The Circadian Rhythm of Renin ROBERT S. MODLINGER, KUROSH SHARIF-ZADEH, NORMAN H. ERTEL, AND MICHAEL GUTKIN Hypertension Section, Department of Medicine, East Orange (New Jersey) Veterans Administration Hospital,* and the CMDNJ-New Jersey Medical School, Newark, New Jersey in sodium intake, basal blood pressure, and mean plasma renin activity. Peaks of lesser magnitude were also frequently noted, most commonly at 1000 h and 1800-2000 h. Minimum PRA values were not restricted to a particular time of day and did not generally recur at the same time upon retesting. The mean ratio of maximum to minimum PRA in each study was
ABSTRACT. The circadian rhythm of plasma renin activity during continuous recumbency was determined fifty-one times in thirty subjects who either slept at night or remained awake for 24 h. Both groups had maximum values between 2400 and 0800 h, despite absence of the expected early morning fall in blood pressure, pulse, and glomerular filtration rate in the awake subjects. Infusion of normal saline between 2300 and 0300 h initially suppressed renin, but did not prevent its subsequent rise regardless of the amount of sodium appearing in the urine. Of thirteen patients tested two to five times, twelve had recurrence of the zenith within a single 4 h period on retesting, despite differences
246% ± 18.3%
(±1SEM).
The circadian rhythm of renin appears to be independent of known renal mechanisms responsible for regulating renin release. It is possible that this rhythm is controlled by the central nervous system. (J Clin Endocrinol Metab 43: 1276, 1976)
T
He had been receiving decreasing doses of prednisone for 4 weeks. Except for this patient and two others noted in Table 1, no patient received any medications during or for two weeks prior to this study. The diagnosis of essential hypertension was made after a rapid sequence iv pyelogram, serum electrolyte determination, urine culture, urinalysis, creatinine clearance, and 24 h urinary protein and VMA determination were found to be normal. Of the 19 such subjects, 9 had low renin, 7 normal renin, and 3 high renin hypertension, as determined by their 1200 h erect PRA relative to their 24 h sodium excretion (6). Plasma renin activity (PRA) was determined as described previously (6,7). All samples from a single test date were incubated at the same time. Patients and Methods Studies in which the average PRA was less than Thirty male patients (ages 26-61) were hos- 1 ng/ml/h were incubated for 18 h instead of the pitalized in the Special Diagnostic and Treatment usual 3 h (7). The intra- and inter-assay coefUnit of the East Orange Veterans Administration ficients of variation of this long incubation are Hospital. They included 19 patients with essen- 6.8% and 8.2% (±1 SD) respectively at 0.53 tial hypertension, 7 normotensive volunteers, 2 ng/ml/h. The incubation proceeds linearly in patients with primary hyperaldosteronism, 1 with samples with PRA's in excess of 1.2 ng/ml/h. acromegaly, and 1 with Graves' disease and The mean intra- and inter-assay coefficients ophthalmopathy. This last patient was tested of variation of the 3 h incubation are 4.5% and while euthyroid, receiving propylthiouracil 100 8.5% (±1 SD) respectively at 1.4, 2.6, and 5.7 mg every 8 h and prednisone 10 mg every 8 h. ng/ml/h (6).
HE CIRCADIAN rhythm of renin in continuously recumbent subjects was first described by Gordon et al. in 1966 (1). Although subsequent reports (2-5) have generally confirmed that plasma renin activity (PRA) is highest in the early morning hours, they have not elucidated the mechanism responsible for this variation. The studies detailed below indicate that this periodicity is not determined by any accepted mechanism of renin control and suggest the possibility that the circadian rhythm of PRA had its origin within the central nervous system.
Received February 26, 1976. * Project number 5771-01. Reprint requests to: Dr. R. S. Moldinger, Veterans Administration Hospital, East Orange, NJ. 07019.
