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Influence of posture and diurnal rhythm on the renal excretion of acid: Observations in normal and adrenalectomized subjects
Influence of Posture and Diurnal Rhythm on the Renal Excretion of Acid : Observations in Normal and Adrenalectomized Subjects ByPHILIP R.
STEINME-IZ AND ROBERTP. EISINCER
The influence of posture and diurnal rhythm on the renal excretion of acid was examined in 4 normal and 2 adrenalectomized subjects. Assumption of the recumbent position in normal subjects resulted in inhibition of acid excretion, the extent of inhibition being influenced by the diurnal rhythm. Postural inhibition of acid excretion was also observed at high levels of acid excretion following methionine loading. In adrenalectomized subjects assumption of the recumbent position resulted in postural natriuresis but not in any decrease in
acid excretion. The postural inhibition of acid excretion occurring in normal subjects could not be restored in adrenalectomized subjects by administration of hydrocortisone, methylprednisolone or aldosterone. It is suggested that (1) postural inhibition of acid excretion is dependent on adrenal function but not directly on the presence of glucocorticoid hormone or aldosterone, (2) that the mechanism of postural and diurnal variations in acid excretion may share a common factor. (Metabolism 15: No. 1, January, 76-87, 1966)
of acid by the kidney, like the excretion of sodium, is greatly influenced by the diurnal rhythm2J and by posture.4B5 Diurnal and postural changes in acid excretion have been shown to occur independently of food intake and systemic acid-base balance.“--5 These changes are of sufficient magnitude to require consideration in any acute studies of renal acidifying capacity. The mechanisms that underlie these changes are only partially understood. In general the excretion of hydrogen ions increases when sodium excretion decreases, i.e., during the night or in the upright position, and decreases during the natriuresis of recumbency or the diurnal natriuresis. These variations in the excretion of hydrogen ions have been attributed to changes in either renal hemodynamics or adrenal cortical hormone activity. Diurnal and postural variations in renal hemodynamics, however, are relatively small.“-* Assumption of the upright position results in a slight decrease in renal blood ____
T
HE EXCRETION
From the Department qf Medicine, New York University School of Medicine and the New York University Divisions, Bellevue Hospital, New York, New York. Supported by U. S. Public Health Service Grant H-3272, Nationul Heart Institute. Clinical facilities provided by Grant FR-96, Nationul Institutes of Health, Bethesda, Mayland. Presented in part at the Annual Meeting of the American Physiological Society, Chicago, Illinois, April 15, 1964.1 Received for publication Oct. 7, 1965. PHILIP R. STEINMETZ, M.D.: Instructor of Medicine, New York University rchool of Medicine, New York, New York. Recipient of a Career Development Award S-K3-HE12,113~02, National Heart Institute, Bethesda, Md. At present: Research Associate in Medicine, Harvard Medical School and Beth lsrael Hospital, Boston, Mass. ROBERT P. EISINGER, M.D.: Instructor of Medicine, New York University School of Medicine; Clinical Investigator, Manhattan Veterans Adminbtration Hospital, New York, N. Y. 76
POSTURE, DIURNAL RHYTHM
77
ON RENAL EXCRETION
flow but has little effect on glomerular filtration rate as long as the subject does not stand immobile.“z”J Increased adrenocortical hormone activity might provide an explanation for the aciduria of the upright position by acceleration of the exchange of sodium for hydrogen ions, since MullerQJo and Gowenlock11 and their associates have reported that the urinary excretion of aldosterone is greater in the upright than in the recumbent position. However, in patients with Addison’s disease and in adrenalectomized subjects both diurnal and postural changes in sodium excretion are preserved.*2-15 This suggests that these changes in sodium excretion, and perhaps also changes in acid excretion, are independent of the adrenal. Since no data on postural and diurnal variations in the excretion of acid are available in adrenalectomized patients, observations are presented in the present study in 2 adrenalectomized subjects and in a group of normal controls. METHODS Fifteen
series
of observations
were made on either
the effect
of
posture or the diurnal
rhythm in 2 adrenalectomized patients and 4 normal volunteers, ranging in age from 23 to 36 years. In the postural studies observations were made first in the upright position, for which the subjects remained standing and were permitted to move about, and there-
after in the recumbent position, for which the subjects remained flat in bed except for the collection of voided urine specimens. In the normal subjects 5 postural studies were performed in the morning between 7330 a.m. and 1:30 p.m. and 2 in the evening between 5:00 p.m. and 1O:OO p.m.; one diurnal study was carried out during continued recumbency from midnight
to noon.
The following protocol given for 12 hours prior
was employed in all postural to study or during the study.
studies. No food or fluids To maintain a comparable
were anti-
diuretic state 2 units of aqueous vasopressin (Pitressin, Parke, Davis & Co.) were administered subcutaneously every 2 hours. The subjects had been on a regular diet prior to the day of study. In 2 series of observations 9 Gm. of methionine were added to the diet daily individed oral doses for 2 days prior to study and during the study to increase the acid load. In the adrenalectomized patients 6 postural studies were performed in the morning in the same manner as in the normal subjects. The administration of steroid hormones was discontinued at 3:00 p.m. on the day before study. In 5 of the 6 studies steroid hormone was administered intravenously during the second hour of recumbency; either 20 mg. 80 mg. hydrocortisone sodium succinate (Upjohn methylprednisolone sodium succinate, Co.) or 1 mg. dl-aldosterone 21 monoacetate (Ciba Pharmaceutical Products, Inc.). In one study methylprednisolone and aldosterone were administered together. In one of the subjects a diurnal study was carried out during continued
recumbency
from midnight to noon; the details of this study are given under Results. The first adrenalectomized patient was a 26 year old man (K. M.) who had undergone bilateral adrenalectomy because of Cushing’s syndrome. He was asymptomatic on 2 mg. prednisolone 3 times a day, and 9-a-fluoro-hydrocortisone, 0.05 mg. every other day. He had normal over-all renal function as judged from concentrating ability and the endogenous creatinine clearance (see TabIe 2). The other subject, a 23 year old woman (L. S. ) had undergone a right nephrectomy and bilateral adrenalectomy because of hypertension associated with hyperaldosteronism. She became normotensive after adrenalectomy and was maintained in good health on 25 mg. cortisone twice a day. The creatinine clearance of the remaining kidney ranged from 60 to 80 ml/minute and concentrating ability was normal (maximal urine osmolality over 900 mOsm/per Kg. H,O). Each subject had a normal urinalysis and intravenous pyelogram. Urine was collected
by spontaneous
voiding
into graduated
cylinders
containing
mineral
.28 .30
.53 .68
.45
.46 .59
122-173 173-226
226-276
276-336 336-387
Urine Flow ml./min.
O-62 6%122
Time min.
134 210 296 335 315 290
112
UNaV pEq./min.
104 112
109
122 130
113 112
27
29 34
Recumbent
34 34
Upright
uxv fiEq./min.
133
138 214
69 62
uClv wEq./min.
130 100
35 38
152 115
20 mg. Methyl Prednisolcnwix.
124
131 207
51 49
%JaV pEq./min.
