Vasopressin regulates human sleep by reducing rapid-eye-movement sleep J. BORN,
C. KELLNER,
D. UTHGENANNT,
W. KERN,
AND
H. L. FEHM
Abteilung Psychophysiologie, UniversiCit Bamberg, W-8600 Bamberg; and Medizinische Medizinische Universit& Liibeck, 2400 Liibeck, Federal Republic of Germany. Born, J., C. Kellner, D. Uthgenannt, W. Kern, and H. L. Fehm. Vasopressin regulates human sleep by reducing rapid-eye-movement sleep. Am. J. Physiol. 262 (Endocrid. Me&&. 25): E295-E300, 1992.-In two double-blind experiments, effects of intravenous infusion of arginine vasopressin (AVP) on sleep were evaluated in 2 groups of 10 men (20-35 yr). In experiment I, subjects were tested on two occasions, during which they received either placebo or 0.33 IU/h AVP. In experiment II, on three different occasions, subjects received either placebo or 0.66 or 0.99 IU/h AVP. Infusions were administered between 2200 and 0700 h. Nocturnal plasma AVP concentrations were close to the upper limit of the normal physiological range during 0.66 IU/h AVP (16.6 t 2.2 pg/ml) but markedly exceeded this range during 0.99 IU/h AVP (25.0 & 1.6 pg/ml). Results indicate primary effects of AVP on rapideye-movement (REM) sleep, with moderate reductions in REM sleep during 0.33 IU/h AVP (averaging -10.5%) and with substantial reductions in REM sleep (-24.0%) during 0.66 IU/ h AVP. During 0.99 IU/h AVP the effect did not further increase (-24.4%). Less consistent effects of AVP were an increase in stage 2 sleep and in time awake. Effects of AVP were not mediated by changes in cortisol or blood pressure. Results suggest AVP to participate in REM sleep regulation under normal physiological conditions. arginine vasopressin; slow-wave sleep; arousal; blood pressure; cortisol THE NEUROHORMONE VA~OPRESSIN (VP) has been shown to exert important actions on central nervous functions and different behaviors in animals, apart from
its role in the regulation of water homeostasis. In rats, subcutaneous or intracerebroventricular administration of VP improved memory of avoidance behavior (10, 18, 20). Moreover, AVP has been found to decrease overall spectral power of the cortical electroencephalogram (EEG) in these animals, indicating that rats given VP were less drowsy but more aroused during the recording periods than rats given saline injections (12). That in these experiments similar changes were obtained with systemic vs. central administration of VP suggests a common brain state may be induced by the two routes of administration. Some evidence exists that VP increases cortical arousal also in healthy human subjects after intranasal administration (14, 24), whereas direct effects of the peptide on human memory functions are still discussed controversially (3, 14, 16, 26). Besides a general arousing effect, specific influences of VP on sleep and the sleep-wake cycle have been demonstrated. Rats with hereditary diabetes insipidus (Brattleboro rats) displayed a slowing of the hippocampal theta rhythm during rapid-eye-movement (REM) sleep that was normalized after administration of VP (28, 29). In another study (8), such rats showed reduced REM sleep and slow-wave sleep (SWS). After intravenous
Klinik,
infusion of VP, but also when the normal daily water intake was infused intravenously, normal or increased amounts of both sleep stages occurred; however, the findings of deficits in REM sleep and SWS could not be replicated in Brattleboro rats obtained from another breeding colony (7). Unlike Brattleboro rats, normal rats infused with VP did not display enhanced REM sleep or SWS (1, 19). Consonant with an arousing effect of VP in these rats, continuous intracerebroventricular infusion of the peptide increased the time spent awake (1,19) and reduced the time spent in REM sleep or quiet sleep (19). In one of these studies (19), changes in awake time, quiet sleep, and REM sleep concentrated on the dark period (active) and were not apparent during the light period (rest) of the nychthemeron, thus resulting in an increased amplitude of the sleep-wake cycle. Although animal studies provide considerable evidence that VP acts to modify sleep, either directly or via changes in arousal or sleep-wake regulation, to our knowledge, so far only one study has been reported investigating the effects of VP in human beings (27). In these experiments, after intranasal administration of lysine-VP (7 or 14 IU), a slight but significant increase in stage 2 (S2) sleep was observed. At the same time, stage 3 sleep and REM sleep tended to be reduced; however, in view of the small size