fig. 2), b u t showed no trend in the other 4. Body weight always fell below control levels 3 to 4 days after cessation of h o r m o n e administration. T h e r e were no significant changes in serum electrolyte concentrations or blood pressure. I n the 3 subjects who received 2.0 mg. of aldosterone p e r d a y the responses of sweat electrolytes were quite similar to those on 1.0 rag. p e r d a y (Fig. 3). T h e natriuresis after t e r m i n a t i o n of a d m i n i s t r a t i o n of aldosterone was m o r e marked, as was the weight gain.
Potassium Control
Aldosterone N
N
7.4 -+0.28 7,0 + 0.24 10.3 + 0.40 6.2 • 0.11 7.1 + 0.27 5.8 - 0.18 9.8 + 0.18 8.2 -+0.28
7 7 7 5 7 7 7 7
8.5 + 0.57 7.3 + 0.36 11.2 + 0.54 6.7 -+0.27 8.2 + 0.83 7.1 +-0.26 10.3 -+ 0.42 8.3 -+0.23
7 7 7 7 7 7 7 7
7.7 -+ 0.22
54
8.5 -+ 0.26
10.1 + 0.95 8.6 +0.55 7.9 + 0.46 7.1 +-0.92 7.2 + 0.22 10.8 + 0.96 8.7 -+0.50
7 7 5 7 5 7 38
11.4 + 0.62 6.9 -+0.50 9.8 + 0.44 9.7 -+0.77 8.6 + 0.72 11.2 • 0.47 9.7 -+0.35
6 4 5 7 5 7
34
Control Mean + SE (mEar/L. }
7 7 7 7 7 7 7 7 56
N
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SE (mEq./L.)
Mean +
3 4 9
Aldosterone " N
Mean + S E (mEa./L.)
6.86 -+0.20 3.59 -+0.12 3.27 -+0.14 3.17 + 0.16 7.54 + 0.21 2.34 -+0.13 3.07 -+0.17 3.77 -+ 0.32
7 7 7 5 7 7 7 7
3.56 + 0.39 2.61 + 0.19 2.09 + 0.11 2.72 -+0.27 5.46 + 0.87 1.51 +--0.12 1.97 -+0.21 2.19 -+0.15
56
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54
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6 4 5 7 5 7 34
1.07 + 0.15 1.21 -+0.13 1.93 -+0.04 2.67 + 0.49 1.74 -+0.09 1.32 -+0.25 1.69 + 0.15
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0.73 -+0.06 1.13 -+0.13 1.16 -+0.22 1.37 + 0.14 1.37 -+ 0.25 0.63 -+0.12 1.04 -+0.07
350
The ]ournal of Pediatrics March 1967
Grand et al.
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Volume 70 Number 3, part 1
Exogenous aldosterone and sweat electrolytes. I
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adults consistently showed parallel changes in these variables (Fig. 6, R. B., E. G., T. P., C. N . ) ; one showed inverse changes (A. K.). In the others, and in all the children (Fig. 7), the relationship was less regular. During administration of aldosterone no consistent relationship between sweat output
352
Grand et aL
The ]ournal of Pediatrics March 1967
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and sweat sodium concentration was found in any subject. There was a tendency toward decreasing sweat output and sodium concentrations in 4 adults and 3 children. However, the remainder were able to diminish the concentration of sweat sodium without a change in sweat output (Fig. 8). Comparison of data. Mean sweat electrolyte values for each subject during the control and aldosterone periods are shown in Table I. In view of individual differences in initial control levels, the data were also expressed as the mean per cent change during the week when aldosterone was given from the mean of the control week (Table I I ) . A statistically significant fall in sweat sodium concentration and rise in sweat potassium concentration did not occur in every subject. However, there were significant
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Fig. 8. C o m p a r i s o n of sweat rate a n d sweat s o d i u m c o n c e n t r a t i o n in t h e control period a n d d u r i n g aldosterone a d m i n i s t r a t i o n . A significant fall of sweat s o d i u m occurs w i t h o u t a c h a n g e in sweat output.
changes in both variables and in the sodiumto-potassium ratio when the group means were compared (Table II). There was no significant difference in the per cent responses of the 2 age groups (TabIe I I ) . Because of the lag period in onset of sweat gland responses, mean variations
Volume 70 Number 3, part 1
Exogenous aldosterone and sweat electrolytes. I
353
T a b l e I I . M e a n p e r c e n t c h a n g e in s w e a t e l e c t r o l y t e s for w e e k w h e n a l d o s t e r o n e was a d m i n i s t e r e d f r o m m e a n of c o n t r o l w e e k
Subiect Adults A.K. R. B, L.S. P. DF, E.G. L.F. T.P. C.N. Group Children D.S. D.W. D.K. C.W. S.K. S.W. Grout)
No. o[ days ot obwrvation 7 7 7 5 7 7 7 7 54 7 7 5 7 5 7 38
Decrease in sodium Mean + SE (%)
Increase in potassium Mean + SE ,(%)
33.9--24.7 + 33.3 + 10.4-+ 16.8-+ 21.8 + 34.2 + 39.3-+
14.5 -+ 7.70 4.1 -+ 5.12 8.5 + 5.67 7.3 + 4.33 15.5 -+ 11.55 23.0 + 4.42 4.3 -+ 4.30 1.2 -+ 2.74
4.25 3.87 2.91 6.51 6.18 4.57 4.94 3.38
27,4 + 1.95 ~
Decrease in sodium-to-potassium ratio Mean + SE (%) 48.1 + 27.1 + 36.2 + 14.3 + 27.7 + 35.4 + 35,8 + 42.1 +
9.9 + 2.32 ~
16.6-+ 7.86 18.7-+ 8.39 26.4 + 13.32 18.0 -+ 11.51 10.2 + 11.32 33.9 + 12.06
34.0 + 2.53 ~
13.1 -+ 6.14 -19.1 + 5.86 23.7 -+ 5.54 37.2 + 10.79 18.6 + 10.00 4.4 -+ 4.37
20.9 -+ 4.25 ~
5.67 5.18 3.36 8,55 11.55 5.22 6.89 3.86
31.5 -+ 5.92 6.1 + 10.87 39,7 + 11.54 4 8 . 6 -+ 5.14 21.3 + 14.48 52.7 -+ 9.33
12.1 -+ 4.12+
33.6 -+ 4.50 ~
~Significance of difference from zero, p < 0.001. (Two-tailed Student's t test.) tSignificance of difference from zero, p < 0.01. (Two-tailed Student's t test.)