175 212 252 284 286 275
153 6.5 7.7 7.7 7.7 7.6 7.5
5.5
5.3 5.3
5.3
5.3 5.1
5.1 5.4
PH
on Renal Acid and Salt Excretion
97 150 129 125 112 92
Recumbent
67
PH
7 0 0 0 0 0
18
UTAV zEq./min.
16 18
19
21 18
22 22
/IEq./min.
u “H4 v
19 19
20
24 22
18 19
UTAV gEq./min.
in an Adrenulectomiaed
14 5 6 6 7 8
28
v
1110 1168
1110
1019 1063
1004 1057
-
U osm mOsm/Kg. Hz0
Subject
913 844 879 868 881 865
851
U osm mOsm/Kg. Hz0
in a Normal Subject
NH4 slk./min.
u
Acid and Salt Excretion
uClv wEq./min.
on Renal
Upright
uIcv /LEq./min.
Position
Position
the Recumbent
the Recumbent
CR ml./min.
C
144 137 134 132 126 128
129
CR ml./min.
C
of Assuming
of Assuming
.73 1.1 1.2 1.3 1.2 1.2
78-112 112-147 147-169 169-203 203-233 233-266
Table 2.-Effects
.80
Urine Flow ml./min.
O-78
Time min.
Table l.-Eflects
z E R oz m *I
Ei
2
2 E
79
POSTURE,DIURNALRHYTHMONRENALEXCRETION
oil. Errors of urine collection were minimized by employing relatively long collection periods. Glomerular filtration rate was estimated from the endogenous creatinine clearance (Cc,).la Urine and plasma osmolality, Na+, K+, Cl-, HCO;, pH, and urine ammonium (NH:
) and titratable
rates and ckarance
acid
(TA)
were
values were corrected
determined for a surfacr
as previously
described.5
Excretion
area of 1.73 sq. metrr.
RESULTS He&
Acid” Excretion during Postural Natriuresis in Normal Subjects
In Table 1 changes in Na f, K+, Cl-, NHt and TA excretion and urine pH are presented in a normal hydropenic subject who assumed the recumbent position at 9:OO a.m. Postural natriuresis was associated with alkaluria and decreases in NHt; and TA excretion and with a slight kaliuresis. The alkaluria persisted for at least 3 hours, whereas the kaliuresis decreased during the second hour of recumbency. Changes in the endogenous creatinine clearance were small. In Figure 1 values in the upright position are compared with those of the second hour of recumbency in this and 2 other fasting subjects who had been on a regular diet. The observed changes were similar in all *3 subjects. In Figure 2 data are presented for 2 normal subjects who received methionine supplements for 2 days before and during the study. Despite the acid load assumption of the recumbent position resulted in a rise in urine pH, marked decreases in NH: and slight decreases in TA excretion. The effects of assuming the recumbent position were also studied in the evening when normally K-1 excretion decreases and acid excretion increases as part of the diurnal rhythm.“~“~‘” In Figure 3 studies in the evening are presented for 2 of the subjects shown in Figure 1. NH: and TA excretion decreased with recumbency at a time that an increase was expected from the diurnal cycle, whereas K-t excretion decreased in the direction expected from the diurnal
trend.
Renal Acid Excretion during Postural Natriuresis in Adrenalectomized
Subjects
In Table 2 the effects of assuming the recumbent position are shown for an adrenalectomized subject ( K. M. ) . Na+ excretion increased from an average value of 50 pEq./minute in the upright position to a maximum of 207 pEq./minute during recumbency. K-1 excretion changed little. In contrast to the relative alkaluria observed in normal subjects, the urine remained acid and NH: excretion remained approximately constant, while TA excretion increased slightly. Intravenous administration of 20 mg. methylprednisolone was followed by a small decrease in Na+ and increase in K+ excretion but urine pH was unaffected. NH2 excretion decreased slightly, whereas TA excretion was comparable to that in the upright position. In Figure 4 solid lines represent 6 studies in the 2 adrenalectomized subjects. For comparison average values for the 3 normal subjects (Fig. 1) are indicated by hatched lines. Postural natriuresis occurred in all the studies in ___.___-___ ‘The
term acid is employed
to indicate the sum of ammonium
and titratable
acid.
80
STEINMETZ
“No”
“K”
pEq /min U
AND EJSINGER
NEq /min R
U
300
300
200
200
R U = UPRIGHT R = RECUMBENT
100 0
pEq / min
pEq /min
Fig. L-Postural changes in Na+, K+, ammonium and titratable acid excretion and urine pH in 3 normal subjects who had been on a regular diet. U represents average values for urine collections in the upright position. R represents the value at 100 minutes after assumption of the recumbent position. Morning studies. adrenalectomized subjects without much change in K+ excretion. Urine pH remained acid. Changes in NHI,- and TA excretion were small, the sum of the 2 remaining virtually constant. In Figure 5 are shown the effects of acute replacement of hydrocortisone, methylprednisolone and aldosterone during recumbency in adrenalectomized subjects. The values for R are the same as in Figure 4, R’ represents the second hour after hormone administration.* Following hormone administration Na+ excretion changed little or decreased slightly and K+ excretion increased, changes consistent with known effects of these hormones. With one possible exception steroid administration did not affect urine pH; and renal acid excretion, measured as the sum of NH: and TA excretion, did not change. No significant difference was observed between hydrocortisone, methylprednisolone and aldosterone in these studies. In one study in which aldosterone and methylprednisolone were administered simultaneously the results were the same. The hatched lines indicate the effects of continued recumbency on 3 normal subjects not given hormones. Natriuresis and alkaluria persisted into the fourth hour of recumbency, whereas K+ excretion tended to return to the initial value of the upright position. Diurnal Rhythm, Glomerular
Filtration Rate and Systemic Acid-Base
Balance
To take into account diurnal variations in renal acid and salt excretion control observations were made during continued recumbency from midnight “In 2 studies observations were administration. The values for Na+, from the second to the third hour.
extended to include the third hour after hormone K+ and H+ excretion did not change significantly
POSTURE,
DIURNAL
RHYTHM
ON RENAL
j.!Eq/min R
U
81
EXCRETION
pEq /min U R
U = UPRIGHT R = RECUMBENT
U
“TA”
“NH ’
PH R
pEq /4nin U R
HEq/min R U
Fig. 2.-Postural changes in Na+, K+, ammonium and titratable acid excretion and urine pH in 2 normal subjects receiving methionine supplements before and during study. Morning studies.
