(Hypertension. 1997;30:71-76.)
© 1997 American Heart Association, Inc.
Articles |
Plasma Epinephrine and Norepinephrine Concentrations of Healthy Humans Associated With Nighttime Sleep and Morning Arousal
From the Department of Internal Medicine I, Clinical Research Group "Clinical Neuroendocrinology," Medical University of Lübeck (Germany).
Correspondence to Christoph Dodt, MD, Department of Internal Medicine I, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, FRG.
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Abstract |
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Abstract We assessed the activity of the sympathetic nervous system during undisturbed nocturnal sleep and periods of wakefulness directly before and after sleep in healthy young men. Changes induced by periods of rapid eye movement and by morning awakening, both periods reported to demonstrate an enhanced risk for the onset of cardiovascular diseases, were of particular interest. In 13 healthy men (age, 18 to 35 years), blood for determination of epinephrine and norepinephrine was drawn every 7 minutes between 9:30 PM and 8:30 AM with the subjects resting in a strictly horizontal position. Lights were switched off at 11 PM until awakening at 7 AM. At 8:30 AM, subjects stood up and a final blood sample was drawn. Sleep was monitored somnopolygraphically, and heart rate and blood pressure were continuously measured. Average epinephrine but not norepinephrine concentrations were significantly lower during nocturnal sleep than during wakefulness before and after sleep. In parallel, heart rate and blood pressure declined significantly during sleep. During rapid eye movement sleep, both epinephrine and norepinephrine concentrations were significantly lower than during sleep stages 1 and 2 and slow-wave sleep. Whereas epinephrine concentrations gradually began to increase after morning awakening, norepinephrine levels were not significantly enhanced. However, standing up at the end of the experiment sharply increased norepinephrine concentrations by 180%, whereas epinephrine levels were less enhanced (46%) by the change of body position. This study suggests that the decrease in the activity of the sympathoadrenal branch of the sympathetic nervous system is probably due to an entrainment to the sleep-wake cycle, whereas the low activity of the noradrenergic branches depends mainly on horizontal body position during nocturnal sleep. The activities of the sympathoadrenal and noradrenergic branches of the sympathetic nervous system seem to be downregulated during rapid eye movement sleep. Awakening itself selectively enhances epinephrine levels. Subsequent orthostasis activates both the sympathoadrenal and, most prominently, the noradrenergic branches of the sympathetic nervous system.
Key Words: epinephrine • sympathetic nervous system • norepinephrine • sleep • human
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Introduction |
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The onset of cardiovascular diseases such as sudden cardiac death, myocardial infarction, and ischemic stroke is subject to a clear circadian rhythm: peak rates occur during the morning hours after awakening, with such events least likely to occur during the nighttime.1 2 3 This could be the consequence of changes in the activity of the sympathetic nervous system (SNS) occurring during nocturnal sleep or associated with the process of awakening.
A connection between central nervous sleep processes and SNS activity in humans has been demonstrated in several studies. The sympathetic outflow to the heart,4 the muscle vascular bed, and sympathetic effector organs of the skin has been shown to be reduced5 6 7 8 during phases of non–rapid eye movement (REM) sleep compared with wakefulness. Some studies focusing on catecholamine concentrations as a parameter for circadian changes in SNS activity have suggested that lower levels of epinephrine9 10 11 12 and norepinephrine10 11 12 13 occur during the nighttime, but unchanged nocturnal concentrations have also been reported for both catecholamines.9 14 15 However, a comparison among these studies is difficult because the study protocols differed, particularly with regard to the control of body position and physical activity. Also, only a few studies monitored sleep, and there is even less information on changes in catecholamine concentrations in relation to the different sleep stages.