Protocol
All subjects were in bed by 2200 h on the night preceding testing. At 0800-0830 h, an in1276
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CIRCADIAN RHYTHM OF RENIN TABLE
1. Data concerning patients studied more than once Time of
Sodium
Patient
Diagnosis
i ntcilcc
RlnnH
Mpan PRA
(grams)
Pressure*
(ng/ml/hr)
Zenith
Nadir
1
Normotensive volunteer
0.25 2.0
105/70 110/70
16.90 0.69
2400h 2400h
0800h 1600h
2
Essential hypertension
0.50 2.00
150/100 155/110
1.82 0.40
2400h 2400h
1200h 1200h
3
Essential hypertension
0.25 2.00
120/80 140/108
4.45 0.23
0800hf 0800h
0800hJ 2400h
4
Essential hypertension
0.25 2.5 4.0
138/60 130/80 132/96
1.48 0.72 0.32
0400h 0800h 0400h
1200h 1600h 1200h
5
Primary hyperaldosteronism (indeterminate type) (24)
0.50 2.0
160/100 180/115
0.10 0.11
0800h 0400h
2400h 1200h
6
Labile hypertension
0.5 2.5
120/80 120/70
2.54 1.05
0400h 0400h
2400h 0800h
7
Normotensive volunteer
0.5 4.0 6.0
90/60 110/80 115/68
8.21 2.40 0.93
0400h 0400h 0400h
1200h 1200h 2400h
8
Essential hypertension
0.25 2.5
120/90 114/98
0.54 1.41
0800M 0400h
0800hJ 0800h
Essential hypertension extreme obesity
1.0
130/90
0.24
0800h
1600h
1.0 1.0
150/82 160/110
0.26 0.13
0800h 0800h
1600h 2400h
Primary hyperaldosteronism
0.25
110/65
23.90
0400h
1200h
(nodular hyperplasia)"
0.25
110/70
26.70
2000h
2400h
0.25
180/110
0.27
0400h
0800h
0.25
150/110
0.30
0600h
0800h
4.5
165/105
0.43
0800h
1200h
9
10
1277
Comments
K+ = 3.4 mEq/1 K+ = 3.1 mEq/1
Sarcoidosis, hypercalciuria. normocalcemia, elevated PRA of undetermined cause Dexamethasone 2.0 mg every 6 h, day 3 Fasting, 4th day, receiving sodium dextrose tablets 1000 calorie diet Fasting, 4th day, receiving sodium dextrose tablets K+ = 4.7 mEq/1 spironolactone 400 mg per day, 10th week + K = 4.5 mEq/1, spironolactone 400 mg per day, 11th week. Plasma volume§ = 1229 ml/sq m + K = 3.1 mEq/1. Plasma volume§ = 1117 ml/sq m K+ = 4.6 mEq/1, KC1 elixir 80 mEq/day. Plasma volume§ = 1276 ml/sq m K+ = 3.0 mEq/1. Plasma volume§ = 1412 ml/sq m
11
Normotensive volunteer
4.5 4.5
110/60 120/70
1.16 2.26
0800h 0400h
2400h 1600h
Awake for 24 h Asleep at night
12
Normotensive volunteer
2.5 4.0
90/60 110/75
2.27 1.27
0400h 0400h
1800h 2200h
Awake for 24 h Awake for 24 h
13
Labile hypertension
2.5 2.5
115/80 130/90
3.62 1.49
0800h 0800h
2400h 1400h
Asleep at night Awake for 24 h
* Obtained at 0700h on day of study. t Second 0800h sample, at close of study. t First 0800h sample, at commencement of study.
§ Obtained day before study using 125I Iodinated albumin Normal: 1300-1700 ml/sq m. 11 The data from this patient have previously been published (7).
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1278
JCE & M • 1976 Vol 43 • No 6
MOLDINGER ET AL.
dwelling 19 gauge needle was inserted in a forearm vein, the first PRA obtained, and 5% dextrose begun at 0.3 ml/min. Additional samples were obtained at 2 to 4 h intervals without venipuncture. Patients remained completely recumbent except for 15 min periods immediately after the 0800 h and 1200 h samples and at 1700 h when the head of the bed was elevated 30° to allow eating. At 0730-0800 h the following day, the last recumbent PRA sample was obtained, the iv needle was removed and the patient arose. Following 4 h of ambulation, an additional PRA was obtained (1200 h, erect). Group I Forty-four studies were completed in 26 patients who remained awake during the day and slept at night. Plasma samples were obtained at 0800 h, 1200 h, 1600 h, 2000 h, 2400 h, 0400 h, and 0800 h in 27 studies, at 0200 h and 0600 h in addition in fifteen, and at 2 h intervals around the clock in two. In patients studied on more than one occasion (Table 1), the various sodium intakes were always maintained for at least 5 days prior to each testing date. Group II Six patients (including two from Group I) were studied seven times while remaining awake under observation for the entire 24 h period. Plasma renin activity was determined at 2 h intervals beginning at 0800 h. Each of these subjects had previously been observed to have normal sleep-wake cycles for a minimum of 7 days. In each, apical pulse and blood pressure were recorded throughout the day, the latter at quarterhourly intervals by an Arteriosonde 1216, (Roche). Urine for creatinine was collected at 0800-1600 h, 1600-2400h, 2400-0400 h, and 0400-0800 h, and corresponding serum creatinines at 0800, 1600, 2400, 0400 and 0800 h. Creatinine clearances were performed for each interval by the method of Bonsnes and Taussky (8). Group HI In ten patients the protocol was altered to include the iv infusion of 0.9% NaCl, 250 ml/h, between 2300 and 0300 h. All of these patients slept during the night. Urine was collected as in Group II studies, but was analyzed for sodium by internal standard flame photometry.