in s w e a t e l e c t r o l y t e s w e r e also c a l c u l a t e d w i t h t h e first 2 days of t h e " a l d o s t e r o n e w e e k " o m i t t e d . T h e r e was n o significant diff e r e n c e in s w e a t g l a n d response b e t w e e n this time and the 7 day mean. M a x i m a l c h a n g e s in s w e a t electrolytes a r e s h o w n in T a b l e I I I . I n all subjects this response o c c u r r e d o n o r a f t e r t h e fifth d a y of aldosterone administration. DISCUSSION T h e p r e s e n t studies d e m o n s t r a t e a n a c t i v e s w e a t g l a n d r e s p o n s e to e x o g e n o u s aldosterone, w i t h c h a r a c t e r i s t i c s in m a n y w a y s q u i t e d i f f e r e n t f r o m those of t h e kidney. While both the sweat glands and the kidneys h a v e a d e c r e a s e d e x c r e t i o n of sodium, t h e s w e a t g l a n d e x c r e t i o n of p o t a s s i u m is m o r e i r r e g u l a r ; t h e t i m e lag for t h e o n s e t of t h e m a x i m a l s w e a t g l a n d effect is g r e a t e r ; t h e r e is n o r e a l c o u n t e r p a r t to t h e r e n a l escape p h e n o m e n o n ; a n d s w e a t g l a n d e x c r e t i o n of s o d i u m a f t e r d i s c o n t i n u a n c e of a l d o s t e r o n e has a d i f f e r e n t p a t t e r n .
T a b l e III. M a x i m u m p e r c e n t c h a n g e in s w e a t e l e c t r o l y t e s f r o m m e a n of c o n t r o l w e e k
sodium (%)
Increase in potassium (%)
Decrease in sodium-topotassium ratio (%)
46.1 38.4 40.9 27.5 37.2 37.2 50.0 58.8
37.8 28.5 33,8 27.5 60.5 72.4 21.1 14.8
68.1 52.7 48.4 34.3 72.0 52.1 51.6 52.6
42.0 7.9
37.0 20.5
54.0 12.5
49.5 27.8 46.8 64.9 35.7 66.6
30.6 82.0 36.7 90.1 44.4 14,8
50.9 86.6 59.1 70.3 55.6 75.3
48.6 15.4
49.8 29.7
66.3 13.0
Decrease ~n
Subiee! Adults A.K. R.B. L.S. P. DF. E,G. L.F. T.P. C.N. Mean SE Children D.S. D.W. D.K. C.W. S.K. S.W. MeaI1
SE
354
Grand et al.
When aldosterone is given intramuscularly to adults, urinary sodium output falls markedly within the first 24 hours, while sweat sodium retention occurs more slowly, a significant fall requiring 24 to 48 hours. Thereafter, the sweat sodium concentration remains well below control values for as long as aldosterone is administered, while, as expected, sodium diuresis increases. The renal rebound natriuresis after cessation of hormone treatment is quite different from the sweat gland response; sweat sodium values rise slowly toward, and only rarely exceed, control levels. The timing of responses to aldosterone in the sweat gland and kidney is similar for both the intravenous and intramuscular routes of administration. Sweat sodium retention has begun at a time when urinary sodium excretion is at its lowest point, and is maximal during the renal escape. In both instances, the renal recovery precedes that of the sweat gland. The chronology of events reported for the kidney during the intravenous infusions agrees with previous findings by other workers. TM 12 In children, the sweat gland response to intramuscularly administered aldosterone is similar to that of adults except for the longer lag in the onset of retention of sweat sodium and for the longer recovery period after treatment ends. On the other hand, the renal response is quite different from the well-established adult patterns seen both in this and previous studies? ~ 13 Children do show some evidence of a renal effect in the small initial fall of urinary sodium excretion, the modest rebound after the last injection, and the consistent elevation of body weight. However, the urinary sodium escape is virtually absent, and urinary electrolyte excretion during the period of aldosterone administration is not significantly different from that in the control period. An escape from the sodium retaining effects could have masked the sodium response on day one of aldosterone treatment, but a kaliuresis should still have appeared. The absence of this response and the constant serum electrolytes suggest that the kidneys of these children were less responsive than those of
The Journal o[ Pediatrics March 1967
adults to the dose of aldosterone given during a sodium intake of 100 mEq. per day. It is known that with sodium depletion and elevated urinary aldosterone excretion the normal juvenile kidney responds in a fashion comparable to that of the adult. 6 Furthermore, excretion of aldosterone (and presumably endogenous production) in this age group is either similar to 17 or lower than that in older subjects. 18 One would therefore expect a greater renal responsiveness to additional aldosterone under conditions of sodium and potassium balance than was found in the present study, especially since the sweat gland responses in adults and children are comparable. This renal behavier is unexplained, but that it may be related to. age is supported by the finding of an adult response in the oldest child (D. S.). Siegenthaler and de Hailer 8 gave aldosterone intramuscularly to normal subjects for 4 days and demonstrated an average maximal reduction of sweat sodium concentration similar to that in the present investigation. However, further comparison is not possible since no data are reported concerning dietary intake, activity of subjects, sweat output, o.r sweat potassium values. Using very high doses of 9-alpha-fluorohydrocortisone, Lobeck and McSherry 19 produced a maximal fall in sweat sodium concentration of 26.6 per cent and a rise in sweat potassium concentration of 7.9 per cent in normal adults, but only a 15.2 per cent fall in sweat sodium concentration and 2.9 per cent rise in potassium concentration in normal children. The drug was given for only 2 consecutive days, and in view of the lag in onset of the sweat gland response to aldosterone demonstrated by the present study, a similar occurrence may be assumed to have prevented more impressive responses to 9alpha-fluorohydrocortisone. In contrast to the effects of intravenous aldosterone on the sweat gland, no consistent change in the salivary sodium-to-potassium ratio was obtained during a comparable study. 11 However, when aldosterone was given intramuscularly for 2 weeks, a~ depression of salivary sodium concentration and sodium-to-potassium ratio occurred and con-
Volume 70 Number 3, part 1
Exogenous aldosterone and sweat electrolytes. I
