0021-972X/98/$03.00/0
Journal of Clinical Endocrinology and Metabolism
Copyright © 1998 by The Endocrine Society
Vol. 83, No. 5
Printed in U.S.A.
Oscillations in Sympatho-Vagal Balance Oppose
Variations in d-Wave Activity and the Associated
Renin Release
ANNE CHARLOUX, HÉLÈNE OTZENBERGER, CLAUDE GRONFIER,
EVELYNE LONSDORFER-WOLF, FRANÇOIS PIQUARD, AND
GABRIELLE BRANDENBERGER
Laboratoire des Régulations Physiologiques et des Rythmes Biologiques chez l’Homme, Institut de
Physiologie, 67085 Strasbourg Cedex, France
ABSTRACT
To determine the potential role of the sympathetic nervous system
in the generation of the oscillations in PRA over the 24-h period, we
used the autocorrelation coefficient of RR interval (rRR), a new tool
to evaluate the sympatho-vagal balance continuously. We determined
the influence of the sympathetic nervous system both on the nocturnal
PRA oscillations associated to increases in d-wave activity and on the
daytime oscillations that occur randomly in awake subjects.
PRA and rRR were determined every 10 min during 24 h in nine
healthy subjects under continuous bed rest. Electroencephalographic
spectral analysis was used to establish the variations in d-wave activity during sleep, from 2300 – 0700 h. The overnight profiles in PRA,
rRR, and d-wave activity were analyzed using a modified version of
the pulse detection program ULTRA. The temporal link among the
profiles of rRR, PRA, and d-wave activity was quantified using crosscorrelation analysis.
D
URING sleep, PRA displays large oscillations that are
strongly linked to sleep stage alternation; PRA increases during nonrapid eye movement (NREM) sleep and
decreases during REM sleep (1). Drugs such as converting
enzyme inhibitors, b-blockers, and diuretics or a low sodium
diet modulate the amplitude of these oscillations, but do not
abolish the relationship between PRA and sleep structure (2).
In patients with sleep disorders, PRA variations reflect the
disorganization in the internal sleep structure quite precisely
(3–5). More recently, we demonstrated by spectral analysis of
the sleep electroencephalogram (EEG) that PRA oscillations
are correlated with variations in d relative power that reflect
sleep deepness; PRA increases are associated with increases
in slow waves, and PRA decreases are associated with decreases in slow waves (6).
It is well known that renin release by the juxtaglomerular
apparatus is induced peripherally by a fall of perfusion pressure in the afferent arterioles of the kidney, a decrease in
sodium chloride concentration at the macula densa, or the
stimulation of b-adrenoceptors on the juxtaglomerular cells
(7). Numerous animal experiments have described the stimReceived October 7, 1997. Revision received December 31, 1997. Accepted January 14, 1998.
Address all correspondence and requests for reprints to: Dr. Anne
Charloux, Laboratoire des Régulations Physiologiques et des Rythmes
Biologiques, Institut de Physiologie, 4 rue Kirschleger, 67085 Strasbourg
Cedex, France.
During sleep, large oscillations in PRA were strongly linked to
variations in d-wave activity. They were preceded by opposite oscillations in rRR, decreases in rRR reflecting predominant vagal activity, and increases in rRR reflecting sympathetic dominance. During
the waking periods, the levels of rRR were higher, with smaller variations. The daytime PRA oscillations were not associated with any
significant changes in rRR, and conversely, significant oscillations in
rRR were not followed by any significant changes in PRA.
In conclusion, the sympathetic nervous system is not directly involved in the generation of renin oscillations observed under basal
conditions. During sleep, the oscillations in sympatho-vagal balance
are inversely related to the variations in d-wave activity and the
associated renin release. The processes that give the intermittent
signal for concomitant increases in slow wave activity and renin
release from the kidney remain to be identified. (J Clin Endocrinol
Metab 83: 1523–1528, 1998)
ulatory effect of sympathetic activation on renin secretion
either by direct electrical renal nerve stimulation or indirectly
by compression of the carotid artery sinus or b-agonist infusion (8 –11). However, the relationship between spontaneous variations in autonomic nervous system activity and
renin release has not been studied.