Results Groups I and II The circadian pattern of PRA was similar in all studies whether or not the patient was asleep, hypertensive, or receiving steroids. Maximum PRA values occurred at the first 0800 h sample or between 2400 h and 0800 h in 50 of 51 studies. Of the 13 patients studied more than once (32 studies), 12 had peaks within one sampling interval on retesting (Table 1) (P < .005 by a sign test (9)). These studies included two patients who were tested once while sleeping and once while continuously awake. The single exception to this observed reproducibility was a patient with hyperaldosteronism secondary to nodular hyperplasia. He was studied 5 times. While the zeniths of four rhythms recurred in the early morning hours, the peak of the fifth occurred at 2000 h, with the second highest value occurring in the early morning (Table 1, patient no. 10). Data regarding this patient have previously been published (7). Minimum PRA values occurred 12 times at 0800 h and 11 times at 1200, 1600 and 2400 h. In only four of the 13 retested patients did the minimums recur within a 4 h interval. Although dips were often noted between early morning spikes, the lowest point never occurred at 0200, 0400, or 0600 h. Since the mean PRA obtained in the 51 studies varied from 0.10 to 26.7 ng/ml/h, construction of a composite diurnal variation curve by averaging all the values obtained at each sampling time was judged unsuitable. Such a technique would result in obscuring the rhythm occurring in the many low and normal renin patients by those taking place in the few patients with high renin levels. To avoid this, the PRA's obtained at 0800, 1200, 1600, 2000, 2400, 0400 and 0800 h of each study were averaged and the value at each of these sampling times expressed as a percent of this mean. All the values so obtained were then aver-
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CIRCADIAN RHYTHM OF RENIN
1279
140 aged for each 4-h sampling time and the results plotted in Fig. 1. Paired t studies 130 indicated that the fall in PRA between 0800 and either 1200 or 1600 h was significant (P < .025) while the fall between 1200 and 120 1600 h was not. PRA rose significantly between 1600 and 2000 h (P < .05), fell back 110slightly at 2400 h (P = not significant) and then rose sharply between 2400 and 0400 h IOO (P
ABSTRACT. The circadian rhythm of plasma renin activity during continuous recumbency was determined fifty-one times in thirty subjects who either slept at night or remained awake for 24 h. Both groups had maximum values between 2400 and 0800 h, despite absence of the expected early morning fall in blood pressure, pulse, and glomerular filtration rate in the awake subjects. Infusion of normal saline between 2300 and 0300 h initially suppressed renin, but did not prevent its subsequent rise regardless of the amount of sodium appearing in the urine. Of thirteen patients tested two to five times, twelve had recurrence of the zenith within a single 4 h period on retesting, despite differences
246% ± 18.3%
(±1SEM).
The circadian rhythm of renin appears to be independent of known renal mechanisms responsible for regulating renin release. It is possible that this rhythm is controlled by the central nervous system. (J Clin Endocrinol Metab 43: 1276, 1976)
T
He had been receiving decreasing doses of prednisone for 4 weeks. Except for this patient and two others noted in Table 1, no patient received any medications during or for two weeks prior to this study. The diagnosis of essential hypertension was made after a rapid sequence iv pyelogram, serum electrolyte determination, urine culture, urinalysis, creatinine clearance, and 24 h urinary protein and VMA determination were found to be normal. Of the 19 such subjects, 9 had low renin, 7 normal renin, and 3 high renin hypertension, as determined by their 1200 h erect PRA relative to their 24 h sodium excretion (6). Plasma renin activity (PRA) was determined as described previously (6,7). All samples from a single test date were incubated at the same time. Patients and Methods Studies in which the average PRA was less than Thirty male patients (ages 26-61) were hos- 1 ng/ml/h were incubated for 18 h instead of the pitalized in the Special Diagnostic and Treatment usual 3 h (7). The intra- and inter-assay coefUnit of the East Orange Veterans Administration ficients of variation of this long incubation are Hospital. They included 19 patients with essen- 6.8% and 8.2% (±1 SD) respectively at 0.53 tial hypertension, 7 normotensive volunteers, 2 ng/ml/h. The incubation proceeds linearly in patients with primary hyperaldosteronism, 1 with samples with PRA's in excess of 1.2 ng/ml/h. acromegaly, and 1 with Graves' disease and The mean intra- and inter-assay coefficients ophthalmopathy. This last patient was tested of variation of the 3 h incubation are 4.5% and while euthyroid, receiving propylthiouracil 100 8.5% (±1 SD) respectively at 1.4, 2.6, and 5.7 mg every 8 h and prednisone 10 mg every 8 h. ng/ml/h (6).