tinued throughout the treatment period despite renal escape. Only 4 adults (and only in the control period) showed a distinct correlation between sweat output and sweat sodium concentration. At sweat rates comparable to those in this study, and with sweat induced and collected in the same manner, Lobeck and Huebner 2~ described a concomitant rise in both sweat output and sweat sodium concentration in normal adults during the collection period, but not in normal children. The variability in their study and in the present one m a y be explained by the very low sweat rates obtained with pilocarpine iontophoresis when sweat is collected only once at the end of 45 minutes. This represents the summation of a changing rate (and sodium concentration) which has been decreasing since the initial, presumably maximal, stimulation of the sweat gland. Indeed, experiments with collections performed every 10 minutes after an initial subcutaneous injection of methacholine, 21 and continuous observations of the electrical conductivity of sweat following pilocarpine iontophoresis, ~have shown that there is a rise in the first 10 minutes followed by a steady decline in sweat output and sodium concentrations after initial stimulation. Recently a consistent relationship between increasing sweat rate and sodium concentration has been found both in normal adults 2a and normal children 24 with sequential sweat collections, when physical exercise in a heated, constant-temperature room was the stimulant for sweating. Although this is quite a different set of circumstances from, and not really comparable to, the present study, it is interesting that despite comparable stimuli, sweat rates in children were never as high as in adults. At lower sweat rates (approaching those described in this paper) the relationship between rate and sodium concentration was not nearly as clear. Schwartz and Thaysen 2s originally suggested that there is a limit to the capacity of the sweat gland duct to reabsorb sodium, and that when this limit is exceeded, any further output of water and sodium by the coil leads to an increase of sweat electrolyte eoncentra-
3 55
tion. If this postulate is correct, a linear relationship between increasing rate and increasing concentration of sodium will not necessarily be present at low sweat rates since the minimum rate required for expression of this finding may not have been reached. T h a t aldosterone may induce retention of sweat sodium independently of sweat output is supported by the fact that half of the subjects in the present study were able to. Iower their sweat sodium concentration significantly without lowering their sweat output. However, the other subjects did show a trend toward decreasing both sweat sodium concentration and sweat output in response to aldosterone. Similar variability has been described by Lobeck and McSherry in subjects given 9-alpha-fluorohydrocortisone and desoxycorticosterone? s These inconsistencies may result from low sweat outputs. Further studies on the action of aldosterone and other sodium retaining steroids at high sweat rates are needed. SUMMARY
In the normal adult there is an active sweat gland response to exogenous aldosterone with characteristics in many ways different from responses of the kidneys. Both show a fall in excretion of sodium; but sweat gland excretion of potassium is less regular; the time lag in onset of the sweat gland effect is greater; there is no counterpart to the renal escape; and the sweat gland recovery after discontinuance of aldosterone is slower. These effects are independent of dose. Spironolaetone administered during the use of aldosterone produces changes of the same type as withdrawal of aldosterone. Sweat patterns of children in response to administration of aldosterone are similar to those oI adults. Sweat sodium retention in response to exogenous aldosterone is not necessarily dependent upon a decrease in sweat output. At low sweat rates, the relationship between rate and sodium concentration is irregular, in contrast to the situation at high sweat rates. Contrary to the similarity in behavior of the sweat glands in adults and children, the renal responses to exogenous aldosterone were
356
Grand et al.
quite different in the two age groups. T h e urine of the children had a less dramatic initial fall in sodium excretion, no change in potassium excretion, lack of a d e a r - c u t escape p h e n o m e n o n , and less marked posttreatment natriuresis. These characteristics may be related to age. The authors are especially indebted to: Miss Joan Gurian, Biometrics Research Branch, National Heart Institute, for statistical analyses; Mrs. Ruby Lee and Mrs. Joan Mok for valuable technical and secretarial assistance; Miss Kathryn Doherty, Miss Louise Boyer, Miss Ernestina Bou, and Miss Janet Ledbury for the dietary management of the study patients; Miss Isabelle Ambrose; Dr. Joseph F. Gallelli, Pharmacy Department, National Institutes of Health; and the Nursing Staff of the National Institute of Arthritis and Metabolic Diseases. REFERENCES 1. Streeten, D. H. P., Conn, J. W., Louis, L. H., Fa~ans, S. S., Seltzer, H. S., Johnson, R. D., Gittler, R. D., and Dube, A. H.: Secondary aldosteronism: Metabolic and adrenocortical responses of normal men to high environmental temperatures, Metabolism 9: 1071, 1960. 2. Ladell, W. S. S., and Shephard, R. J.: Aldosterone inhibition and acclimatization to heat, J. Physiol. 160: 19P, 1962. Abst. 3. Corm, J. W.: Aldosteronism in man, J. A. M. A. 183: 775, 1963. 4. McConahay, T. P., Robinson, S., and Newton, J. L.: d-Aldosterone and sweat electrolytes, J. AppI. Physiol. 19: 575, 1964. 5. Siegenthaler, P., de Haller, R., Veyrat, R., and Muller, A. F. : Influence d 'un inhibiteur et d'un antagoniste de l'aldosterone sur la concentration du sodium sudoraI, Helvet. med. acta 29: 550, 1962. 6. Oliver, W. J., and Watson, D. F.: Effect of salt intake on sweat electrolytes in children, Am. J. Dis. Child. 107: 470, 1964. 7. Collins, K. j.: Effects of aldosterone and spironolactone on Na:K in drug-induced sweat, J. Physiol. 165: 49P, 1963. Abst. 8. Siegcnthaler, P., and de Hailer, R.: Contribution au probl~me du diagnostic de la fibrose kystique du pancr6as ou mucoviscidose chez l'adulte, Helvet. reed. acta 32: 1, 1965. 9. Thorn, G. W., Sheppard, R. H., Morse, W. I., Reddy, W. J., Beigelman, P. M., and Renold, A. E.: Comparative action of aldosterone and 9-alp.ha-fluorohydrocortisone in man, Ann. New York Acad. Sc. 61: 609, 1955. 10. August, J. T., Nelson, D. H., and Thorn, G. W.: Response of normal subjects to large
The Journal o[ Pediatrics March 1967
11.
12.
13.
14.
15.
16.
17.
18. i9.
20.
21.
22. 23.