Heart rate variability, based on analysis of the time interval
between two electrocardiographic R waves (RR interval),
results mostly from the interaction between the sympathetic
and the parasympathetic system activities. The Poincaré plot
is a nonlinear procedure based on a scatterplot of the current
RR interval against the previous RR interval. It provides a
qualitative picture of beat to beat interval behavior (12).
Using autonomic blocking agents, it has been demonstrated
that the Poincaré plots have distinctive and characteristic
patterns according to the degree of activity of the sympathetic and parasympathetic systems (13). Quantitative measures of the Poincaré plots based on statistical evaluation of
the RR interval variance or d RR histogram have been accepted as indexes of either sympathetic or parasympathetic
activity (12). In a previous study, we calculated, every
minute, the interbeat autocorrelation coefficients of RR interval (rRR) derived from the Poincaré plot and reported that
their overnight profiles are highly related to the variations in
EEG mean frequency, which reflect deepness of sleep (14).
More recently, we demonstrated that the overnight profiles
of rRR are closely cross-correlated with the profile of low- to
1523
1524
CHARLOUX ET AL.
high-frequency power ratio. The power in the two main
frequency peaks, the high frequency and low frequency
peaks, detected by spectral analysis of RR intervals is widely
used as a quantitative measure of autonomic nervous system
activity. Therefore, rRR can be regarded as a tool to evaluate
the sympatho-vagal balance continuously in man, with an
increase in rRR reflecting an increase in sympathetic tone.
In the present study, we used this new index to establish
the potential role of the sympathetic nervous system in the
generation of PRA oscillations over the 24-h period. PRA and
rRR were determined concomitantly every 10 min in subjects
under continuous bed rest. EEG spectral analysis was used
to establish the concomitant variations in d-wave activity
during sleep. We determined the influence of the autonomic
nervous system on both the nocturnal PRA oscillations associated with increases in d-wave activity and the daytime
peaks occurring randomly in awake subjects.
Subjects and Methods
Subjects
Nine healthy male volunteers, aged 21–28 yr, gave their written
informed consent to participate in this study. They had regular sleepwake habits and did not take any medication. During the experiment,
they did not take alcohol or caffeine-containing beverages and were not
allowed to smoke or participate in sports. This study was approved by
the local ethic committee.
Procedures
The measurements were performed in a sleep room equipped for
polysomnographic recordings and blood sampling. After a habituation
night, a catheter was inserted into an antecubital vein 4 h before the
beginning of recordings and was kept patent by a heparinized solution.
Heart rate was recorded from 1800 –1800 h, and sleep recording was
carried out from 2300 – 0700 h. When awake, the subjects read, listened
to music, watched television, and conversed with an experimentor to
prevent daytime sleep. To avoid the influence of repeated meal intake,
the subjects received continuous enteral nutrition through a nasogastric
feeding tube that began 4 h before blood sampling (Sondalis, ISO,
Sopharga, Puteaux, France; 50% carbohydrate, 35% fat, and 15% protein;
378 kJ/h).
Sleep recording
Sleep recordings were based on two EEG derivations (C3-A2 and
C4-A1), one chin electromyogram and one horizontal electrooculogram
(upper canthus of one eye vs. lower canthus of the other eye). The EEG
signal was converted from analog to digital with a sampling frequency
of 128 Hz. Subsequently, spectra were computed for consecutive 2-s
periods using a Fast Fourier Transformation algorithm (15). To yield
10-min power density values, the median was calculated for 300 consecutive 2-s periods. The spectral parameter considered was d absolute
power (0.5–3.5 Hz).