SNS activity during REM sleep could be of particular clinical interest. This period is characterized by short-term hemodynamic changes,16 and it has been hypothesized that SNS activity is enhanced during this period, which could induce cardiovascular diseases in people at risk.17 18 19 In fact, microneurographic methods continuously measuring SNS activity have demonstrated dynamic changes during short periods of nocturnal and daytime REM sleep, with an enhanced sympathetic outflow to the muscle vascular bed.5 6 7 Such changes in SNS activity have been reported to correlate with plasma norepinephrine concentrations.20 Therefore, the determination of plasma norepinephrine concentrations allows an appropriate assessment of SNS activity throughout the night that is difficult to perform with more invasive methods, such as microneurography or the determination of regional catecholamine spillover. Furthermore, the determination of plasma epinephrine concentrations in the same blood sample allows a reliable assessment of sympathoadrenal activity. However, considering the dynamics of sleep processes with short REM periods 10 to 15 minutes long during the first half of the night and rapid catecholamine clearance within minutes,21 it seems to be essential to determine catecholamine concentrations as frequently as possible. Studies reporting on epinephrine and norepinephrine levels during different sleep stages that sampled blood every 2022 or 3012 minutes may have missed some of the REM phases, especially during the first half of the night. This could explain why some studies observed differences in catecholamine concentrations between REM sleep and slow-wave sleep (SWS) and wakefulness23 and others failed to find REM sleep–specific changes in SNS activity.12 22 Therefore, in the present study, we sampled blood frequently (every 7 minutes) to determine catecholamine concentrations to assess the relationship between SNS activity and nocturnal sleep with its different sleep stages.
Considering the well-known preponderance of cardiovascular accidents during the morning, a second important aspect of this study was the evaluation of changes in SNS activity induced by the awakening process after physiological nocturnal sleep. A detailed knowledge of SNS activity during this critical period could be important for the timing of sympathoinhibitory drugs such as ß-blockers to minimize the risk of the onset of cardiovascular diseases. With this background, the present study also examined plasma catecholamine concentrations during a 90-minute period after the nocturnal sleep period and after arousal from the horizontal position.
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Methods |
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Thirteen nonsmoking male subjects (age, 18 to 35 years) participated in the study. They were healthy, drug-free, and did not report any sleep disturbances. They did not work a night shift at least 2 weeks before the experiment. Subjects were asked to maintain their normal diet but had to abstain from tea and coffee on the day of the experiment. The last meal before the start of the experimental session was ingested between 4 and 6 PM. The study was approved by the local ethics committee, and all participants gave written informed consent.
Subjects had adjusted to the experimental setting by spending 1 prior night under the conditions of the experiment. On the experimental night, subjects arrived at the laboratory at 8 PM and were prepared for blood sampling, physiological sleep recordings, and blood pressure recordings. Beginning at 9 PM, they rested in a strictly horizontal position but remained awake for at least 2 additional hours until 11 PM, when lights were turned off. Subjects woke up spontaneously before 7 AM (n=2) or were gently awoken at 7 AM the next day but remained in a strictly horizontal position until 8:30 AM. At this time, subjects were asked to stand up.
For blood sampling, a catheter was inserted into a forearm vein and connected to a long, thin plastic tube that enabled blood collection from an adjacent room without disturbing the subject's sleep. Blood was sampled every 7 minutes starting at 9:30 PM until 8:30 AM. A final sample was collected 10 minutes after subjects had stood up. The removed blood volume was substituted by a continuous isotonic saline infusion totaling a volume of 300 mL. Blood samples were centrifuged immediately, and plasma was stored at -80°C until assay. Plasma norepinephrine and epinephrine levels were determined by high-performance liquid chromatography with electrochemical detection. The sensitivity was 35.64 pmol/L for norepinephrine and 35.46 pmol/L for epinephrine. The interassay coefficients of variation were 6.1% and 5.6% for norepinephrine and epinephrine, respectively.
Electroencephalogram, electrooculogram, and electromyogram were recorded continuously between 11 PM and 7 AM and were scored off-line according to the criteria of Rechtschaffen and Kales.24
Blood pressure was continuously measured at the finger with the Finapres device (Ohmeda Monitoring Systems). This noninvasive method photoplethysmographically measures relative changes in blood pressure.25 The position of the finger equipped with the Finapres cuff was kept constant by fixating the arm. This allowed a sleeping position either on the back or the front but not on the side. To acquaint the subject with this procedure, he had to fixate his arm in a similar way during 2 preceding nights at home and 1 additional night in the sleeping laboratory before the adaptation night.