24. 25.
amounts of aldosterone, J. Clin. Invest. 37: 1549, 1958. Ross, E. J., Reddy, W. J., Rivera, A., and Thorn, G. W.: Effects of intravenous infusions of dl-aldosterone acetate on sodium and potassium excretion in man, J. Clin Endocrinol. 19: 289, 1959. Sonnenblick, E. H., Cannon, P. J., and Laragh, J. H.: The nature of the action of intravenous aldosterone: Evidence for a rote of the hormone in urinary dilution, J. Clin. Invest. 40: 903, 1961. Rosemberg, E., Demany, M., Budnitz, E., Underwood, R., and Leard, R. S.: Effects of administration of large amounts of d-aldosterone in normal subjects and in a patient with Sheehan's syndrome, J. Clin. Endocrinol. 22: 465, 1962. Grand, R. J., di Sant'Agnese, P. A., Talamo, R~ C., and Pallavicini, J. C.: The effects of exogenous aldosterone on sweat electrolytes. II. Patients with cystic fibrosis of the pancreas, J. PEmAT. 70: 357, 1967. Gibson, L. E., and Cooke, R. E.: A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing piloearp~ne by iontophoresis, Pediatrics 23: 545, 1959. Cotlove, E., Trantham, H. V., and Bowman, R. L.: An instrument and method for automatic, rapid, accurate, and sensitive titration of chloride in biological samples, J. Lab. & Clin. Med. 51: 461, 1958. New, M. I., Miller, B., and Peterson, R. E.: Aldosterone excretion in normal children and in children with adrenal hyperplasia, J. Clin. Invest. 45: 412, 1966. Minick, M. C., and Conn, J. W.: Aldosterone excretion from infancy to adult life, Metabolism 13: 681, 1964. Lobeck, C. C., and McSherry, N. R.: Response of sweat electrolyte concentrations to 9-alpha-fluorohydrocortisone in patients with cystic fibrosis and their families, J. PEDlAr. 62: 393, 1963. Lobeck, C. C., and Huebner, D.: Effect of age, sex, and cystic fibrosis on the sodium and potassium content of human sweat, Pediatrics 30: 172, 1962. Sibinga, M. S., and Barbero, G. J.: Sweat sodium content and flow rate in cystic fibrosis of the pancreas: J. Appl. Physiol. 18: 1226, 1963. Gibson, L. E., and di Sant'Agnese, P. A.: Studies of salt excretion in sweat, J. P~DIAT. 62: 855, 1963. Cage, G. W., and Dobson, R. L.: Sodium secretion and reabsorption in the human ecerine sweat gland, J. Clin. Invest. 44: 1270, 1965. Cage, G. W., Dobson, R. L., and Waller, R.: Sweat gland function in cystic fibrosis, J. Clin. Invest. 45: 1373, 1966. Schwartz, I. L., and Thaysen, J. H.: Excretion of sodium and potassium in human sweat, J. CIin. Invest. 34: 114, 1956.
March, 1967 T h e Journal o[ P E D I A T R I C S
The effects of exogenous aldosterone on sweat electrolytes I. Normal subjects
Six normal children and eight normal adults received exogenous aldosterone intramuscularly while being maintakned on constant sodium, potassium, and fluid intake. Both groups showed active sweat gland responses, with characteristics in many ways different [rom responses o[ the kidney. The effects were independent o[ dosage and were reversible with spironoIaetone. Sweat sodium retention during administration of aldosterone was not necessarily dependent upon a decrease in sweat rate. The re,naI response to exogenous aldosterone in children was quite different [rom that o[ adults, and may be related to age.
Richard J. Grand, M.D., Paul A. di Sant'Agnese, M.D., * Richard C. Talamo, M.D., and J. Charles Pallavieini, Ph.D. WITH
THE
TECHNICAL
ASSISTANCE
OF
Kenneth Rich BETHESDA~
MD.
S T U D I E S of acclimatization to heat a-4 and to sodium depletion a, ~, Gsuggest that the normal sweat gland in both adults and children responds to endogenous aldosterone by retaining sodium and excreting potassium, effects which can be reversed by spironolactone.2, 5 Under conditions which avoid sweating and salt loss from prolonged or re-
From the Pediatric Metabolism Branch, Natio.nal Institute o[ Arthritis and Metabolic Diseases, Bethesda, Md. Presented in part at the Third International Research Conference on Pathogenesis o/ Cystic Fibrosis, Sept. 29, 1964, Bethesda, Md. ~'Address, Pediatric Metabolism Branch, National Institute o] Arthritis and Metabolic Diseases, Bethesda, Md. 20014.
Vol. 70, No. 3, part 1, pp. 346-356
peated exposure to heat, and consequent endogenous secretion of the steroid, the effect of exogenous aldosterone can be studied without superimposed acclimatization. This requires pharmacologic agents to stimulate sweating. Few such studies are available, and only isolated features of the electrolyte response have been described. ~'s Similarly there is no information regarding the response of the juvenile kidney to exogenous aldosterone, although there are numerous reports of the renal action of this hormone in adults? -la In preparation for similar studies of patients with cystic fibrosis, 1. the present investigation was undertaken in an effort to
Volume 70 Number 3, part 1
Exogenous aldosterone and sweat electrolytes. I
elucidate the electrolyte response in pilocarpine-induced sweat of normal adults and children and in the urine of normal children, during short term intravenous and prolonged intramuscular administration of aldosterone, with and wkhout spironolactone. METHODS
Eight healthy white adult volunteers (5 males, 3 females), aged 17 to 23 years, and 6 healthy white normal children (2 males, 4 females), aged 9 to 12 years, were studied. A similar protocol was followed for both groups. Each study lasted 3 to 4 weeks. The environment was kept constant (ranging 40 to 50 per cent relative humidity and 72 to 76 ~ F.) and strenuous exercise a n d / o r exposure to heat were forbidden. Thus seasonal variations were considered insignificant. In the adult group the diet averaged 2,700 calories per 24 hours and contained 125 mEq. of sodium, 100 mEq. potassium; the total fluid volume was 2,100 c.c. In children, this diet contained 2,400 calories with 100 mEq. of sodium, 100 mEq. of potassium and a total fluid volume of 1,800 c.c. per 24 hours. Sweat was induced 2 to 4 times daily by iontophoresis of 0.2 per cent pilocarpine nitrate a5 at different sites each time on the volar surface of both forearms in an area of 38.46 cm. 2, and collected on preweighed Whatman No. 44 ashless filter paper for 45 minutes. Output of sweat was expressed as milliliters per minute per square meter of surface area. Urine for each 24 hour period was pooled. Sodium and potassium in sweat and urine were determined in a flame photometer* with lithium as internal standard. Chloride was determined with a Cotlove chloridometer. 16 The subjects were weighed daily before breakfast, after voiding, and serum electrolyte values were obtained frequently. Preliminary studies were performed on 5 of the normal adults with 2.0 mg. of d-aldosterone in 95 per cent ethanol,t given intravenously in 400 ml. of 5 per cent dextrose *National Instrument Laboratories, Rockville, Md. ~Aldosterone supplied by CIBA Pharmaceutical Company, Summit, N. J.