Blood sampling and PRA assessment
Blood was collected from 1800 –1800 h in an adjoining room. Blood
was removed continuously using a peristaltic pump and was sampled
at 10-min intervals in tubes containing ethylenediamine tetraacetate-K2
salt. A maximum of 200 mL was removed during the 24 h. The samples
were collected in a refrigerated container and centrifuged at 4 C within
the subsequent 20 min. The plasma was immediately stored at 225 C.
PRA was measured by a RIA of angiotensin I generated after incubation
of the plasma (commercial kits, Sorin Biomedica, Saluggia, Italy). The
intraassay coefficient of variation for duplicate samples was 4% for levels
between 10 –20 ng/mLzh, 6% for levels between 2–10 ng/mLzh, 10% for
levels between 1–2 ng/mLzh, and 30% for levels below 1 ng/mLzh. The
JCE & M • 1998
Vol 83 • No 5
detection limit was 0.18 ng/mLzh. All samples from one subject were
measured in the same assay to avoid interassay variations.
Heart rate analysis
The electrocardiogram signal was fed into a generator that produces
a pulse at the rising phase of each R wave. The trigger event times were
recorded with an accuracy of 61 ms, and the RR intervals were calculated on a computer equipped with a data acquisition control board
including a timer. Each RR interval was plotted against the previous RR
interval to produce a cardiac Poincaré plot (RRn11 vs. RRn) for each
minute. The rRR values (i.e. Pearson’s correlation coefficients between
the RRn and RRn11) were calculated for each minute and averaged over
a 10-min period.
Data analysis
The pulse analysis program ULTRA (16) was used for quantitative
detection and characterization of PRA oscillations with a threshold of 3
times the coefficient of variation. This program takes into account the
limit of detection of the analytical procedure and the precision of the
assay for various ranges of concentrations. To identify the main oscillations in d absolute power and rRR, the individual profiles were analyzed using a modified pulse analysis algorithm. Taking into account the
large interindividual variability, identification of the main oscillations
was achieved using a subject-adapted threshold for detection. This
threshold was set at 20% of the maximum increment in d absolute power
or in rRR observed for each subject. During sleep, mean PRA oscillations
were obtained by averaging point by point the levels of the significant
oscillations aligned by their maximum. To calculate a mean oscillation
for the group of nine subjects, all individual pulses were averaged for
each subject, giving the subjects the same weight. Corresponding d-wave
activity and rRR levels were considered, and their variations were analyzed using an ANOVA with repeated measures (BMDP Statistical
Software, Los Angeles, CA). Similar analyses were performed during the
day. Firstly, mean significant PRA oscillations were calculated and
aligned by their maximum, and corresponding rRR levels were plotted
with regard to PRA oscillations. Secondly, the mean significant rRR
oscillations were calculated, and the corresponding PRA levels were
considered. For all of these analyses, two periods were considered: the
sleep period (2300 – 0700 h) and the subsequent waking period (0700 –
1500 h). Mann-Whitney test was used to assess the statistical differences
among the mean values, the number of oscillations, their amplitude, and
the sd for the series of data obtained during these two periods.
The temporal relationship between rRR and PRA or EEG d-wave
activity was quantified using cross-correlation analysis between two
chronological series for lags 23 to 13, each lag corresponding to 10-min
interval (Box Jenkins Time Series Analysis, BMDP Statistical Software).
For PRA, a least squared polynome was adjusted to the night and day
PRA profiles, and the polynomial values were subtracted point by point
from the series of PRA levels. The residual data were then used for
cross-correlation analysis. The level of significance for each cross-correlation coefficient was assessed by estimating the se. The se was given
by (N 2 k)21/2, where N denotes the number of samples in the series,
and k is the particular lag. The cross-correlation coefficient is considered
significant (P , 0.05) when it exceeds zero by more than 2 times the se.