“No” pEq /min U R
%” ”
PH
U
“K” pEq /min U R
R
pEq /4min U R
“TA” pEq / min U R
Fig. %-Postural changes in Na +, K+, ammonium and titratable acid excretion and urine pH in 2 normal subjects who had been on a regular diet. Evening studies.
to noon in one adrenalectomized subject (L. S.) and one normal subject. The subjects received no food, fluids or steroid medication during this period. In Table 3 is shown that in the adrenakctomized subject the excretion of Na 1 and K+ increased in the morning in the same direction as in the normal subject (although to a lesser extent) in accord with previous studies in patients
STEINMETZ
82
AND EISINGER
“If” UEq / min U
pEq /min
R
R
U
U = UPRIGHT 200
R = RECUMBENT
100
Ill = MEAN OF NORMALS
0
NEq /min U
R
U
HEq/min R
U
R
Fig. 4.-Six studies of postural changes in Na+, K-t, ammonium and titratable acid excretion and urine pH in 2 adrenalectomized subjects whose steroid treatment had been withheld for 16 hours. Solid lines represent studies in adrenalectomized subjects, hatched lines the average of the 3 normal subjects of Figure 1. Morning studies. with Addison’s disease and in adrenalectomized subjects.iJ-i5 In the adrenalectomized subject urine pH and renal acid excretion changed little from midnight to noon, This cons,tancy of acid excretion contrasts with the alkaluria which occurs in the morning in normal subject+” and which is also demonstrated in our normal subject. In Table 4 values of the endogenous creatinine clearance are compared between the upright periods and the second hour of recumbency. Inconsistent increases in CCR were observed in the studies of the adrenalectomized and normal subjects. Since the plasma bicarbonate did not change with posture, differences in the filtered load of bicarbonate could not explain the recumbent alkaluria of the normal subjects or the absence of alkaluria in the adrenalectomized subjects. Blood pH values were within normal range and the plasma total CO2 ranged between 25 and 29 mM/L. in different studies except for one of the studies in which methionine was given and one of the studies in the adrenalectomized woman, where the plasma total CO% values were 23 and 22 mM/L., respectively. No significant differences in blood pH and plasma total COZ were observed between samples obtained in the upright and the recumbent position. DISCUSSION These results confirm observations by Thomas4 that in normal subjects postural natriuresis is associated with inhibition of hydrogen ion excretion.
POSTURE, DIURNAL
RHYTHM
ON RENAL
“I?
uMlv
pEq /min U
R
53
EXCRETION
pEq imin R’
U
=
UPRIGHT
R
=
RECUMBENT
(IO0
min I
R’
=
RECUMBENT
(200
min)
I I I
q
MEAN
OF NORMALS
PH
UEq /min U
R
H_,+, R’ ------
HYDRGCORTISCNE PREONISOLONE
OR
ALDOSTERONE
Fig. S.-Effect of acute administration of hormone on the excretion of Na+, K+, the sum of ammonium and titratable acid excretion and urine pH during recumbency in 5 studies of 2 adrenalectomized subjects. U = upright, R = recumbent at 100 minutes and R' = recumbent at 200 minutes or 100 minutes after
hormone administration (interrupted lines). Hatched lines represent average of the 3 normal subjects receiving no hormone. Morning studies. Thomas observed that acid excretion was less in the recumbent than in the upright position in day studies regardless of the sequence in which posture was changed. In the present study the reduction in acid excretion following assumption of the recumbent position occurred in morning as well as in evening studies, but the extent of the postural inhibition was far greater in the morning. Such diurnal influence on the effects observed with the acute change to the recumbent position might have been expected from the diurnal variations in acid excretion that are known to occur during continued recumbency, i.e., alkaluria during the middle of the day and aciduria during the night. The observations of Thomas4 as well as our own, however, indicate that postural inhibition of acid excretion can be demonstrated at different times of the diurnal cycle. Even at high levels of acid excretion following methionine loading assumption of recumbency results in decreased renal acid excretion. The efl’ects of lying down on K~imexcretion were less consistent. The kaliuresis observed in the morning was transient and followed the pattern of the diurnal rhythm. In the evening lying down was associated with decreased K+ excretion, the direction of the change again being that of the diurnal trend. These results are in agreement with observations by Borst et a1.16 that posture per se has little effect on K+ excretion in healthy subjects,
113 121 133 126
82 78 76
73
C CT ml. jmin.
27 25 132 226
NOW&
50 60 70
44
Subjecl
.__
29 34 70 90
10 18 21
15
Subject
Yzv /LEq./min.
A4drenalectonked
uN*v pEq./min.
ux,*v
41.5 42.8 21.8 9.9
5.2 6.9 7.6
11.7 9.6 7.6
8.4
pEq./min.
30.8 5.1 0
30.5
14.7 15.1 14.6
13.6
+
TAV
(L.
S.) re.
73.6 26.9 9.9
72.0
26.4 24.7 22.2
22.0
,uEq./min.
usIil
subject
in an
UTAV pEq./min.
Recumbency
5.3
5.4 5.3 5.3
5.3
PH
Continued
Note: Food and fluid were withheld from 9:00 p. m. the evening before study until the end of study. The adrenalectomized ceived her last dose of steroid medication at 3:00 p. m. the afternoon before study and no medication was given during study.
.92 .42 .90 1.1
12:OO M-5:00 a. m. 5:00-8:OO a. m. 8:00-10:00 a. m. 10:00-12:OO noon
.35
.38 .43 .49
a. m.
ml./min.
Urine Flow
Variations in Renal Acid and Salt Excretion during Adrenulectomized and a Normal Subject
6:00-8:OO a. m. 8:00-1O:OO a. m. lO:OO-12:00 noon
12:OO M-6:00
Time
Table 3.-Diurnal
8
m t: z
3
z $
2
9 g
POSTURE,
DIURNAL
RHYTHM
Table 4.-Effect
ON
RENAL
of Posture on the Endogenous Creatinine in Normal and Adrenalectomized Subjects
Studies in Normal Subjects Upright
--
Recumbent
Ccl. ml./min.
Clearance
Studies in Adrenalectomized Subjects Upright
Recumbent
132
112
130
102 99
104 116
106 120
109 109 118 100 120
91 102
87 100
-129
94 97 114
Note:
85
EXCRETION
The values for recumbency
63 65
62* 60’
represent
the second
point of urine collection being at approximately normal subjects are given in sequence of Figures *Values for left kidney.
hour of recumbency,
100 minutes 1, 2 and 3.
of recumbency.
the midStudies in
The inhibitory effect of recumbency on the renal excretion of acid, on the other hand, appears to be consistent. Although urine bicarbonate was not measured in the present study changes in “net acid” excretion (defined as NH+ + TA - HCO- ) were in the same direction as the changes in acid excre4
3
(defined as the sume of NH: + TA). In the upright position urine pH was sufficiently low in all studies to exclude the presence of bicarbonate.’ In the adrenalectomized subjects and in the normal subjects receiving acid loads bicarbonate excretion was insignificant in either the upright or recumbent position. Hence, net acid excretion equalled the sum of NH: and TA excretion. Little is known about the mechanism of inhibition of acid excretion during postural natriuresis. Changes in systemic acid-base balance do not appear to account for it. Increases in filtration rate and hence the load of bicarbonate delivered to the tubules might reduce the excretion of hydrogen ions, but in the present study there was no consistent difference in the endogenous creatinine clearance+ between the periods of upright posture and the second hour of recumbency when acid excretion was fully inhibited. These observations suggest that the postural effect does not depend on changes in the filtered load of bicarbonate. Could an increase in renal blood flow or a change in the distribution of of blood flow within the kidney explain the inhibition of acid excretion? In unilateral renal artery stenosis the affected kidney often excretes a more acid urine than the contralateral kidney despite the fact that the 2 kidneys are in .~~______~~ -__ tion
*Observations by Thomas4 indicate that the inhibition of acid excretion during recumbency would have been greater in terms of “net acid” excretion since subtraction of bicarbonate would have reduced the acid values further and have led to calculation of “net alkali” excretion in the recumbent normal subjects. fThe ratio between endogenous creatinine clearance and inalin clearance in this laboratory is approximately 0.9.lr Similar values were obtained in an earlier study in which it was shown that this ratio was not affected by the diurnal cyc1e.f;
86
STEINMEl7.