of the effects, the authors seemed reluctant to attribute these changes to the hormone’s action. The present experiments were designed to examine whether VP affects human sleep. Unlike Timsit-Berthier et al. (27), using an intranasal administration of VP, we infused the hormone intravenously at a constant rate. Plasma VP concentrations were determined during sleep to ascertain that stable increases in plasma VP levels were achieved. Moreover, by testing different doses of VP (0.33,0.66, and 0.99 IU/h), dose-response characteristics of the effects of AVP on sleep could be evaluated. METHODS Two experiments were conducted. In each, 10 healthy men (students of the medical school), aged between 20 and 35 yr (mean 26.7 yr) in experiment I and between 23 and 30 yr (mean 25.2 yr) in experiment 11 participated. None of the subjects of experiment I also participated in experiment II. All subjects were nonsmokers, and none had a history of sleep disturbances. It was ascertained that the subjects’ weight (deviation ~15% from reference, according to Broca index) and height were within the normal range. Physical examination excluded any cardiovascular abnormalities. Three of the subjects in experiment I and five subjects in experiment II regularly participated in physical exercises at least two times per week. Subjects were required to get up before 0700 h on the day of
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Society
E295
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E296
AVP AND SLEEP
an experimental night and not to take any naps during the day. They were acclimated to the experimental sleep conditions by spending one night under the conditions of the experiment, including the placements of catheters and the infusion of placebo (saline solution). The experiments were approved by the Committee on Research Involving Human Subjects of the University of Ulm. Procedure and design. The experiments took place in an airconditioned room. Upon arrival at the laboratory, subjects were prepared for somnopolygraphic recording and blood sampling. Continuous recordings were obtained from 2300 h, when lights were turned off, to 0700 h, when the subjects were awakened. In the morning, each subject was asked whether he thought he received an active agent or placebo. Two intravenous forearm catheters were placed, one for infusion of treatment substances, the other (placed distally to the infusion catheter) for blood sampling during the experimental nights. This catheter was connected to a long thin tube (vol 1.5 ml), which enabled blood collection from an adjacent room without disturbing the subject’s sleep. To prevent clotting of this catheter, -200 ml of saline solution were infused throughout the night. In experiment I, subjects were studied on two occasions, in addition to the first adaptation night. In one condition, arginine vasopressin (0.33 IU/h AVP diluted in 11 ml/h saline solution; Pitressin; Parke Davis, Berlin, FRG) was infused at a constant rate from 2200 to 0700 h; in the other condition, placebo (11 ml/h saline solution) was infused during the same time interval. The order of presentations of these experimental conditions was counterbalanced, with half of the subjects receiving first placebo and then AVP and the other half receiving first AVP and then placebo. In experiment II, subjects were studied on three occasions, in addition to the first adaptation night. During one condition, placebo (11 ml/h) was infused constantly; during the other conditions, AVP was infused at a rate of either 0.66 or 0.99 IU/ h (diluted in 11 ml/h saline solution). As in experiment I, infusions started at 2200 h and lasted until 0700 h. The order of presentations of the three experimental conditions was counterbalanced across subjects according to a Latin square. In both experiments, any two experimental nights for a subject were separated by an interval of at least 10 days. Both experiments were held double blind. Recordings and data analysis. Sleep stages were determined from recordings of EEG, electromyogram, and electrooculogram, which were scored off-line according to the criteria described by Rechtschaffen and Kales (22). Blood samples taken at 2300,0100,0400, and 0700 h were used to determine plasma cortisol and plasma VP concentrations. Radioimmunoassays (Hermann Biermann, Bad Nauheim, FRG) were used to measure plasma cortisol (sensitivity 0.17 pg/dl, intra-assay coefficient of variation ~3% between 1 and 50 pg/dl) and VP (sensitivity 0.6 pg/ml, intra-assay coefficient of variation
C. KELLNER,
D. UTHGENANNT,