Results
24-h PRA and rRR profiles
Figure 1 illustrates a 24-h profile for PRA with regard to
the profile for rRR in one representative subject. As previously described (1), large oscillations in PRA occurred during
the sleep period. Variations in PRA were also observed during the waking periods, but they were usually small, more
irregularly distributed, and variable according to individuals. The rRR coefficient decreased 15–35 min before sleep
onset and then had a series of large falls during the sleep
period before returning to high initial levels during the subsequent waking period, thus indicating sympathetic activa-
PRA, SYMPATHETIC ACTIVITY AND SLEEP
tion. Table 1 summarizes the results obtained in the nine
subjects. Mean PRA levels were significantly higher during
sleep than during the waking period. In contrast, the rRR
levels were significantly lower during the sleep period. However, for both PRA and rRR, the amplitude, number of oscillations, and sd of the data were higher during the 8-h sleep
period than during the subsequent 8-h waking period. In the
nine subjects studied, the overnight profiles of rRR showed
coordinate variations with the low/high frequency power
ratio, a customary measure of sympatho-vagal balance. The
cross-correlation coefficients ranged between 0.468 – 0.805
(P , 0.001).
1525
cients ranging respectively between 20.30 and 20.65 (P ,
0.001 in all subjects but one) and between 20.29 and 20.65
(P , 0.05). rRR variations preceded PRA oscillations with a
10-min lag in most subjects (Table 2). During the sleep periods, in the 9 subjects, 29 significant oscillations of PRA were
detected using the ULTRA program. Figure 3 shows the
Sleep period
Figure 2 illustrates the concomitant profiles of PRA, d
absolute power, and rRR in a representative subject during
sleep. d absolute power and PRA oscillations were positively
correlated with cross-correlation coefficients ranging between 0.29 – 0.65 (P , 0.05). Oscillations in d-wave activity
were concomitant with or preceded PRA oscillations by 10
min. rRR was inversely correlated with d absolute power and
the associated renin release, with cross-correlation coeffi-
FIG. 1. Twenty-four-hour profiles of PRA and rRR in a representative
subject.
FIG. 2. Concomitant overnight profiles of PRA, absolute d power, and
rRR, after z-score transformation, in a representative subject. Ascending phases of d absolute power indicate sleep deepening. Ascending phases of rRR indicate increased sympathetic activity.
TABLE 1. Characteristics of the significant oscillations in PRA and of the autocorrelation coefficient of RR intervals (rRR) during the 8-h
sleep period and the subsequent 8-h waking period in nine subjects
PRA
Mean levels (ng/mLzh)
No. of oscillations
Absolute amplitude of oscillations (ng/mLzh)
SD
rRR
Mean levels
No. of oscillations
Absolute amplitude of oscillations
SD
Values are the mean 6
SE.
Sleep period
Waking period
P
1.69 6 0.19
3.2 6 0.3
1.52 6 0.09
0.69 6 0.07
1.17 6 0.13
1.8 6 0.3
0.91 6 0.15
0.31 6 0.03
0.05
0.004
0.003
0.001
0.37 6 0.03
3.0 6 0.3
0.51 6 0.08
0.15 6 0.01
0.58 6 0.04
1.7 6 0.4
0.22 6 0.09
0.10 6 0.01
0.008
,0.001
,0.001
,0.001
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CHARLOUX ET AL.
JCE & M • 1998
Vol 83 • No 5
TABLE 2. Cross-correlation coefficients (r) and lags between
PRA, absolute delta power (delta), and the autocorrelation
coefficient of RR intervals (rRR) during the sleep period and the
subsequent 8-h waking period
Sleep period
Subject
no.
1
2
3
4
5
6
7
8
9
Delta/PRA
Waking period
rRR/Delta
rRR/PRA
rRR/PRA
Lag
r
Lag
r
Lag
r
Lag
r
0
21
22
21
0
21
0
0
21
0.29a
0.51b
0.42c
0.58b
0.47b
0.29a
0.52b
0.65b
0.32a
21
0
21
21
0
21
0
21
0
20.56b
20.48b
20.57b
20.55b
20.65b
20.30a
20.53b
20.53b
20.58b
21
21
22
22
21
21
21
22
21
20.29a
20.48b
20.45c
20.59b
20.65b
20.38c
20.48b
20.30a
20.53b
1
1
1
21
2
21
3
23
1
0.27
0.16
20.25
0.27
0.27
20.35a
20.39c
0.31a
20.20
Each lag corresponds to a 10-min bood sampling interval. For
negative lags, the first variable precedes the second one.
a
P , 0.05.
b
P , 0.001.
c
P , 0.01.
mean values of PRA oscillations aligned by their maximum
together with the oscillations in d absolute power and the
inverse oscillations in rRR.