AND EISINGER
the same acid-base milieu.18 Although it is possible that hemodynamic changes cause postural variations in acid excretion, the postural effect was not fully developed until the second hour of recumbency; this delay argues against a hemodynamic effect. It is more likely that the changes in acid excretion depend on a hormonal effect. Gowenlock and his associatesll and Muller g,10 observed a greater aldosterone output in the urine in the upright than in the recumbent position and suggested that aldosterone might increase sodium reabsorption and accelerate sodium-hydrogen ion exchange during standing. In the absence of adrenocortical hormones, however, our adrenalectomized subjects differed from the normal subjects in the recumbent rather than in the upright position. In all 6 studies aciduria was present during standing, but the expected inhibition of acid excretion failed to occur following assumption of recumbency. The fact that acid excretion was not influenced by posture was of particular interest since the postural sodium diuresis was preserved in the adrenalectomized subjects in accord with previous reports by Ten Holt,12 Rosenbaum14 and Borst15 and their associates. Since administration of hydrocortisone, methylprednisolone ,or aldosterone failed to reproduce the normal inhibition of acid excretion during recumbency, it is unlikely that the effect is directly dependent on the presence of these hormones. It is possible that recumbency causes the release of another adrenal hormone, not examined in the present study, that inhibits H+ secretion by the tubules. Although several investigators lDm2’ have postulated that the adrenal produces a natriuretic hormone, the existence of such a hormone has not been definitely established. If this horm,one acted like a carbonic anhydrase inhibitor, it might provide an explanation for the alkaluria of recumbency. Alternatively it is possible that some humoral factor originating- outside the adrenal, either in the kidney itself or elsewhere, governs the postural inhibition of acid excretion and that the adrenal plays a permissive role in this humoral system. In the adrenalectomized subject studied during continued recumbency the diurnal variation in acid excretion was virtually absent even though variations in Na+ and K+ excretion were present. The fact that both diurnal and postural changes in acid excretion were absent in this patient suggests that the two may share a comm,on mechanism. Such a possibility is also consistent with the observation in normal man that the extent of the postural inhibition of acid excretion depends on the time of day. Whatever mechanisms are involved in postural and diurnal changes in acid excretion they appear to depend on the adrenal in a way which has not yet been elucidated. ACKNOWLEDGMENT We are grateful
to
Misses Nancy Burton, Susan Baron and Francine
Reff for technical
assistance. REFERENCES 1. Steinmetz, P. R., Eisinger, R. P., and Chasis, H.: On the inhibition of H+ secretion during postural natriuresis.
Fed. Proc. 23~307, 1964. 2. Simpson, G. E.: Diurnal variations in the rate of urine excretion for two
POSTURE,
DIURNAL
hour
intervals:
tors.
J.
1924. 3. Stanbury, Diurnal cretion.
Biol.
RHYTHM
some Chem.
ON RENAL
associated
87
EXCRETION
en
fac-
Ned.
59:107-122,
S. W., and Thomson, A. E.: variations in electrolyte exClin. Sci. 10:267-293, 1951.
4. Thomas, S.: Some effects of change of posture on water and electrolyte excretion by the human kidney. J. Physiol. 139:337-352, 1957. 5. Steinmetz, P. R., and Bank, N.: Effects of acute increases in the excretion of solute and water on renal acid excretion in man. J. Clin. Invest. 42: 1142-l 149, 1963. 6. Sirota, J. H., Baldwin, D. S., and Villarreal, H.: Diurnal variations of renal function in man. J. Clin. Invest. 29: 187-192. 1950. 7. Wesson, L. G., Jr., and Lauler, D. P.: Diurnal cycle of glomerular filtration rate and sodium and chloride excretion during responses to altered salt and water balance. J. Clin. Invest. 40:1967-1977, 1961. 8. Smith, H. W.: The Kidney Structure and Function in Health and Disease. New York, Oxford University Press, 1951, pp. 432-435. 9. Muller, A. F., Manning, E. L., and Riondel. A. M.: Diurnal variation of aldosterone related to position and activity in normal subjects and patients with pituitary insufficiency. In: An international Symp. on Aldosterone. Boston, Little, Brown & Company, 1958, p. 111. 10. -: Some aspects of the hormonal control of water and electrolytes. In: Proc. Symposium on Water and Electrolyte Metabolism. Amsterdam. Elsevier, 1961, p. 64. 11. Gowenlock, A. H., Mills, J. N., and Thomas, S.: Acute postural changes in aldosterone and electrolyte excretion in man. J. Physiol. 146:133-141, 1959. 12. Ten Holt, S. P.. De Vries, L. A., and Borst, J. G. G.: Over de invloed van houding en beweging op de uitscheiding van water en electrolyten
over
het
ontstaan
Tijdschrift
van
Geneesk
nycturie. 96:2244-
2251, 1952. 13. Borst, J. G. G., and DeVries, L. A.: The three types of “natural” diuresis. Lancet 259 (ii) :1-B, 1950. 14. Rosenbaum, J. D., Papper, S., and Ashley, M. M.: Variations in renal excretion of sodium independent of adrenocortical hormone change in dosage in patients with Addison’s disease. J. Clin. Endocrinol. & Metab. 15: 1459-1474, 1955. 15. Borst, J. G. G., DeVries, L. A., Van Leeuwen, A. M., Den Ottolander, G. J. H., and Cejka, V.: The maintenance of circulatory stability at the expense of volume and electrolyte stability. Clin. Chim. Acta 5: 887-914, 1960. 16. Brod, J., and Sirota, J. H.: The renal clearance of endogenous “creatinine” in man. J. Clin. Invest. 27:645-654, 1948. 17. Steinmetz, P. R., and Smith, H. W.: Urea and the renal concentrating operation in man. Amer. J. Med. 35: 18. -,
727-736, 1963. Eisinger, R. P., and Lowenstein, J.: The excretion of acid in unilateral renal disease 44:582-591,
in man. 1965.
J. Clin.
Invest.
19. Nrher, R., Desaulles, P., Vischer, E., Wieland, P., and Wettstein, A.: Isolierung, Konstitution and Synthese eines neuen Steroides aus Nebennieren. Helv. Chim. Acta 41:16671692. 1958. 20.
Rosemberg, E., Dufault, F. X., Jr., Bloch, E., Budnitz, E., Butler, P., and Brem, J.: The effects of progressive reduction of sodium intake on adrenal steroid excretion and electrolyte balance in a case of congenital adrenal hyperplasia of the salt-losing type. J. Clin. Endocrinol. & Metab. 20~214-228, 1960. 21. Hollowell, J. G., and Frazer, J.: Isolation of sodium transport inhibitor, New Eng. J. Med. 270:154-155, 1964.