W. KERN,
AND
H. L. FEHM
Abteilung Psychophysiologie, UniversiCit Bamberg, W-8600 Bamberg; and Medizinische Medizinische Universit& Liibeck, 2400 Liibeck, Federal Republic of Germany. Born, J., C. Kellner, D. Uthgenannt, W. Kern, and H. L. Fehm. Vasopressin regulates human sleep by reducing rapid-eye-movement sleep. Am. J. Physiol. 262 (Endocrid. Me&&. 25): E295-E300, 1992.-In two double-blind experiments, effects of intravenous infusion of arginine vasopressin (AVP) on sleep were evaluated in 2 groups of 10 men (20-35 yr). In experiment I, subjects were tested on two occasions, during which they received either placebo or 0.33 IU/h AVP. In experiment II, on three different occasions, subjects received either placebo or 0.66 or 0.99 IU/h AVP. Infusions were administered between 2200 and 0700 h. Nocturnal plasma AVP concentrations were close to the upper limit of the normal physiological range during 0.66 IU/h AVP (16.6 t 2.2 pg/ml) but markedly exceeded this range during 0.99 IU/h AVP (25.0 & 1.6 pg/ml). Results indicate primary effects of AVP on rapideye-movement (REM) sleep, with moderate reductions in REM sleep during 0.33 IU/h AVP (averaging -10.5%) and with substantial reductions in REM sleep (-24.0%) during 0.66 IU/ h AVP. During 0.99 IU/h AVP the effect did not further increase (-24.4%). Less consistent effects of AVP were an increase in stage 2 sleep and in time awake. Effects of AVP were not mediated by changes in cortisol or blood pressure. Results suggest AVP to participate in REM sleep regulation under normal physiological conditions. arginine vasopressin; slow-wave sleep; arousal; blood pressure; cortisol THE NEUROHORMONE VA~OPRESSIN (VP) has been shown to exert important actions on central nervous functions and different behaviors in animals, apart from
its role in the regulation of water homeostasis. In rats, subcutaneous or intracerebroventricular administration of VP improved memory of avoidance behavior (10, 18, 20). Moreover, AVP has been found to decrease overall spectral power of the cortical electroencephalogram (EEG) in these animals, indicating that rats given VP were less drowsy but more aroused during the recording periods than rats given saline injections (12). That in these experiments similar changes were obtained with systemic vs. central administration of VP suggests a common brain state may be induced by the two routes of administration. Some evidence exists that VP increases cortical arousal also in healthy human subjects after intranasal administration (14, 24), whereas direct effects of the peptide on human memory functions are still discussed controversially (3, 14, 16, 26). Besides a general arousing effect, specific influences of VP on sleep and the sleep-wake cycle have been demonstrated. Rats with hereditary diabetes insipidus (Brattleboro rats) displayed a slowing of the hippocampal theta rhythm during rapid-eye-movement (REM) sleep that was normalized after administration of VP (28, 29). In another study (8), such rats showed reduced REM sleep and slow-wave sleep (SWS). After intravenous
Klinik,
infusion of VP, but also when the normal daily water intake was infused intravenously, normal or increased amounts of both sleep stages occurred; however, the findings of deficits in REM sleep and SWS could not be replicated in Brattleboro rats obtained from another breeding colony (7). Unlike Brattleboro rats, normal rats infused with VP did not display enhanced REM sleep or SWS (1, 19). Consonant with an arousing effect of VP in these rats, continuous intracerebroventricular infusion of the peptide increased the time spent awake (1,19) and reduced the time spent in REM sleep or quiet sleep (19). In one of these studies (19), changes in awake time, quiet sleep, and REM sleep concentrated on the dark period (active) and were not apparent during the light period (rest) of the nychthemeron, thus resulting in an increased amplitude of the sleep-wake cycle. Although animal studies provide considerable evidence that VP acts to modify sleep, either directly or via changes in arousal or sleep-wake regulation, to our knowledge, so far only one study has been reported investigating the effects of VP in human beings (27). In these experiments, after intranasal administration of lysine-VP (7 or 14 IU), a slight but significant increase in stage 2 (S2) sleep was observed. At the same time, stage 3 sleep and REM sleep tended to be reduced; however, in view of the small size of the effects, the authors seemed reluctant to attribute these changes to the hormone’s action. The present