HE CIRCADIAN rhythm of renin in continuously recumbent subjects was first described by Gordon et al. in 1966 (1). Although subsequent reports (2-5) have generally confirmed that plasma renin activity (PRA) is highest in the early morning hours, they have not elucidated the mechanism responsible for this variation. The studies detailed below indicate that this periodicity is not determined by any accepted mechanism of renin control and suggest the possibility that the circadian rhythm of PRA had its origin within the central nervous system.
Received February 26, 1976. * Project number 5771-01. Reprint requests to: Dr. R. S. Moldinger, Veterans Administration Hospital, East Orange, NJ. 07019.
Protocol
All subjects were in bed by 2200 h on the night preceding testing. At 0800-0830 h, an in1276
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CIRCADIAN RHYTHM OF RENIN TABLE
1. Data concerning patients studied more than once Time of
Sodium
Patient
Diagnosis
i ntcilcc
RlnnH
Mpan PRA
(grams)
Pressure*
(ng/ml/hr)
Zenith
Nadir
1
Normotensive volunteer
0.25 2.0
105/70 110/70
16.90 0.69
2400h 2400h
0800h 1600h
2
Essential hypertension
0.50 2.00
150/100 155/110
1.82 0.40
2400h 2400h
1200h 1200h
3
Essential hypertension
0.25 2.00
120/80 140/108
4.45 0.23
0800hf 0800h
0800hJ 2400h
4
Essential hypertension
0.25 2.5 4.0
138/60 130/80 132/96
1.48 0.72 0.32
0400h 0800h 0400h
1200h 1600h 1200h
5
Primary hyperaldosteronism (indeterminate type) (24)
0.50 2.0
160/100 180/115
0.10 0.11
0800h 0400h
2400h 1200h
6
Labile hypertension
0.5 2.5
120/80 120/70
2.54 1.05
0400h 0400h
2400h 0800h
7
Normotensive volunteer
0.5 4.0 6.0
90/60 110/80 115/68
8.21 2.40 0.93
0400h 0400h 0400h
1200h 1200h 2400h
8
Essential hypertension
0.25 2.5
120/90 114/98
0.54 1.41
0800M 0400h
0800hJ 0800h
Essential hypertension extreme obesity
1.0
130/90
0.24
0800h
1600h
1.0 1.0
150/82 160/110
0.26 0.13
0800h 0800h
1600h 2400h
Primary hyperaldosteronism
0.25
110/65
23.90
0400h
1200h
(nodular hyperplasia)"
0.25
110/70
26.70
2000h
2400h
0.25
180/110
0.27
0400h
0800h
0.25
150/110
0.30
0600h
0800h
4.5
165/105
0.43
0800h
1200h
9
10
1277
Comments
K+ = 3.4 mEq/1 K+ = 3.1 mEq/1
Sarcoidosis, hypercalciuria. normocalcemia, elevated PRA of undetermined cause Dexamethasone 2.0 mg every 6 h, day 3 Fasting, 4th day, receiving sodium dextrose tablets 1000 calorie diet Fasting, 4th day, receiving sodium dextrose tablets K+ = 4.7 mEq/1 spironolactone 400 mg per day, 10th week + K = 4.5 mEq/1, spironolactone 400 mg per day, 11th week. Plasma volume§ = 1229 ml/sq m + K = 3.1 mEq/1. Plasma volume§ = 1117 ml/sq m K+ = 4.6 mEq/1, KC1 elixir 80 mEq/day. Plasma volume§ = 1276 ml/sq m K+ = 3.0 mEq/1. Plasma volume§ = 1412 ml/sq m
11
Normotensive volunteer
4.5 4.5
110/60 120/70
1.16 2.26
0800h 0400h
2400h 1600h
Awake for 24 h Asleep at night
12
Normotensive volunteer
2.5 4.0
90/60 110/75
2.27 1.27
0400h 0400h
1800h 2200h
Awake for 24 h Awake for 24 h
13
Labile hypertension
2.5 2.5
115/80 130/90
3.62 1.49
0800h 0800h
2400h 1400h
Asleep at night Awake for 24 h
* Obtained at 0700h on day of study. t Second 0800h sample, at close of study. t First 0800h sample, at commencement of study.