STEINME-IZ AND ROBERTP. EISINCER
The influence of posture and diurnal rhythm on the renal excretion of acid was examined in 4 normal and 2 adrenalectomized subjects. Assumption of the recumbent position in normal subjects resulted in inhibition of acid excretion, the extent of inhibition being influenced by the diurnal rhythm. Postural inhibition of acid excretion was also observed at high levels of acid excretion following methionine loading. In adrenalectomized subjects assumption of the recumbent position resulted in postural natriuresis but not in any decrease in
acid excretion. The postural inhibition of acid excretion occurring in normal subjects could not be restored in adrenalectomized subjects by administration of hydrocortisone, methylprednisolone or aldosterone. It is suggested that (1) postural inhibition of acid excretion is dependent on adrenal function but not directly on the presence of glucocorticoid hormone or aldosterone, (2) that the mechanism of postural and diurnal variations in acid excretion may share a common factor. (Metabolism 15: No. 1, January, 76-87, 1966)
of acid by the kidney, like the excretion of sodium, is greatly influenced by the diurnal rhythm2J and by posture.4B5 Diurnal and postural changes in acid excretion have been shown to occur independently of food intake and systemic acid-base balance.“--5 These changes are of sufficient magnitude to require consideration in any acute studies of renal acidifying capacity. The mechanisms that underlie these changes are only partially understood. In general the excretion of hydrogen ions increases when sodium excretion decreases, i.e., during the night or in the upright position, and decreases during the natriuresis of recumbency or the diurnal natriuresis. These variations in the excretion of hydrogen ions have been attributed to changes in either renal hemodynamics or adrenal cortical hormone activity. Diurnal and postural variations in renal hemodynamics, however, are relatively small.“-* Assumption of the upright position results in a slight decrease in renal blood ____
T
HE EXCRETION
From the Department qf Medicine, New York University School of Medicine and the New York University Divisions, Bellevue Hospital, New York, New York. Supported by U. S. Public Health Service Grant H-3272, Nationul Heart Institute. Clinical facilities provided by Grant FR-96, Nationul Institutes of Health, Bethesda, Mayland. Presented in part at the Annual Meeting of the American Physiological Society, Chicago, Illinois, April 15, 1964.1 Received for publication Oct. 7, 1965. PHILIP R. STEINMETZ, M.D.: Instructor of Medicine, New York University rchool of Medicine, New York, New York. Recipient of a Career Development Award S-K3-HE12,113~02, National Heart Institute, Bethesda, Md. At present: Research Associate in Medicine, Harvard Medical School and Beth lsrael Hospital, Boston, Mass. ROBERT P. EISINGER, M.D.: Instructor of Medicine, New York University School of Medicine; Clinical Investigator, Manhattan Veterans Adminbtration Hospital, New York, N. Y. 76
POSTURE, DIURNAL RHYTHM
77
ON RENAL EXCRETION
flow but has little effect on glomerular filtration rate as long as the subject does not stand immobile.“z”J Increased adrenocortical hormone activity might provide an explanation for the aciduria of the upright position by acceleration of the exchange of sodium for hydrogen ions, since MullerQJo and Gowenlock11 and their associates have reported that the urinary excretion of aldosterone is greater in the upright than in the recumbent position. However, in patients with Addison’s disease and in adrenalectomized subjects both diurnal and postural changes in sodium excretion are preserved.*2-15 This suggests that these changes in sodium excretion, and perhaps also changes in acid excretion, are independent of the adrenal. Since no data on postural and diurnal variations in the excretion of acid are available in adrenalectomized patients, observations are presented in the present study in 2 adrenalectomized subjects and in a group of normal controls. METHODS Fifteen
series
of observations
were made on either
the effect
of
posture or the diurnal
rhythm in 2 adrenalectomized patients and 4 normal volunteers, ranging in age from 23 to 36 years. In the postural studies observations were made first in the upright position, for which the subjects remained standing and were permitted to move about, and there-
after in the recumbent position, for which the subjects remained flat in bed except for the collection of voided urine specimens. In the normal subjects 5 postural studies were performed in the morning between 7330 a.m. and 1:30 p.m. and 2 in the evening between 5:00 p.m. and 1O:OO p.m.; one diurnal study was carried out during continued recumbency from midnight
to noon.
The following protocol given for 12 hours prior
was employed in all postural to study or during the study.
studies. No food or fluids To maintain a comparable
were anti-
diuretic state 2 units of aqueous vasopressin (Pitressin, Parke, Davis & Co.) were administered subcutaneously every 2 hours. The subjects had been on a regular diet prior to the day of study. In 2 series of observations 9 Gm. of methionine were added to the diet daily individed oral doses for 2 days prior to study and during the study to increase the acid load. In the adrenalectomized patients 6 postural studies were performed in the morning in the same manner as in the normal subjects. The administration of steroid hormones was discontinued at 3:00 p.m. on the day before study. In 5 of the 6 studies steroid hormone was administered intravenously during the second hour of recumbency; either 20 mg. 80 mg. hydrocortisone sodium succinate (Upjohn methylprednisolone sodium succinate, Co.) or 1 mg. dl-aldosterone 21 monoacetate (Ciba Pharmaceutical Products, Inc.). In one study methylprednisolone and aldosterone were administered together. In one of the subjects a diurnal study was carried out during continued
recumbency
from midnight to noon; the details of this study are given under Results. The first adrenalectomized patient was a 26 year old man (K. M.) who had undergone bilateral adrenalectomy because of Cushing’s syndrome. He was asymptomatic on 2 mg. prednisolone 3 times a day, and 9-a-fluoro-hydrocortisone, 0.05 mg. every other day. He had normal over-all renal function as judged from concentrating ability and the endogenous creatinine clearance (see TabIe 2). The other subject, a 23 year old woman (L. S. ) had undergone a right nephrectomy and bilateral adrenalectomy because of hypertension associated with hyperaldosteronism. She became normotensive after adrenalectomy and was maintained in good health on 25 mg. cortisone twice a day. The creatinine clearance of the remaining kidney ranged from 60 to 80 ml/minute and concentrating ability was normal (maximal urine osmolality over 900 mOsm/per Kg. H,O). Each subject had a normal urinalysis and intravenous pyelogram. Urine was collected
by spontaneous
voiding
into graduated
cylinders
containing
mineral
.28 .30
.53 .68
.45
.46 .59
122-173 173-226
226-276
276-336 336-387
Urine Flow ml./min.
O-62 6%122
Time min.
134 210 296 335 315 290
112
UNaV pEq./min.
104 112
109
122 130
113 112
27
29 34
Recumbent
34 34
Upright
uxv fiEq./min.
133
138 214
69 62
uClv wEq./min.
130 100
35 38
152 115
20 mg. Methyl Prednisolcnwix.
124
131 207
51 49
%JaV pEq./min.