347
and water over an 8 hour period with a constant-infusion pump (4.2/~g per minute). In other studies, the 8 adults were given d-aldosterone in sesame oilt (1.0 mg. per 24 hours) intramuscularly in equal doses every 8 hours for 7 days. A second experiment was performed on 3 of these subjects with 2.0 mg. of aldosterone in oil per 24 hours. Three other normal subjects also received this higher dose of aldosterone; but instead of discontinuing the hormone after the seventh day (study day 14), it was continued for 5 days more (through study day 19) and spironolactone* (200 rag. orally every 12 hours) was added from study day 15 through 19, inclusive. Normal children were given the same preparation of d-aldosterone in oil intramuscularly in equal doses every 8 hours for 7 days, but at a dosage of 0.5 mg. per 10 Kg. of body weight per 24 hours (range of total dose: 1.0 to 2.25 mg., Table I). The 7 day period of aldosterone administration for both children and adults was preceded by a control period of 7 to 10 days and was followed by a similar period of at least 2 days. RESULTS
Intravenous aldosterone--normal adults. Following intravenous administration of aldosterone, the maximal renal response always preceded that of the sweat gland, but the time interval varied from subject to subject. In 4 subjects maximal fall of urinary sodium output and of the sodium-to-potassium ratio occurred 4 to 6 hours after the start of the infusion (Fig. 1). One subject showed this maximal fall 2 to 4 hours following the end of the infusion. In all cases there was a concomitant potassium diuresis. In contrast, sweat sodium concentration and the sodium-to-potassium ratio decreased maximally at the end of the infusion or shortly thereafter. Three of the 5 subjects showed a concomitant rise in sweat potassium concentration. The reduction in the concentration of sweat sodium and in the sodium-to-potassium ratio continued for as ~In the form of aldactone-A, G. D. Searle & Co., Chicago, Ill.
348
The Journal of Pediatrics March 1967
Grand et aI. d-ALDOSTERONE 2 mg lV
I
tr
m
I
t
[
r
I
~ I
I
I
I
I
i
I
I
I
4
~I5I
z_~
o
I
'~ z ~
i
i
0 2
R B. r
-
r
6
t
IO 1 4 HOURS
16
22
26
W
Fig. 1. The effect of intravenous administration of 2.0 mg. of d-aldosterone on sweat and urinary excretion of electrolytes in a 20-year-old male.
long as 14 hours following the end of the infusion in 2 subjects. I n all subjects the concentration of sweat sodium a n d the sodium-to-potassium ratio were still diminished at a time when a r e t u r n of u r i n a r y sodium excretion toward control levels or a r e b o u n d natriuresis was taking place. Intramuscular aldosterone--normal adults. T h e responses to intramuscularly administered aldosterone in the adult subjects were quite u n i f o r m (Fig. 2). As described in the literature, a0, 18 all a d u l t subjects in the present study experienced a fall in urinary excretion of sodium within the first 24 hours after administration of aldosterone was beg~an. T h e r e was then a stepwise escape, a n d a marked r e b o u n d natriuresis when administration of aldosterone was discontinued. U r i n a r y diuresis of potassium occurred at the start of aldosterone treatment. Changes in the urinary sodium-to-potassium ratio a n d in the excretion of chloride paralleled those of sodium. I n all adults, sweat sodium values began to fall within the first 48 hours after aldo-
T a b l e I. C o m p a r i s o n of sweat electrolytes in control period a n d d u r i n g aldosterone a d m i n i s t r a t i o n Sodium
Subiect
Adults A.K. R.B. L.S. P. DF. E.G. L.F. T.P. C.N.
Sex
Age (yr.)
Dose o[ aldosterone (reg.~day)
M M F M F M F M
23 20 20 19 19 18 18 17
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
Group~. Children D.S. D.W. D.K. C.W. S.K. S.W. Group~
1V[ M F F F F
12 11 10 10 9 9
2.25 1.5 1.7 1.3 1.2 1.0
Control N* 7 7 7 7 7 7 7 7
Mean _+SEt (mEq./L. ) 49.1 _+2.92 25.2 +_1.16 33.0 _+0.59 20.1 +- 1.03 53.3 _+2.21 13.4_+0.83 30.0-+ 1.19 30.4 _+2.24
N
Mean _+SE (mEa./L.)
7 7 7 5 7 7 7 7
32.5 -+2.09 19.0 -+0.98 22.0.+ 0.96 I7.8_+1.31 44.3 + 3.29 10.4+_0.61 19.7 _+1.48 18.4 .+ 1.03
56
31.8 + 1.80
54
23.2 -+ 1.48
6 7 5 7 5 7 37
10.1 -+0.65 9.7 -+0.75 15.3 .+ 1.14 15.9.+0.74 12.3 -+0.42 12.1 + 1.47 12.5 + 0.54
7 7 5 7 5 7 38
8.4 + 0.79 7.9_+0.81 11.3 +-2.04 13.0 + 1.83 11.1 .+ 1.40 8.0 .+ 1.46 9.8 +-0.63
*Number of days on which observations were made. The daily average for each subject was used. ~Standard error of mean. :~Total of observations from all subjects.
Aldosterone
Volume 730 Number 3, part 1
E x o g e n o u s a l d o s t e r o n e a n d s w e a t electrolytes. I
Fig. 4 depicts a typical study combining the high dose of atdosterone with the later a d d i t i o n of spironolactone. T h e results were indistinguishable f r o m those o b t a i n e d b y completely discontinuing a d m i n i s t r a t i o n of aldosterone. W i t h i n the first 24 hours of spironolactone administration, a sodium diuresis occurred, a n d the u r i n a r y sodium-topotassium ratio increased markedly. W i t h i n 48 hours there was a rise in the concentration of sweat sodium a n d in the sodium-to-potassium rati% a n d a fall in the concentration of sweat potassium. Body weight also decreased rapidly. I n t r a m u s c u l a r a l d o s t e r o n e - - n o r m a l children. T h e sweat electrolyte response in all 6 n o r m a l c h i l d r e n was similar to t h a t of n o r m a l adults. T h e lag phase at the start of h o r m o n e a d m i n i s t r a t i o n a n d the recovery p e r i o d a t t h e end were m o r e p r o l o n g e d (Fig. 5). I n d e e d , aidosterone seemed to have little effect on the sweat glands of these children in the first 48 hours. T h e r e a f t e r , sweat sodium c o n c e n t r a t i o n declined, stayed low d u r i n g the t r e a t m e n t period, a n d rose after-
sterone t r e a t m e n t was b e g u n (Fig. 2 ) ; in 2 of them, the d r o p occurred within the initial 24 hours. T h e concentration of sweat sodium decreased progressively a n d r e m a i n e d low as long as the h o r m o n e was a d m i n i s t e r e d ; it rose slowly t o w a r d control values after administration of aldosterone was discontinued. T h e concentration of sweat chloride a n d the sodium-to-potassium ratio changed similarly. T h e concentration of sweat potassium showed no consistent p a t t e r n in i n d i v i d u a l subjects. Body weight rose in 4 subjects while they were receiving aldosterone (Fig. 2), b u t showed no trend in the other 4. Body weight always fell below control levels 3 to 4 days after cessation of h o r m o n e administration. T h e r e were no significant changes in serum electrolyte concentrations or blood pressure. I n the 3 subjects who received 2.0 mg. of aldosterone p e r d a y the responses of sweat electrolytes were quite similar to those on 1.0 rag. p e r d a y (Fig. 3). T h e natriuresis after t e r m i n a t i o n of a d m i n i s t r a t i o n of aldosterone was m o r e marked, as was the weight gain.
