Click here to load reader
Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
Fax to: +49622148768168Jörg TheurerSpringer Heidelberg, 69121 Heidelberg
From:Re: Psychopharmacology DOI 10.1007/s00213-005-2236-0
Sleep-related vagotonic effect of zolpidem in ratsAuthors: Chen · Kuo · Shaw · Lai · Yang
I. Permission to publishDear Jörg Theurer,
I have checked the proofs of my article and
❑ I have no corrections. The article is ready to be published without changes.
❑ I have a few corrections. I am enclosing the following pages:
❑ I have made many corrections. Enclosed is the complete article.
II. Offprint order❑ I do not wish to order offprints❑ Offprint order enclosed
Remarks:
Date / signature
III. Copyright Transfer Statement (sign only if not submitted previously)The copyright to this article is transferred to Springer-Verlag (for U.S. government employees: to the extenttransferable) effective if and when the article is accepted for publication. The author warrants that his/hercontribution is original and that he/she has full power to make this grant. The author signs for and acceptsresponsibility for releasing this material on behalf of any and all co-authors. The copyright transfer covers theexclusive right to reproduce and distribute the article, including reprints, translations, photographic reproductions,microform, electronic form (offline, online) or any other reproductions of similar nature.An author may self-archive an author-created version of his/her article on his/her own website and his/her
institution’s repository, including his/her final version; however he/she may not use the publisher’s PDF versionwhich is posted on www.springerlink.com. Furthermore, the author may only post his/her version providedacknowledgement is given to the original source of publication and a link is inserted to the published articleon Springer’s website. The link must be accompanied by the following text: “The original publication is availableat www.springerlink.com.”Please use the appropriate DOI for the article (go to the Linking Options in the article, then to OpenURL
and use the link with the DOI). Articles disseminated via www.springerlink.com are indexed, abstracted andreferenced by many abstracting and information services, bibliographic networks, subscription agencies, librarynetworks, and consortia.After submission of this agreement signed by the corresponding author, changes of authorship or in the order
of the authors listed will not be accepted by Springer.
Date / Author’s signature
Journal: PsychopharmacologyDOI: 10.1007/s00213-005-2236-0
Offprint Order Form• If you do not return this order form, we assume thatyou do not wish to order offprints.
• To determine if your journal provides free offprints,please check the journal’s instructions to authors.
• You are entitled to a PDF file if you order offprints. • If you order offprints after the issue has gone to press,costs are much higher. Therefore, we can supply• Please specify where to send the PDF file:offprints only in quantities of 300 or more after thistime.
• For orders involving more than 500 copies, please askthe production editor for a quotation.
❑
Please note that orders will be processed only if a credit card number has beenprovided. For German authors, payment by direct debit is also possible.
I wish to be charged in ❑ Euro ❑ USD
Prices include surface mail postage and handling.Customers in EU countries who are not registered for VATshould add VAT at the rate applicable in their country.
VAT registration number (EU countries only):
For authors resident in Germany: payment by directdebit:I authorize Springer to debit the amount owed frommy bank account at the due time.
Account no.:
Bank code:
Bank:
Date / Signature:
Please enter my order for:
Price USDPrice EURCopies330.00300.0050❑405.00365.00100❑575.00525.00200❑750.00680.00300❑940.00855.00400❑1,130.001,025.00500❑
Please charge my credit card❑ Eurocard/Access/Mastercard❑ American Express❑ Visa/Barclaycard/Americard
Number (incl. check digits):_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _Valid until: _ _ / _ _
Date / Signature:
Ship offprints to:Send receipt to:
❑ Cheryl C.H. YangTzu Chi UniversityDept. Physiology701 Chung Yang RoadHualien970, Taiwan R.O.C.
❑ Cheryl C.H. YangTzu Chi UniversityDept. Physiology701 Chung Yang RoadHualien970, Taiwan R.O.C.