175 212 252 284 286 275
153 6.5 7.7 7.7 7.7 7.6 7.5
5.5
5.3 5.3
5.3
5.3 5.1
5.1 5.4
PH
on Renal Acid and Salt Excretion
97 150 129 125 112 92
Recumbent
67
PH
7 0 0 0 0 0
18
UTAV zEq./min.
16 18
19
21 18
22 22
/IEq./min.
u “H4 v
19 19
20
24 22
18 19
UTAV gEq./min.
in an Adrenulectomiaed
14 5 6 6 7 8
28
v
1110 1168
1110
1019 1063
1004 1057
-
U osm mOsm/Kg. Hz0
Subject
913 844 879 868 881 865
851
U osm mOsm/Kg. Hz0
in a Normal Subject
NH4 slk./min.
u
Acid and Salt Excretion
uClv wEq./min.
on Renal
Upright
uIcv /LEq./min.
Position
Position
the Recumbent
the Recumbent
CR ml./min.
C
144 137 134 132 126 128
129
CR ml./min.
C
of Assuming
of Assuming
.73 1.1 1.2 1.3 1.2 1.2
78-112 112-147 147-169 169-203 203-233 233-266
Table 2.-Effects
.80
Urine Flow ml./min.
O-78
Time min.
Table l.-Eflects
z E R oz m *I
Ei
2
2 E
79
POSTURE,DIURNALRHYTHMONRENALEXCRETION
oil. Errors of urine collection were minimized by employing relatively long collection periods. Glomerular filtration rate was estimated from the endogenous creatinine clearance (Cc,).la Urine and plasma osmolality, Na+, K+, Cl-, HCO;, pH, and urine ammonium (NH:
) and titratable
rates and ckarance
acid
(TA)
were
values were corrected
determined for a surfacr
as previously
described.5
Excretion
area of 1.73 sq. metrr.
RESULTS He&
Acid” Excretion during Postural Natriuresis in Normal Subjects
In Table 1 changes in Na f, K+, Cl-, NHt and TA excretion and urine pH are presented in a normal hydropenic subject who assumed the recumbent position at 9:OO a.m. Postural natriuresis was associated with alkaluria and decreases in NHt; and TA excretion and with a slight kaliuresis. The alkaluria persisted for at least 3 hours, whereas the kaliuresis decreased during the second hour of recumbency. Changes in the endogenous creatinine clearance were small. In Figure 1 values in the upright position are compared with those of the second hour of recumbency in this and 2 other fasting subjects who had been on a regular diet. The observed changes were similar in all *3 subjects. In Figure 2 data are presented for 2 normal subjects who received methionine supplements for 2 days before and during the study. Despite the acid load assumption of the recumbent position resulted in a rise in urine pH, marked decreases in NH: and slight decreases in TA excretion. The effects of assuming the recumbent position were also studied in the evening when normally K-1 excretion decreases and acid excretion increases as part of the diurnal rhythm.“~“~‘” In Figure 3 studies in the evening are presented for 2 of the subjects shown in Figure 1. NH: and TA excretion decreased with recumbency at a time that an increase was expected from the diurnal cycle, whereas K-t excretion decreased in the direction expected from the diurnal
trend.
Renal Acid Excretion during Postural Natriuresis in Adrenalectomized
Subjects
In Table 2 the effects of assuming the recumbent position are shown for an adrenalectomized subject ( K. M. ) . Na+ excretion increased from an average value of 50 pEq./minute in the upright position to a maximum of 207 pEq./minute during recumbency. K-1 excretion changed little. In contrast to the relative alkaluria observed in normal subjects, the urine remained acid and NH: excretion remained approximately constant, while TA excretion increased slightly. Intravenous administration of 20 mg. methylprednisolone was followed by a small decrease in Na+ and increase in K+ excretion but urine pH was unaffected. NH2 excretion decreased slightly, whereas TA excretion was comparable to that in the upright position. In Figure 4 solid lines represent 6 studies in the 2 adrenalectomized subjects. For comparison average values for the 3 normal subjects (Fig. 1) are indicated by hatched lines. Postural natriuresis occurred in all the studies in ___.___-___ ‘The
term acid is employed
to indicate the sum of ammonium
and titratable
acid.
80
STEINMETZ
“No”
“K”
pEq /min U
AND EJSINGER
NEq /min R
U
300
300
200
200
R U = UPRIGHT R = RECUMBENT
100 0
pEq / min
pEq /min
Fig. L-Postural changes in Na+, K+, ammonium and titratable acid excretion and urine pH in 3 normal subjects who had been on a regular diet. U represents average values for urine collections in the upright position. R represents the value at 100 minutes after assumption of the recumbent position. Morning studies. adrenalectomized subjects without much change in K+ excretion. Urine pH remained acid. Changes in NHI,- and TA excretion were small, the sum of the 2 remaining virtually constant. In Figure 5 are shown the effects of acute replacement of hydrocortisone, methylprednisolone and aldosterone during recumbency in adrenalectomized subjects. The values for R are the same as in Figure 4, R’ represents the second hour after hormone administration.* Following hormone administration Na+ excretion changed little or decreased slightly and K+ excretion increased, changes consistent with known effects of these hormones. With one possible exception steroid administration did not affect urine pH; and renal acid excretion, measured as the sum of NH: and TA excretion, did not change. No significant difference was observed between hydrocortisone, methylprednisolone and aldosterone in these studies. In one study in which aldosterone and methylprednisolone were administered simultaneously the results were the same. The hatched lines indicate the effects of continued recumbency on 3 normal subjects not given hormones. Natriuresis and alkaluria persisted into the fourth hour of recumbency, whereas K+ excretion tended to return to the initial value of the upright position. Diurnal Rhythm, Glomerular
Filtration Rate and Systemic Acid-Base
Balance
To take into account diurnal variations in renal acid and salt excretion control observations were made during continued recumbency from midnight “In 2 studies observations were administration. The values for Na+, from the second to the third hour.
extended to include the third hour after hormone K+ and H+ excretion did not change significantly
POSTURE,
DIURNAL
RHYTHM
ON RENAL
j.!Eq/min R
U
81
EXCRETION
pEq /min U R
U = UPRIGHT R = RECUMBENT
U
“TA”
“NH ’
PH R
pEq /4nin U R
HEq/min R U
Fig. 2.-Postural changes in Na+, K+, ammonium and titratable acid excretion and urine pH in 2 normal subjects receiving methionine supplements before and during study. Morning studies.