Data Analysis
For each night, total sleep time and the percentage of time
spent in the different sleep stages (wakefulness: W; sleep stages 1 and
2: S1 and S2; SWS: corresponding to S3+S4; and REM sleep) were
calculated with reference to the total sleep time. The total sleep time
lasted from sleep onset, defined as the onset of the first S1 epoch
followed by S2 sleep, until final awakening. Sleep onset latency was
computed with reference to the time when lights were switched off.
Latencies of S2, SWS, and REM sleep were determined with reference to
sleep onset.
Average values were calculated of plasma epinephrine and norepinephrine concentrations and of heart rate and systolic and diastolic pressures during the period of wakefulness before sleep onset (between 9:30 PM and sleep onset), during the sleep period, and during the period of wakefulness following sleep (between final awakening at or before 7 and 8:30 AM). Also, average values were calculated for these parameters separately for the time spent in the different sleep stages. These calculations were based on plasma catecholamine concentrations for subsequent 30-second intervals, which were estimated by linear interpolation.
Ultradian rhythms in the time series of plasma catecholamine concentrations, heart rate, and systolic and diastolic pressures were evaluated using autocorrelations. Autocorrelation functions can be used to detect periodic oscillations in a time series of data. The function is calculated by correlating the time series of a variable that has the same time series with a stepwise increasing time displacement, ie, at successively increasing time lags. The correlation functions were determined for each individual night, and after Fisher's z transformation,26 average correlations were computed.
Statistical evaluations of the effects of sleep versus wakefulness and of the effects of the different sleep stages, plasma catecholamine concentrations, and cardiovascular measurements relied on ANOVA and subsequent pairwise comparisons between the effects of any two conditions. Degrees of freedom were adjusted after the method of Greenhouse-Geisser. A value of P<.05 was considered significant.
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Results |
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Sleep
Means (±SEM) for the different sleep parameters are shown in the Table
. Subjects slept an
average of 7.5 hours until final awakening. All sleep stages
were passed in each subject, with a mean of 22.4% of total sleep time
spent in SWS and 17.6% in REM sleep. Sleep in all but three subjects
was interrupted by short, spontaneously occurring phases of
wakefulness. As expected, SWS dominated during the first half of sleep
(mean±SEM: 31.0±0.04%, compared with the second half: 13.8±0.03%;
P<.05), whereas REM sleep dominated in the second half of
sleep (24.2±0.02%, compared with the first half: 11.0±0.03%;
P<.005). Together, the sleep patterns indicated a preserved
physiological structure of sleep under the
conditions of the experiment.
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Plasma Catecholamines
Plasma concentrations of epinephrine declined
significantly after sleep onset and increased gradually after awakening
in the morning, resulting in substantially lower average plasma
concentrations of epinephrine during sleep than during awake
periods before and after sleep. In contrast, a tendency toward a
similar decline in norepinephrine concentrations during
nocturnal sleep did not reach significance compared with the periods
before and after sleep, during which subjects were confined to a
horizontal position but were awake (Figs 1 through 3).
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P<.01, 
P<.005,
P<.001.
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Within non-REM sleep, sleep stage had no effect on plasma
catecholamine levels. However, epinephrine and
norepinephrine concentrations were significantly lower
during REM sleep than during any of the non-REM sleep stages (Fig 4). During spontaneous intermittent phases of
wakefulness within the period of nocturnal sleep, epinephrine
and norepinephrine levels (92.4±23.0 and 615.4±67.8
PMol/L, respectively; mean±SEM) did not differ
significantly from those of non-REM sleep (81.8±19.0 and 616.5±51.4
pmol/L).
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Standing up from the horizontal position elevated epinephrine levels from 120.3±26.9 to 177.1±36.3 pmol/L (P<.05) and norepinephrine levels from 778.76±88.9 to 2202.7±247.55 pmol/L (P<.001).