§ Obtained day before study using 125I Iodinated albumin Normal: 1300-1700 ml/sq m. 11 The data from this patient have previously been published (7).
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1278
JCE & M • 1976 Vol 43 • No 6
MOLDINGER ET AL.
dwelling 19 gauge needle was inserted in a forearm vein, the first PRA obtained, and 5% dextrose begun at 0.3 ml/min. Additional samples were obtained at 2 to 4 h intervals without venipuncture. Patients remained completely recumbent except for 15 min periods immediately after the 0800 h and 1200 h samples and at 1700 h when the head of the bed was elevated 30° to allow eating. At 0730-0800 h the following day, the last recumbent PRA sample was obtained, the iv needle was removed and the patient arose. Following 4 h of ambulation, an additional PRA was obtained (1200 h, erect). Group I Forty-four studies were completed in 26 patients who remained awake during the day and slept at night. Plasma samples were obtained at 0800 h, 1200 h, 1600 h, 2000 h, 2400 h, 0400 h, and 0800 h in 27 studies, at 0200 h and 0600 h in addition in fifteen, and at 2 h intervals around the clock in two. In patients studied on more than one occasion (Table 1), the various sodium intakes were always maintained for at least 5 days prior to each testing date. Group II Six patients (including two from Group I) were studied seven times while remaining awake under observation for the entire 24 h period. Plasma renin activity was determined at 2 h intervals beginning at 0800 h. Each of these subjects had previously been observed to have normal sleep-wake cycles for a minimum of 7 days. In each, apical pulse and blood pressure were recorded throughout the day, the latter at quarterhourly intervals by an Arteriosonde 1216, (Roche). Urine for creatinine was collected at 0800-1600 h, 1600-2400h, 2400-0400 h, and 0400-0800 h, and corresponding serum creatinines at 0800, 1600, 2400, 0400 and 0800 h. Creatinine clearances were performed for each interval by the method of Bonsnes and Taussky (8). Group HI In ten patients the protocol was altered to include the iv infusion of 0.9% NaCl, 250 ml/h, between 2300 and 0300 h. All of these patients slept during the night. Urine was collected as in Group II studies, but was analyzed for sodium by internal standard flame photometry.
Results Groups I and II The circadian pattern of PRA was similar in all studies whether or not the patient was asleep, hypertensive, or receiving steroids. Maximum PRA values occurred at the first 0800 h sample or between 2400 h and 0800 h in 50 of 51 studies. Of the 13 patients studied more than once (32 studies), 12 had peaks within one sampling interval on retesting (Table 1) (P < .005 by a sign test (9)). These studies included two patients who were tested once while sleeping and once while continuously awake. The single exception to this observed reproducibility was a patient with hyperaldosteronism secondary to nodular hyperplasia. He was studied 5 times. While the zeniths of four rhythms recurred in the early morning hours, the peak of the fifth occurred at 2000 h, with the second highest value occurring in the early morning (Table 1, patient no. 10). Data regarding this patient have previously been published (7). Minimum PRA values occurred 12 times at 0800 h and 11 times at 1200, 1600 and 2400 h. In only four of the 13 retested patients did the minimums recur within a 4 h interval. Although dips were often noted between early morning spikes, the lowest point never occurred at 0200, 0400, or 0600 h. Since the mean PRA obtained in the 51 studies varied from 0.10 to 26.7 ng/ml/h, construction of a composite diurnal variation curve by averaging all the values obtained at each sampling time was judged unsuitable. Such a technique would result in obscuring the rhythm occurring in the many low and normal renin patients by those taking place in the few patients with high renin levels. To avoid this, the PRA's obtained at 0800, 1200, 1600, 2000, 2400, 0400 and 0800 h of each study were averaged and the value at each of these sampling times expressed as a percent of this mean. All the values so obtained were then aver-
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CIRCADIAN RHYTHM OF RENIN
1279
140 aged for each 4-h sampling time and the results plotted in Fig. 1. Paired t studies 130 indicated that the fall in PRA between 0800 and either 1200 or 1600 h was significant (P < .025) while the fall between 1200 and 120 1600 h was not. PRA rose significantly between 1600 and 2000 h (P < .05), fell back 110slightly at 2400 h (P = not significant) and then rose sharply between 2400 and 0400 h IOO (P