“No” pEq /min U R
%” ”
PH
U
“K” pEq /min U R
R
pEq /4min U R
“TA” pEq / min U R
Fig. %-Postural changes in Na +, K+, ammonium and titratable acid excretion and urine pH in 2 normal subjects who had been on a regular diet. Evening studies.
to noon in one adrenalectomized subject (L. S.) and one normal subject. The subjects received no food, fluids or steroid medication during this period. In Table 3 is shown that in the adrenakctomized subject the excretion of Na 1 and K+ increased in the morning in the same direction as in the normal subject (although to a lesser extent) in accord with previous studies in patients
STEINMETZ
82
AND EISINGER
“If” UEq / min U
pEq /min
R
R
U
U = UPRIGHT 200
R = RECUMBENT
100
Ill = MEAN OF NORMALS
0
NEq /min U
R
U
HEq/min R
U
R
Fig. 4.-Six studies of postural changes in Na+, K-t, ammonium and titratable acid excretion and urine pH in 2 adrenalectomized subjects whose steroid treatment had been withheld for 16 hours. Solid lines represent studies in adrenalectomized subjects, hatched lines the average of the 3 normal subjects of Figure 1. Morning studies. with Addison’s disease and in adrenalectomized subjects.iJ-i5 In the adrenalectomized subject urine pH and renal acid excretion changed little from midnight to noon, This cons,tancy of acid excretion contrasts with the alkaluria which occurs in the morning in normal subject+” and which is also demonstrated in our normal subject. In Table 4 values of the endogenous creatinine clearance are compared between the upright periods and the second hour of recumbency. Inconsistent increases in CCR were observed in the studies of the adrenalectomized and normal subjects. Since the plasma bicarbonate did not change with posture, differences in the filtered load of bicarbonate could not explain the recumbent alkaluria of the normal subjects or the absence of alkaluria in the adrenalectomized subjects. Blood pH values were within normal range and the plasma total CO2 ranged between 25 and 29 mM/L. in different studies except for one of the studies in which methionine was given and one of the studies in the adrenalectomized woman, where the plasma total CO% values were 23 and 22 mM/L., respectively. No significant differences in blood pH and plasma total COZ were observed between samples obtained in the upright and the recumbent position. DISCUSSION These results confirm observations by Thomas4 that in normal subjects postural natriuresis is associated with inhibition of hydrogen ion excretion.
POSTURE, DIURNAL
RHYTHM
ON RENAL
“I?
uMlv
pEq /min U
R
53
EXCRETION
pEq imin R’
U
=
UPRIGHT
R
=
RECUMBENT
(IO0
min I
R’
=
RECUMBENT
(200
min)
I I I
q
MEAN
OF NORMALS
PH
UEq /min U
R
H_,+, R’ ------
HYDRGCORTISCNE PREONISOLONE
OR
ALDOSTERONE
Fig. S.-Effect of acute administration of hormone on the excretion of Na+, K+, the sum of ammonium and titratable acid excretion and urine pH during recumbency in 5 studies of 2 adrenalectomized subjects. U = upright, R = recumbent at 100 minutes and R' = recumbent at 200 minutes or 100 minutes after
hormone administration (interrupted lines). Hatched lines represent average of the 3 normal subjects receiving no hormone. Morning studies. Thomas observed that acid excretion was less in the recumbent than in the upright position in day studies regardless of the sequence in which posture was changed. In the present study the reduction in acid excretion following assumption of the recumbent position occurred in morning as well as in evening studies, but the extent of the postural inhibition was far greater in the morning. Such diurnal influence on the effects observed with the acute change to the recumbent position might have been expected from the diurnal variations in acid excretion that are known to occur during continued recumbency, i.e., alkaluria during the middle of the day and aciduria during the night. The observations of Thomas4 as well as our own, however, indicate that postural inhibition of acid excretion can be demonstrated at different times of the diurnal cycle. Even at high levels of acid excretion following methionine loading assumption of recumbency results in decreased renal acid excretion. The efl’ects of lying down on K~imexcretion were less consistent. The kaliuresis observed in the morning was transient and followed the pattern of the diurnal rhythm. In the evening lying down was associated with decreased K+ excretion, the direction of the change again being that of the diurnal trend. These results are in agreement with observations by Borst et a1.16 that posture per se has little effect on K+ excretion in healthy subjects,
113 121 133 126
82 78 76
73
C CT ml. jmin.
27 25 132 226
NOW&
50 60 70
44
Subjecl
.__
29 34 70 90
10 18 21
15
Subject
Yzv /LEq./min.
A4drenalectonked
uN*v pEq./min.
ux,*v
41.5 42.8 21.8 9.9
5.2 6.9 7.6
11.7 9.6 7.6
8.4
pEq./min.
30.8 5.1 0
30.5
14.7 15.1 14.6
13.6
+
TAV
(L.
S.) re.
73.6 26.9 9.9
72.0
26.4 24.7 22.2
22.0
,uEq./min.
usIil
subject
in an
UTAV pEq./min.
Recumbency
5.3
5.4 5.3 5.3
5.3
PH
Continued
Note: Food and fluid were withheld from 9:00 p. m. the evening before study until the end of study. The adrenalectomized ceived her last dose of steroid medication at 3:00 p. m. the afternoon before study and no medication was given during study.
.92 .42 .90 1.1
12:OO M-5:00 a. m. 5:00-8:OO a. m. 8:00-10:00 a. m. 10:00-12:OO noon
.35
.38 .43 .49
a. m.
ml./min.
Urine Flow
Variations in Renal Acid and Salt Excretion during Adrenulectomized and a Normal Subject
6:00-8:OO a. m. 8:00-1O:OO a. m. lO:OO-12:00 noon
12:OO M-6:00
Time
Table 3.-Diurnal
8
m t: z
3
z $
2
9 g
POSTURE,
DIURNAL
RHYTHM
Table 4.-Effect
ON
RENAL
of Posture on the Endogenous Creatinine in Normal and Adrenalectomized Subjects
Studies in Normal Subjects Upright
--
Recumbent
Ccl. ml./min.
Clearance
Studies in Adrenalectomized Subjects Upright
Recumbent
132
112
130
102 99
104 116
106 120
109 109 118 100 120
91 102
87 100
-129
94 97 114
Note:
85
EXCRETION
The values for recumbency
63 65
62* 60’
represent
the second
point of urine collection being at approximately normal subjects are given in sequence of Figures *Values for left kidney.
hour of recumbency,
100 minutes 1, 2 and 3.
of recumbency.
the midStudies in
The inhibitory effect of recumbency on the renal excretion of acid, on the other hand, appears to be consistent. Although urine bicarbonate was not measured in the present study changes in “net acid” excretion (defined as NH+ + TA - HCO- ) were in the same direction as the changes in acid excre4
3
(defined as the sume of NH: + TA). In the upright position urine pH was sufficiently low in all studies to exclude the presence of bicarbonate.’ In the adrenalectomized subjects and in the normal subjects receiving acid loads bicarbonate excretion was insignificant in either the upright or recumbent position. Hence, net acid excretion equalled the sum of NH: and TA excretion. Little is known about the mechanism of inhibition of acid excretion during postural natriuresis. Changes in systemic acid-base balance do not appear to account for it. Increases in filtration rate and hence the load of bicarbonate delivered to the tubules might reduce the excretion of hydrogen ions, but in the present study there was no consistent difference in the endogenous creatinine clearance+ between the periods of upright posture and the second hour of recumbency when acid excretion was fully inhibited. These observations suggest that the postural effect does not depend on changes in the filtered load of bicarbonate. Could an increase in renal blood flow or a change in the distribution of of blood flow within the kidney explain the inhibition of acid excretion? In unilateral renal artery stenosis the affected kidney often excretes a more acid urine than the contralateral kidney despite the fact that the 2 kidneys are in .~~______~~ -__ tion
*Observations by Thomas4 indicate that the inhibition of acid excretion during recumbency would have been greater in terms of “net acid” excretion since subtraction of bicarbonate would have reduced the acid values further and have led to calculation of “net alkali” excretion in the recumbent normal subjects. fThe ratio between endogenous creatinine clearance and inalin clearance in this laboratory is approximately 0.9.lr Similar values were obtained in an earlier study in which it was shown that this ratio was not affected by the diurnal cyc1e.f;
86
STEINMEl7.