Potassium Control
Aldosterone N
N
7.4 -+0.28 7,0 + 0.24 10.3 + 0.40 6.2 • 0.11 7.1 + 0.27 5.8 - 0.18 9.8 + 0.18 8.2 -+0.28
7 7 7 5 7 7 7 7
8.5 + 0.57 7.3 + 0.36 11.2 + 0.54 6.7 -+0.27 8.2 + 0.83 7.1 +-0.26 10.3 -+ 0.42 8.3 -+0.23
7 7 7 7 7 7 7 7
7.7 -+ 0.22
54
8.5 -+ 0.26
10.1 + 0.95 8.6 +0.55 7.9 + 0.46 7.1 +-0.92 7.2 + 0.22 10.8 + 0.96 8.7 -+0.50
7 7 5 7 5 7 38
11.4 + 0.62 6.9 -+0.50 9.8 + 0.44 9.7 -+0.77 8.6 + 0.72 11.2 • 0.47 9.7 -+0.35
6 4 5 7 5 7
34
Control Mean + SE (mEar/L. }
7 7 7 7 7 7 7 7 56
N
Sodium to l)otassium ratio Mean + SE (mEa./L.)
SE (mEq./L.)
Mean +
3 4 9
Aldosterone " N
Mean + S E (mEa./L.)
6.86 -+0.20 3.59 -+0.12 3.27 -+0.14 3.17 + 0.16 7.54 + 0.21 2.34 -+0.13 3.07 -+0.17 3.77 -+ 0.32
7 7 7 5 7 7 7 7
3.56 + 0.39 2.61 + 0.19 2.09 + 0.11 2.72 -+0.27 5.46 + 0.87 1.51 +--0.12 1.97 -+0.21 2.19 -+0.15
56
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6 4 5 7 5 7 34
1.07 + 0.15 1.21 -+0.13 1.93 -+0.04 2.67 + 0.49 1.74 -+0.09 1.32 -+0.25 1.69 + 0.15
7 7 5 7 5 7 38
0.73 -+0.06 1.13 -+0.13 1.16 -+0.22 1.37 + 0.14 1.37 -+ 0.25 0.63 -+0.12 1.04 -+0.07
350
The ]ournal of Pediatrics March 1967
Grand et al.
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ward. R e c o v e r y was m o r e variable in the children t h a n in the adults. All children h a d a rise in the c o n c e n t r a t i o n of sweat sodium w i t h i n 48 hours after aldosterone was discontinued. However, r e t u r n t o w a r d control
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values h a d not yet o c c u r r e d on the last study d a y (Fig. 5). I n all cases, the sweat sodiumto-potasslum ratio a n d sweat chloride conc e n t r a t i o n p a r a l l e l e d changes in sodium concentration. T h e p o t a s s i u m response, as in the adults, showed no consistent p a t t e r n (Fig. 5). T h e renal response to aldosterone in 5 of the 6 children was u n e x p e c t e d l y different from t h a t of adults. T h e r e was only a minim a l decrease in u r i n a r y sodium excretion on the first d a y of aldosterone a d m i n i s t r a t i o n , a n d no clear-cut escape. A small r e b o u n d natriuresis did occur when the steroid was stopped, b u t was less m a r k e d t h a n in adults (Fig. 5). U r i n a r y excretion of potassium r e m a i n e d u n c h a n g e d . T h e p a t t e r n s of the
Volume 70 Number 3, part 1
Exogenous aldosterone and sweat electrolytes. I
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adults consistently showed parallel changes in these variables (Fig. 6, R. B., E. G., T. P., C. N . ) ; one showed inverse changes (A. K.). In the others, and in all the children (Fig. 7), the relationship was less regular. During administration of aldosterone no consistent relationship between sweat output
352
Grand et aL
The ]ournal of Pediatrics March 1967
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and sweat sodium concentration was found in any subject. There was a tendency toward decreasing sweat output and sodium concentrations in 4 adults and 3 children. However, the remainder were able to diminish the concentration of sweat sodium without a change in sweat output (Fig. 8). Comparison of data. Mean sweat electrolyte values for each subject during the control and aldosterone periods are shown in Table I. In view of individual differences in initial control levels, the data were also expressed as the mean per cent change during the week when aldosterone was given from the mean of the control week (Table I I ) . A statistically significant fall in sweat sodium concentration and rise in sweat potassium concentration did not occur in every subject. However, there were significant
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changes in both variables and in the sodiumto-potassium ratio when the group means were compared (Table II). There was no significant difference in the per cent responses of the 2 age groups (TabIe I I ) . Because of the lag period in onset of sweat gland responses, mean variations
Volume 70 Number 3, part 1
Exogenous aldosterone and sweat electrolytes. I
353
T a b l e I I . M e a n p e r c e n t c h a n g e in s w e a t e l e c t r o l y t e s for w e e k w h e n a l d o s t e r o n e was a d m i n i s t e r e d f r o m m e a n of c o n t r o l w e e k
Subiect Adults A.K. R. B, L.S. P. DF, E.G. L.F. T.P. C.N. Group Children D.S. D.W. D.K. C.W. S.K. S.W. Grout)
No. o[ days ot obwrvation 7 7 7 5 7 7 7 7 54 7 7 5 7 5 7 38
Decrease in sodium Mean + SE (%)
Increase in potassium Mean + SE ,(%)
33.9--24.7 + 33.3 + 10.4-+ 16.8-+ 21.8 + 34.2 + 39.3-+
14.5 -+ 7.70 4.1 -+ 5.12 8.5 + 5.67 7.3 + 4.33 15.5 -+ 11.55 23.0 + 4.42 4.3 -+ 4.30 1.2 -+ 2.74
4.25 3.87 2.91 6.51 6.18 4.57 4.94 3.38
27,4 + 1.95 ~
Decrease in sodium-to-potassium ratio Mean + SE (%) 48.1 + 27.1 + 36.2 + 14.3 + 27.7 + 35.4 + 35,8 + 42.1 +
9.9 + 2.32 ~
16.6-+ 7.86 18.7-+ 8.39 26.4 + 13.32 18.0 -+ 11.51 10.2 + 11.32 33.9 + 12.06
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31.5 -+ 5.92 6.1 + 10.87 39,7 + 11.54 4 8 . 6 -+ 5.14 21.3 + 14.48 52.7 -+ 9.33
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~Significance of difference from zero, p < 0.001. (Two-tailed Student's t test.) tSignificance of difference from zero, p < 0.01. (Two-tailed Student's t test.)