To test whether a single determination of plasma catecholamines 10 minutes after standing up accurately reflects SNS activation caused by orthostasis, we performed a supplementary experiment in seven additional men. After sleeping 1 night in the laboratory under the same conditions as the subjects of the main study, subjects woke up at 7 AM and remained strictly horizontal for 30 minutes. Subsequently, they were asked to stand up and remain in an upright position for an additional 30 minutes. Blood was drawn every 7 minutes throughout the periods of supine and upright body position. Concentrations of both catecholamines sharply increased after standing up. Compared with the mean of the supine period, epinephrine increased from 120.7±10.7 to 197.9±29.3 pmol/L (64%) and norepinephrine from 1075.2±48.9 to 3213.4±212.5 pmol/L (200.5%; P<.05 and P<.001, respectively). This increase was comparable to that seen in the initial study. Furthermore, during the standing period, the average catecholamine concentrations at the single time points did not differ significantly. These results confirm those of the initial study based on a single blood collection after 10 minutes of standing.
Plasma catecholamines fluctuated considerably during the individual nights, resulting in a variable number of peaks and troughs. However, calculation of autocorrelations did not show any regular rhythm in epinephrine and norepinephrine plasma concentrations. Furthermore, a supplementary analysis aiming to assess the association of increasing and decreasing plasma epinephrine and norepinephrine concentrations with any of the sleep stages indicated that negative and positive slopes in the time course of plasma catecholamine concentrations were evenly distributed across the different sleep stages.
Cardiovascular Parameters
Heart rate and systolic and diastolic
pressures were significantly higher during periods of wakefulness
before and after sleep than during sleep (Fig 1
). Within the period of
sleep, heart rate levels were significantly lower during REM sleep than
during any other sleep stage (Fig 4). A parallel decrease during REM
sleep was not observed for blood pressure. In the 10 subjects
displaying spontaneous awakenings during nocturnal sleep, heart rate
and systolic and diastolic pressures during
awakenings were 56.8±1.5 beats per minute, 116.8±2.5 mm Hg, and
63.4±2.1 mm Hg, respectively, which did not significantly differ from
values during non-REM sleep (55.9±1.5 beats per minute,
117.3±2.8 mm Hg, and 63.2±1.7 mm Hg).
Autocorrelation functions did not indicate any clear ultradian rhythm underlying the oscillations in cardiovascular activity.
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Discussion |
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The present study examined changes in plasma catecholamine concentrations associated with states of wakefulness and sleep, including non-REM and REM sleep. Falling asleep was followed by a decrease in epinephrine levels, whereas awakening induced an increase in epinephrine. This could be explained by a direct suppressive effect of central nervous sleep processes or a circadian pacemaker entraining sleep events and sympathoadrenal activity. In fact, a circadian rhythm for epinephrine concentrations with lowest levels during the nighttime has been observed in earlier studies using less frequent determination of epinephrine in urine or plasma.9 10 11 Also, Linsell et al,12 who determined epinephrine concentrations every 30 minutes over 25 hours, described a circadian rhythm with a trough during the night. In contrast, Cameron et al14 did not observe any significant nocturnal epinephrine decline. Those authors suggested that changes in posture or physical activity might be responsible for the decrease in epinephrine levels in other studies. However, our study clearly separated the effect of awakening from the effect of assuming an upright posture. This suggests that the sleep process itself is tightly connected to the circadian regulation of sympathoadrenal activity. The lack of a change in epinephrine concentrations during spontaneous nocturnal awakenings does not argue against this assumption since those interspersed periods may be too short to act as a stimulus of epinephrine release. However, for a conclusive statement concerning the presumed direct influence of sleep processes on epinephrine secretion, studies introducing shifts of the sleep period are necessary.