AND EISINGER
the same acid-base milieu.18 Although it is possible that hemodynamic changes cause postural variations in acid excretion, the postural effect was not fully developed until the second hour of recumbency; this delay argues against a hemodynamic effect. It is more likely that the changes in acid excretion depend on a hormonal effect. Gowenlock and his associatesll and Muller g,10 observed a greater aldosterone output in the urine in the upright than in the recumbent position and suggested that aldosterone might increase sodium reabsorption and accelerate sodium-hydrogen ion exchange during standing. In the absence of adrenocortical hormones, however, our adrenalectomized subjects differed from the normal subjects in the recumbent rather than in the upright position. In all 6 studies aciduria was present during standing, but the expected inhibition of acid excretion failed to occur following assumption of recumbency. The fact that acid excretion was not influenced by posture was of particular interest since the postural sodium diuresis was preserved in the adrenalectomized subjects in accord with previous reports by Ten Holt,12 Rosenbaum14 and Borst15 and their associates. Since administration of hydrocortisone, methylprednisolone ,or aldosterone failed to reproduce the normal inhibition of acid excretion during recumbency, it is unlikely that the effect is directly dependent on the presence of these hormones. It is possible that recumbency causes the release of another adrenal hormone, not examined in the present study, that inhibits H+ secretion by the tubules. Although several investigators lDm2’ have postulated that the adrenal produces a natriuretic hormone, the existence of such a hormone has not been definitely established. If this horm,one acted like a carbonic anhydrase inhibitor, it might provide an explanation for the alkaluria of recumbency. Alternatively it is possible that some humoral factor originating- outside the adrenal, either in the kidney itself or elsewhere, governs the postural inhibition of acid excretion and that the adrenal plays a permissive role in this humoral system. In the adrenalectomized subject studied during continued recumbency the diurnal variation in acid excretion was virtually absent even though variations in Na+ and K+ excretion were present. The fact that both diurnal and postural changes in acid excretion were absent in this patient suggests that the two may share a comm,on mechanism. Such a possibility is also consistent with the observation in normal man that the extent of the postural inhibition of acid excretion depends on the time of day. Whatever mechanisms are involved in postural and diurnal changes in acid excretion they appear to depend on the adrenal in a way which has not yet been elucidated. ACKNOWLEDGMENT We are grateful
to
Misses Nancy Burton, Susan Baron and Francine
Reff for technical
assistance. REFERENCES 1. Steinmetz, P. R., Eisinger, R. P., and Chasis, H.: On the inhibition of H+ secretion during postural natriuresis.
Fed. Proc. 23~307, 1964. 2. Simpson, G. E.: Diurnal variations in the rate of urine excretion for two
POSTURE,
DIURNAL
hour
intervals:
tors.
J.
1924. 3. Stanbury, Diurnal cretion.
Biol.
RHYTHM
some Chem.
ON RENAL
associated
87
EXCRETION
en
fac-
Ned.
59:107-122,
S. W., and Thomson, A. E.: variations in electrolyte exClin. Sci. 10:267-293, 1951.
4. Thomas, S.: Some effects of change of posture on water and electrolyte excretion by the human kidney. J. Physiol. 139:337-352, 1957. 5. Steinmetz, P. R., and Bank, N.: Effects of acute increases in the excretion of solute and water on renal acid excretion in man. J. Clin. Invest. 42: 1142-l 149, 1963. 6. Sirota, J. H., Baldwin, D. S., and Villarreal, H.: Diurnal variations of renal function in man. J. Clin. Invest. 29: 187-192. 1950. 7. Wesson, L. G., Jr., and Lauler, D. P.: Diurnal cycle of glomerular filtration rate and sodium and chloride excretion during responses to altered salt and water balance. J. Clin. Invest. 40:1967-1977, 1961. 8. Smith, H. W.: The Kidney Structure and Function in Health and Disease. New York, Oxford University Press, 1951, pp. 432-435. 9. Muller, A. F., Manning, E. L., and Riondel. A. M.: Diurnal variation of aldosterone related to position and activity in normal subjects and patients with pituitary insufficiency. In: An international Symp. on Aldosterone. Boston, Little, Brown & Company, 1958, p. 111. 10. -: Some aspects of the hormonal control of water and electrolytes. In: Proc. Symposium on Water and Electrolyte Metabolism. Amsterdam. Elsevier, 1961, p. 64. 11. Gowenlock, A. H., Mills, J. N., and Thomas, S.: Acute postural changes in aldosterone and electrolyte excretion in man. J. Physiol. 146:133-141, 1959. 12. Ten Holt, S. P.. De Vries, L. A., and Borst, J. G. G.: Over de invloed van houding en beweging op de uitscheiding van water en electrolyten
over
het
ontstaan
Tijdschrift
van
Geneesk
nycturie. 96:2244-
2251, 1952. 13. Borst, J. G. G., and DeVries, L. A.: The three types of “natural” diuresis. Lancet 259 (ii) :1-B, 1950. 14. Rosenbaum, J. D., Papper, S., and Ashley, M. M.: Variations in renal excretion of sodium independent of adrenocortical hormone change in dosage in patients with Addison’s disease. J. Clin. Endocrinol. & Metab. 15: 1459-1474, 1955. 15. Borst, J. G. G., DeVries, L. A., Van Leeuwen, A. M., Den Ottolander, G. J. H., and Cejka, V.: The maintenance of circulatory stability at the expense of volume and electrolyte stability. Clin. Chim. Acta 5: 887-914, 1960. 16. Brod, J., and Sirota, J. H.: The renal clearance of endogenous “creatinine” in man. J. Clin. Invest. 27:645-654, 1948. 17. Steinmetz, P. R., and Smith, H. W.: Urea and the renal concentrating operation in man. Amer. J. Med. 35: 18. -,
727-736, 1963. Eisinger, R. P., and Lowenstein, J.: The excretion of acid in unilateral renal disease 44:582-591,
in man. 1965.
J. Clin.
Invest.
19. Nrher, R., Desaulles, P., Vischer, E., Wieland, P., and Wettstein, A.: Isolierung, Konstitution and Synthese eines neuen Steroides aus Nebennieren. Helv. Chim. Acta 41:16671692. 1958. 20.
Rosemberg, E., Dufault, F. X., Jr., Bloch, E., Budnitz, E., Butler, P., and Brem, J.: The effects of progressive reduction of sodium intake on adrenal steroid excretion and electrolyte balance in a case of congenital adrenal hyperplasia of the salt-losing type. J. Clin. Endocrinol. & Metab. 20~214-228, 1960. 21. Hollowell, J. G., and Frazer, J.: Isolation of sodium transport inhibitor, New Eng. J. Med. 270:154-155, 1964.