in s w e a t e l e c t r o l y t e s w e r e also c a l c u l a t e d w i t h t h e first 2 days of t h e " a l d o s t e r o n e w e e k " o m i t t e d . T h e r e was n o significant diff e r e n c e in s w e a t g l a n d response b e t w e e n this time and the 7 day mean. M a x i m a l c h a n g e s in s w e a t electrolytes a r e s h o w n in T a b l e I I I . I n all subjects this response o c c u r r e d o n o r a f t e r t h e fifth d a y of aldosterone administration. DISCUSSION T h e p r e s e n t studies d e m o n s t r a t e a n a c t i v e s w e a t g l a n d r e s p o n s e to e x o g e n o u s aldosterone, w i t h c h a r a c t e r i s t i c s in m a n y w a y s q u i t e d i f f e r e n t f r o m those of t h e kidney. While both the sweat glands and the kidneys h a v e a d e c r e a s e d e x c r e t i o n of sodium, t h e s w e a t g l a n d e x c r e t i o n of p o t a s s i u m is m o r e i r r e g u l a r ; t h e t i m e lag for t h e o n s e t of t h e m a x i m a l s w e a t g l a n d effect is g r e a t e r ; t h e r e is n o r e a l c o u n t e r p a r t to t h e r e n a l escape p h e n o m e n o n ; a n d s w e a t g l a n d e x c r e t i o n of s o d i u m a f t e r d i s c o n t i n u a n c e of a l d o s t e r o n e has a d i f f e r e n t p a t t e r n .
T a b l e III. M a x i m u m p e r c e n t c h a n g e in s w e a t e l e c t r o l y t e s f r o m m e a n of c o n t r o l w e e k
sodium (%)
Increase in potassium (%)
Decrease in sodium-topotassium ratio (%)
46.1 38.4 40.9 27.5 37.2 37.2 50.0 58.8
37.8 28.5 33,8 27.5 60.5 72.4 21.1 14.8
68.1 52.7 48.4 34.3 72.0 52.1 51.6 52.6
42.0 7.9
37.0 20.5
54.0 12.5
49.5 27.8 46.8 64.9 35.7 66.6
30.6 82.0 36.7 90.1 44.4 14,8
50.9 86.6 59.1 70.3 55.6 75.3
48.6 15.4
49.8 29.7
66.3 13.0
Decrease ~n
Subiee! Adults A.K. R.B. L.S. P. DF. E,G. L.F. T.P. C.N. Mean SE Children D.S. D.W. D.K. C.W. S.K. S.W. MeaI1
SE
354
Grand et al.
When aldosterone is given intramuscularly to adults, urinary sodium output falls markedly within the first 24 hours, while sweat sodium retention occurs more slowly, a significant fall requiring 24 to 48 hours. Thereafter, the sweat sodium concentration remains well below control values for as long as aldosterone is administered, while, as expected, sodium diuresis increases. The renal rebound natriuresis after cessation of hormone treatment is quite different from the sweat gland response; sweat sodium values rise slowly toward, and only rarely exceed, control levels. The timing of responses to aldosterone in the sweat gland and kidney is similar for both the intravenous and intramuscular routes of administration. Sweat sodium retention has begun at a time when urinary sodium excretion is at its lowest point, and is maximal during the renal escape. In both instances, the renal recovery precedes that of the sweat gland. The chronology of events reported for the kidney during the intravenous infusions agrees with previous findings by other workers. TM 12 In children, the sweat gland response to intramuscularly administered aldosterone is similar to that of adults except for the longer lag in the onset of retention of sweat sodium and for the longer recovery period after treatment ends. On the other hand, the renal response is quite different from the well-established adult patterns seen both in this and previous studies? ~ 13 Children do show some evidence of a renal effect in the small initial fall of urinary sodium excretion, the modest rebound after the last injection, and the consistent elevation of body weight. However, the urinary sodium escape is virtually absent, and urinary electrolyte excretion during the period of aldosterone administration is not significantly different from that in the control period. An escape from the sodium retaining effects could have masked the sodium response on day one of aldosterone treatment, but a kaliuresis should still have appeared. The absence of this response and the constant serum electrolytes suggest that the kidneys of these children were less responsive than those of
The Journal o[ Pediatrics March 1967
adults to the dose of aldosterone given during a sodium intake of 100 mEq. per day. It is known that with sodium depletion and elevated urinary aldosterone excretion the normal juvenile kidney responds in a fashion comparable to that of the adult. 6 Furthermore, excretion of aldosterone (and presumably endogenous production) in this age group is either similar to 17 or lower than that in older subjects. 18 One would therefore expect a greater renal responsiveness to additional aldosterone under conditions of sodium and potassium balance than was found in the present study, especially since the sweat gland responses in adults and children are comparable. This renal behavier is unexplained, but that it may be related to. age is supported by the finding of an adult response in the oldest child (D. S.). Siegenthaler and de Hailer 8 gave aldosterone intramuscularly to normal subjects for 4 days and demonstrated an average maximal reduction of sweat sodium concentration similar to that in the present investigation. However, further comparison is not possible since no data are reported concerning dietary intake, activity of subjects, sweat output, o.r sweat potassium values. Using very high doses of 9-alpha-fluorohydrocortisone, Lobeck and McSherry 19 produced a maximal fall in sweat sodium concentration of 26.6 per cent and a rise in sweat potassium concentration of 7.9 per cent in normal adults, but only a 15.2 per cent fall in sweat sodium concentration and 2.9 per cent rise in potassium concentration in normal children. The drug was given for only 2 consecutive days, and in view of the lag in onset of the sweat gland response to aldosterone demonstrated by the present study, a similar occurrence may be assumed to have prevented more impressive responses to 9alpha-fluorohydrocortisone. In contrast to the effects of intravenous aldosterone on the sweat gland, no consistent change in the salivary sodium-to-potassium ratio was obtained during a comparable study. 11 However, when aldosterone was given intramuscularly for 2 weeks, a~ depression of salivary sodium concentration and sodium-to-potassium ratio occurred and con-
Volume 70 Number 3, part 1
Exogenous aldosterone and sweat electrolytes. I