Waking period
During the 8-h waking period, pulse analysis of the residual profiles revealed the existence of 16 significant PRA
oscillations in the 9 subjects. These oscillations in PRA were
not associated with any systematic changes in rRR (see example in Fig. 1). The cross-correlation coefficients between
PRA and rRR ranged between 20.39 and 10.31, with a lag
between 230 and 120 min (Table 2). The mean curves are
given in Fig. 4, which illustrates the absence of a temporal
association between the daytime PRA oscillations aligned by
their maximum and concomitant rRR time courses. Similarly,
the 15 significant daytime oscillations of rRR aligned by their
maximum were not associated with any significant variation
in PRA (Fig. 5).
Discussion
These results demonstrate clear sleep-wake differences in
the relationship between sympatho-vagal balance and renin
release. During the sleep period, large decreases in the rRR,
which was used as an index of sympatho-vagal balance,
preceded increases in d-wave activity and the associated
renin release. Changes in sympathetic activity opposed
changes in d-waves, which reflect sleep deepening and lightening, and also opposed oscillations in PRA, which is normally stimulated by sympathetic nerve activity. In contrast,
rRR during the day was higher with smaller variations, and
renin oscillations were not associated with any significant
variations in sympatho-vagal balance.
The role of the sympathetic nervous system in renin secretion has been defined thanks to animal experiments that
focused on the effect of one particular stimulus, i.e. electrical
stimulation of renal nerves, compression of the carotid artery
sinus, or intraarterial administration of b-adrenergic agonists to rat kidney and incubation of rat kidney slices in
catecholamine-containing medium (7–10). In these experi-
FIG. 3. Mean 6 SE PRA and d absolute power together with the
opposite variations in rRR during the sleep period in nine subjects.
Significant PRA oscillations were aligned by their maximum.
ments, renin release followed a dose-response pattern and
could be prevented by b-blockers (7, 10, 17). However, these
experimental conditions cannot be compared to the physiological stimuli of the sympathetic system observed in daily
life. Moreover, the physiological implications of these experiments are limited by the fact that in conscious subjects,
all stimuli responsible for renin secretion are acting
simultaneously.
In the present experiment, oscillations of PRA in awake
subjects were not preceded by a rise of rRR, and a significant
increase in rRR was not followed by a rise in PRA. It is likely
that sympathetic stimulation in continuously recumbent subjects is too low to produce increases in renin release. Moreover, it has been demonstrated that isoproterenol, a badrenergic agonist, only has a significant effect on renin
release at low blood pressure levels (11). In our healthy
subjects, who have intact renal autoregulation and normal
blood pressure, light sympathetic stimulation is not able to
increase renin release.
During sleep, an inverse cross-correlation between rRR
and PRA was observed; the rises in PRA and slow wave
PRA, SYMPATHETIC ACTIVITY AND SLEEP
FIG. 4. Mean 6 SE PRA and the concomitant values of rRR during the
waking period in nine subjects. Significant PRA oscillations were
aligned by their maximum.
FIG. 5. Mean 6 SE rRR and of the concomitant values of PRA during
the waking period in nine subjects. Significant rRR oscillations were
aligned by their maximum.
activity were preceded by a decrease in sympathetic activity,
as reflected by a decrease in rRR. Assessment of rRR offers
a precise characterization of moment to moment changes in
sympatho-vagal activity in relation to changes in brain activity and renin release. Using microneurography (18, 19) or
spectral analysis of RR intervals (13, 20, 21), it has been
previously reported that rapid eye movement (REM) sleep is
associated with profound sympathetic activation, and
NREM sleep is associated with a predominance of parasympathetic activity. The Poincaré plots, generally based on 5- to
20-min sleep recording, give different patterns according to
1527
sleep stages, as demonstrated by pharmacological tests, reflecting reciprocal sympathetic and vagal influences (13).