Notably, a sleep-associated significant reduction in plasma norepinephrine concentrations was not observed, which seems to contradict a repeatedly reported circadian rhythm in norepinephrine levels, with lowest values during the night.10 11 12 13 Those studies focused on circadian rhythmicity and monitored the catecholamine levels throughout an entire 24-hour period. Some of the early studies did not control for body position and physical activity,9 10 11 and thus, the observed catecholamine changes could probably be attributed to changes in the rest-activity cycle. However, most studies adequately controlled for physical activity throughout the 24-hour period.12 13 24 In contrast to studies focusing on circadian rhythmicity, our study compared SNS activity during 90-minute periods directly before and after sleep with the respective nocturnal parameters in subjects strictly confined to a horizontal position. With this approach, the lack of a significant decline in norepinephrine concentrations indicates that the level of consciousness represents, if at all, only a weak factor in the regulation of global noradrenergic SNS activity and cannot be responsible for the circadian rhythm in norepinephrine levels observed in previous studies. The reported norepinephrine differences between waking and sleeping conditions in other studies could rather be the consequence of activating factors during the day besides physical activity, such as the perception of stress,27 the ingestion of meals,28 or a change in body position, ie, from a horizontal sleeping position during the night to a recumbent sitting position during the day.29
The occurrence of decreased epinephrine and norepinephrine concentrations during REM sleep suggests that a suppression of SNS activity prevails during this period. Studies sampling blood less frequently did not report any change in catecholamine concentrations during desynchronized sleep.12 22 However, a sampling rate every 20 minutes may not provide a reliable estimate of plasma catecholamine concentrations during REM sleep periods, which on average are shorter than the sampling interval. A similar explanation may account for the discrepant findings between the present study and experiments by Prinz et al.23 Those authors, drawing a single blood sample after 5 minutes of the first cycle of persistent SWS and REM sleep, observed a decrease in norepinephrine concentrations during both SWS and REM sleep. The fact that a decrease in plasma catecholamine concentrations can be observed only with the use of continuous rapid blood sampling might suggest that the SNS-suppressive effect of REM sleep is not completely established in the beginning of REM but becomes significant during longer REM sleep periods, prevailing during the second half of the night.
The finding of reduced norepinephrine plasma concentrations during REM sleep seems surprising in the face of the repeatedly reported increase of microneurographically recorded sympathetic nerve traffic to the muscle vascular bed during this sleep stage.5 6 7 However, experiments in animals indicate that during REM sleep, sympathetic outflow to the muscle vascular bed increases while norepinephrine spillover is reduced in other organ systems, such as the splanchnic vascular bed, kidneys, or heart.30 It is estimated that skeletal muscle is responsible for around 20% of total body norepinephrine spillover,21 and this portion is probably reduced during nocturnal inactivity of the musculature. Thus, the effect of REM sleep could well result in a net decline of plasma norepinephrine levels despite an enhanced muscle sympathetic nerve activity.
Awakening enhances catecholamine levels compared with the nighttime period, which could be one important factor triggering the onset of cardiovascular diseases in people at risk. However, it is not known whether awakening itself or the onset of physical activity is responsible for the onset of cardiovascular diseases. Our present data clearly show that the morning activation of the SNS consists of two different steps: In awake but still horizontally resting subjects, only the sympathoadrenal branch of the SNS is stimulated. Subsequent orthostasis induces a strong excitation of the noradrenergic branches of the SNS, together with a further increase in epinephrine levels.
The clinical relevance of the stepwise activation of the SNS is underlined by the observation of an enhanced platelet aggregability in the morning, which is not observed in awake but recumbent subjects and is observed after the onset of physical activity.31 This might suggest that the onset of physical activity represents a particularly dangerous triggering factor for the onset of cardiovascular accidents. However, even the relatively small increase in epinephrine levels after awakening may be relevant in people at risk because the end-organ sensitivity to catecholamines is likely to be enhanced as a consequence of the low nighttime levels.32 33 Furthermore, epinephrine levels reaching the heart are higher than those determined in the antecubital venous blood.
In conclusion, nocturnal SNS activity is differentially affected by sleep and posture. Whereas the sympathoadrenal branch depends on both posture and sleep, the noradrenergic branches are mainly regulated by changes in posture. Both epinephrine and norepinephrine levels are reduced during REM sleep. Awakening immediately enhances sympathoadrenal SNS activity and subsequently, once an upright posture is assumed, the activity of noradrenergic branches is enhanced. The changes in SNS activity during nocturnal sleep and the events occurring during morning awakening may be relevant for the onset of cardiovascular diseases in people at risk, and this should be considered in the prophylactic treatment of these individuals.
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Acknowledgments |
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This work was supported by the Deutsche Forschungsgemeinschaft. The excellent technical assistance of Christiane Zinke and preparation of the figures by Anja Otterbein are gratefully acknowledged. This work is dedicated to Prof Klaus Sack, MD, on the occasion of his 60th anniversary.
Received July 30, 1996; first decision August 26, 1996; accepted December 10, 1996.
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