tinued throughout the treatment period despite renal escape. Only 4 adults (and only in the control period) showed a distinct correlation between sweat output and sweat sodium concentration. At sweat rates comparable to those in this study, and with sweat induced and collected in the same manner, Lobeck and Huebner 2~ described a concomitant rise in both sweat output and sweat sodium concentration in normal adults during the collection period, but not in normal children. The variability in their study and in the present one m a y be explained by the very low sweat rates obtained with pilocarpine iontophoresis when sweat is collected only once at the end of 45 minutes. This represents the summation of a changing rate (and sodium concentration) which has been decreasing since the initial, presumably maximal, stimulation of the sweat gland. Indeed, experiments with collections performed every 10 minutes after an initial subcutaneous injection of methacholine, 21 and continuous observations of the electrical conductivity of sweat following pilocarpine iontophoresis, ~have shown that there is a rise in the first 10 minutes followed by a steady decline in sweat output and sodium concentrations after initial stimulation. Recently a consistent relationship between increasing sweat rate and sodium concentration has been found both in normal adults 2a and normal children 24 with sequential sweat collections, when physical exercise in a heated, constant-temperature room was the stimulant for sweating. Although this is quite a different set of circumstances from, and not really comparable to, the present study, it is interesting that despite comparable stimuli, sweat rates in children were never as high as in adults. At lower sweat rates (approaching those described in this paper) the relationship between rate and sodium concentration was not nearly as clear. Schwartz and Thaysen 2s originally suggested that there is a limit to the capacity of the sweat gland duct to reabsorb sodium, and that when this limit is exceeded, any further output of water and sodium by the coil leads to an increase of sweat electrolyte eoncentra-
3 55
tion. If this postulate is correct, a linear relationship between increasing rate and increasing concentration of sodium will not necessarily be present at low sweat rates since the minimum rate required for expression of this finding may not have been reached. T h a t aldosterone may induce retention of sweat sodium independently of sweat output is supported by the fact that half of the subjects in the present study were able to. Iower their sweat sodium concentration significantly without lowering their sweat output. However, the other subjects did show a trend toward decreasing both sweat sodium concentration and sweat output in response to aldosterone. Similar variability has been described by Lobeck and McSherry in subjects given 9-alpha-fluorohydrocortisone and desoxycorticosterone? s These inconsistencies may result from low sweat outputs. Further studies on the action of aldosterone and other sodium retaining steroids at high sweat rates are needed. SUMMARY
In the normal adult there is an active sweat gland response to exogenous aldosterone with characteristics in many ways different from responses of the kidneys. Both show a fall in excretion of sodium; but sweat gland excretion of potassium is less regular; the time lag in onset of the sweat gland effect is greater; there is no counterpart to the renal escape; and the sweat gland recovery after discontinuance of aldosterone is slower. These effects are independent of dose. Spironolaetone administered during the use of aldosterone produces changes of the same type as withdrawal of aldosterone. Sweat patterns of children in response to administration of aldosterone are similar to those oI adults. Sweat sodium retention in response to exogenous aldosterone is not necessarily dependent upon a decrease in sweat output. At low sweat rates, the relationship between rate and sodium concentration is irregular, in contrast to the situation at high sweat rates. Contrary to the similarity in behavior of the sweat glands in adults and children, the renal responses to exogenous aldosterone were
356
Grand et al.
quite different in the two age groups. T h e urine of the children had a less dramatic initial fall in sodium excretion, no change in potassium excretion, lack of a d e a r - c u t escape p h e n o m e n o n , and less marked posttreatment natriuresis. These characteristics may be related to age. The authors are especially indebted to: Miss Joan Gurian, Biometrics Research Branch, National Heart Institute, for statistical analyses; Mrs. Ruby Lee and Mrs. Joan Mok for valuable technical and secretarial assistance; Miss Kathryn Doherty, Miss Louise Boyer, Miss Ernestina Bou, and Miss Janet Ledbury for the dietary management of the study patients; Miss Isabelle Ambrose; Dr. Joseph F. Gallelli, Pharmacy Department, National Institutes of Health; and the Nursing Staff of the National Institute of Arthritis and Metabolic Diseases. REFERENCES 1. Streeten, D. H. P., Conn, J. W., Louis, L. H., Fa~ans, S. S., Seltzer, H. S., Johnson, R. D., Gittler, R. D., and Dube, A. H.: Secondary aldosteronism: Metabolic and adrenocortical responses of normal men to high environmental temperatures, Metabolism 9: 1071, 1960. 2. Ladell, W. S. S., and Shephard, R. J.: Aldosterone inhibition and acclimatization to heat, J. Physiol. 160: 19P, 1962. Abst. 3. Corm, J. W.: Aldosteronism in man, J. A. M. A. 183: 775, 1963. 4. McConahay, T. P., Robinson, S., and Newton, J. L.: d-Aldosterone and sweat electrolytes, J. AppI. Physiol. 19: 575, 1964. 5. Siegenthaler, P., de Haller, R., Veyrat, R., and Muller, A. F. : Influence d 'un inhibiteur et d'un antagoniste de l'aldosterone sur la concentration du sodium sudoraI, Helvet. med. acta 29: 550, 1962. 6. Oliver, W. J., and Watson, D. F.: Effect of salt intake on sweat electrolytes in children, Am. J. Dis. Child. 107: 470, 1964. 7. Collins, K. j.: Effects of aldosterone and spironolactone on Na:K in drug-induced sweat, J. Physiol. 165: 49P, 1963. Abst. 8. Siegcnthaler, P., and de Hailer, R.: Contribution au probl~me du diagnostic de la fibrose kystique du pancr6as ou mucoviscidose chez l'adulte, Helvet. reed. acta 32: 1, 1965. 9. Thorn, G. W., Sheppard, R. H., Morse, W. I., Reddy, W. J., Beigelman, P. M., and Renold, A. E.: Comparative action of aldosterone and 9-alp.ha-fluorohydrocortisone in man, Ann. New York Acad. Sc. 61: 609, 1955. 10. August, J. T., Nelson, D. H., and Thorn, G. W.: Response of normal subjects to large
The Journal o[ Pediatrics March 1967
11.
12.
13.
14.
15.
16.
17.
18. i9.
20.
21.
22. 23.
24. 25.
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