However, the precise time courses of PRA variations and
EEG mean frequency with regard to variations in sympathovagal activity have not been reported yet.
In experiments performed on isolated or in situ perfused
rat kidney, the delay between arterial isoproterenol infusion
and renin release was very short, i.e. less than 5 min (9, 17).
According to these studies, the rise in PRA observed during
increments in slow waves cannot be attributed to the increase
in sympathetic activity observed concomitantly to decreases
in slow waves. Therefore, it can be concluded that the oscillations in sympatho-vagal balance are not directly involved in generation of the nocturnal oscillations in PRA.
Thus, the nocturnal oscillations in PRA may be generated
by peripheral feedback mechanisms or by sleep-related processes. Scarcely any data have been published on variations
in renal arterial pressure and sodium chloride concentration
at the macula densa during sleep. In man, studies reported
a fall in systemic arterial pressure during slow wave sleep
and a large variability in blood pressure during REM sleep
(18, 22). It is possible that the oscillations in PRA reflect
oscillations in blood pressure, with low perfusion pressure of
the juxtaglomerular apparatus eliciting a release of renin
during NREM sleep. If this hypothesis is correct, then the
sympathetic nervous system is indirectly responsible for renin release during sleep by the mechanism of low blood
pressure. However, the precise temporal relationship between peripheral factors and PRA oscillations has not yet
been described, and the potential roles of these peripheral
factors in generating PRA oscillations have yet to be
evaluated.
The hypothesis according to which central processes related to sleep may play an essential role is supported by
previous studies that demonstrated that the association between sleep stage alternation and PRA cannot be broken
(2–5). This argues in favor of a central control of renin, coupled with or regulated by sleep control processes. Experiments performed in the rat support this hypothesis. The
administration of a serotonin releaser produces a dosedependent increase in renin secretion (23). Discrete cellselective lesions have shown that this increase in PRA is
mediated by neurons in the paraventricular nucleus of the
hypothalamus (24). A renin-releasing factor, which is probably a peptide, has been partially characterized from rat
plasma and hypothalamus (25). The role of the serotoninergic
system in renin secretion during sleep has not yet been confirmed in humans.
In summary, there is a positive relationship between
d-wave activity and PRA oscillations, whereas d-wave activity and PRA oscillations are inversely related to variations
in sympatho-vagal activity, continuously evaluated by rRR.
These temporal links argue in favor of a central generator
synchronizing renin release and autonomic and sleep processes. The inverse temporal relationship between sympathetic activity and renin release, which is normally stimulated by sympathetic nerve activity, raises the question of
how the common processes for concomitant increases in slow
waves and renin release function.
1528
CHARLOUX ET AL.
Acknowledgments
We are indebted to Béatrice Reinhardt and Michèle Siméoni for PRA
measurements, and to Daniel Joly for sleep recording. We also thank Dr.
Eve Van Cauter for providing the ULTRA program.
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Festschrift In Honor of Maria I. New
September 23–24, 1998
To honor Maria New for her lifetime achievements in pediatric endocrinology, a one day symposium will
be held at the Villa Medicea “La Ferdinanda” in Artimino near Florence, Italy on 9/23–9/24/98. This
conference will be held in conjunction with the annual meeting of the European Society for Pediatric
Endocrinology in Florence.
For further information please contact: Paul Saenger, M.D., Division of Pediatric Endocrinology, Montefiore
Medical Center/Albert Einstein College of Medicine, 111 East 210th Street, Bronx, New York 10467. Telephone: 718-920-4664; Fax: 718-405-5609; E-mail: [email protected].