experiments were designed to examine whether VP affects human sleep. Unlike Timsit-Berthier et al. (27), using an intranasal administration of VP, we infused the hormone intravenously at a constant rate. Plasma VP concentrations were determined during sleep to ascertain that stable increases in plasma VP levels were achieved. Moreover, by testing different doses of VP (0.33,0.66, and 0.99 IU/h), dose-response characteristics of the effects of AVP on sleep could be evaluated. METHODS Two experiments were conducted. In each, 10 healthy men (students of the medical school), aged between 20 and 35 yr (mean 26.7 yr) in experiment I and between 23 and 30 yr (mean 25.2 yr) in experiment 11 participated. None of the subjects of experiment I also participated in experiment II. All subjects were nonsmokers, and none had a history of sleep disturbances. It was ascertained that the subjects’ weight (deviation ~15% from reference, according to Broca index) and height were within the normal range. Physical examination excluded any cardiovascular abnormalities. Three of the subjects in experiment I and five subjects in experiment II regularly participated in physical exercises at least two times per week. Subjects were required to get up before 0700 h on the day of
0193~1849/92 $2.00 Copyright 0 1992 the American Physiological
Society
E295
Downloaded from www.physiology.org/journal/ajpendo by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on October 8, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
E296
AVP AND SLEEP
an experimental night and not to take any naps during the day. They were acclimated to the experimental sleep conditions by spending one night under the conditions of the experiment, including the placements of catheters and the infusion of placebo (saline solution). The experiments were approved by the Committee on Research Involving Human Subjects of the University of Ulm. Procedure and design. The experiments took place in an airconditioned room. Upon arrival at the laboratory, subjects were prepared for somnopolygraphic recording and blood sampling. Continuous recordings were obtained from 2300 h, when lights were turned off, to 0700 h, when the subjects were awakened. In the morning, each subject was asked whether he thought he received an active agent or placebo. Two intravenous forearm catheters were placed, one for infusion of treatment substances, the other (placed distally to the infusion catheter) for blood sampling during the experimental nights. This catheter was connected to a long thin tube (vol 1.5 ml), which enabled blood collection from an adjacent room without disturbing the subject’s sleep. To prevent clotting of this catheter, -200 ml of saline solution were infused throughout the night. In experiment I, subjects were studied on two occasions, in addition to the first adaptation night. In one condition, arginine vasopressin (0.33 IU/h AVP diluted in 11 ml/h saline solution; Pitressin; Parke Davis, Berlin, FRG) was infused at a constant rate from 2200 to 0700 h; in the other condition, placebo (11 ml/h saline solution) was infused during the same time interval. The order of presentations of these experimental conditions was counterbalanced, with half of the subjects receiving first placebo and then AVP and the other half receiving first AVP and then placebo. In experiment II, subjects were studied on three occasions, in addition to the first adaptation night. During one condition, placebo (11 ml/h) was infused constantly; during the other conditions, AVP was infused at a rate of either 0.66 or 0.99 IU/ h (diluted in 11 ml/h saline solution). As in experiment I, infusions started at 2200 h and lasted until 0700 h. The order of presentations of the three experimental conditions was counterbalanced across subjects according to a Latin square. In both experiments, any two experimental nights for a subject were separated by an interval of at least 10 days. Both experiments were held double blind. Recordings and data analysis. Sleep stages were determined from recordings of EEG, electromyogram, and electrooculogram, which were scored off-line according to the criteria described by Rechtschaffen and Kales (22). Blood samples taken at 2300,0100,0400, and 0700 h were used to determine plasma cortisol and plasma VP concentrations. Radioimmunoassays (Hermann Biermann, Bad Nauheim, FRG) were used to measure plasma cortisol (sensitivity 0.17 pg/dl, intra-assay coefficient of variation ~3% between 1 and 50 pg/dl) and VP (sensitivity 0.6 pg/ml, intra-assay coefficient of variation