❑ ❑
PsychopharmacologyDOI 10.1007/s00213-005-2236-0
Original Investigation
Sleep-related vagotonic effect of zolpidem in ratsHsiao Ying Chen · Terry B. J. Kuo · Fu-Zen Shaw · Ching J. Lai · Cheryl C. H. Yang (✉)
H. Y. Chen · T. B. J. Kuo · F.-Z. Shaw · C. J. Lai · C. C. H. YangInstitute of Neuroscience, Tzu Chi University, Hualien, 970, Taiwan
H. Y. ChenDepartment of Pharmacy, Mackay Memorial Hospital Taitung Branch, Taitung, 950, Taiwan
T. B. J. KuoDepartment of Neurology, Tzu Chi Buddhist General Hospital, Hualien, 970, Taiwan
T. B. J. Kuo · F.-Z. Shaw · C. J. Lai · C. C. H. YangDepartment of Physiology, Tzu Chi University, No. 701 Chung Yang Road, Section 3, Hualien,970, Taiwan
✉ C. C. H. YangPhone: +886-3-8565301Fax: +886-3-8580639E-mail: [email protected]
Received: 13 September 2004 / Accepted: 11 February 2005
Abstract
Rationale Zolpidem is a relatively new nonbenzodiazepine sedative–hypnotic. The effects of
zolpidem on autonomic functions remain unclear.
Objectives The aim of this study was to evaluate the effects of zolpidem on sleep and related
cardiac autonomic modulations as compared with triazolam in Wistar–Kyoto rats.
Methods Continuous power spectral analyses of electroencephalogram (EEG), electromyogram,
and heart rate variability were performed on freely moving rats during daytime sleep. The
consciousness states were classified into active waking (AW), quiet sleep (QS), and paradoxical
sleep (PS). Drugs were administered via gavage and data within 2 h were analyzed.
Results All zolpidem (ZP3, 3 mg/kg; ZP30, 30 mg/kg) and triazolam (TZ0.075, 0.075 mg/kg;
TZ0.75, 0.75 mg/kg) groups had longer accumulated QS time and averaged QS duration as
compared with the vehicle control. The accumulated QS time and averaged QS duration of ZP3
1
were similar to those of TZ0.075. Significant suppressions of PS time were noted in all drug groups
except ZP3. During QS, ZP3 and ZP30 exhibited significant increases of magnitude and percentage
of EEG δ power, whereas TZ0.075 and TZ0.75 did not. Heart period and high-frequency power
of heart rate variability increased significantly in ZP3 during all sleep–wake states. Both parameters,
however, did not increase but even decreased in ZP30, TZ0.075, and TZ0.75.
Conclusions Zolpidem not only caused a longer and deeper sleep but also led to an elevated
cardiac vagal activity at a specific dose in the rat.
Keywords Heart rate variability · Hypnotic · Zolpidem · Triazolam
IntroductionSleep disorders are widespread problems that almost everyone has experienced, and insomnia is
the most common. It has been reported that chronic sleep disorders may influence the cardiovascular
system. Researchers have found that chronic insomniacs have increased risk for coronary artery
disease and hypertension (Bonnet and Arand 1998; Schwartz et al. 1999; Suka et al. 2003). Infants
with short-term sleep deprivation may be at high risk for sudden infant death syndrome (Franco
et al. 2003). Recently, interactions between sleep apnea and hypertension have received much
more attention (Peppard et al. 2000; Salo et al. 2000). Some links between sleep disorders and
autonomic nervous system disturbances may exist. However, the research and treatment of sleep
disorders have mostly focused on the variations of the sleep, but little has been mentioned about
the extraordinary changes of the autonomic functions. Sedative–hypnotics have been the major
choices for the treatment of insomnia (Trevor and Way 2004). Surprisingly, it was reported that
the people who used sleeping pills often had 1.5 times the mortality rate of those who never used
them (Kripke et al. 1979; Rumble and Morgan 1992). Investigators still do not know the causes
or effects of sleep disorders and side effects of hypnotics. It is perceived that hypnotics may reduce
the problems of some types of sleep disorders, but they may also produce some problems in the
cardiovascular system. Thus, the effects of hypnotics on autonomic nervous system functions,
especially for long-term use, should be studied.
Zolpidem is a relatively novel nonbenzodiazepine hypnotic. Unlike traditional hypnotics, it
causes only minor effects on sleep patterns and has fewer undesirable effects (Declerck et al.
1992). As previously reported, zolpidem rarely caused adverse effects on the cardiovascular system,
such as hypotension or tachycardia in animals, healthy humans, and even hemodynamically
2
compromised subjects such as the elderly and astronauts (Mccann et al. 1993; Ganzoni et al. 1995;
Mailliet et al. 2001; Shi et al. 2003). Reports on the effects of zolpidem on sleep-related autonomic
functions, however, are still lacking.
The autonomic nervous functions change vigorously with sleep/wake transitions (Zemaityte et
al. 1984; Cajochen et al. 1994; Baharav et al. 1995; Vaughn et al. 1995). Previous studies (Zemaityte
et al. 1984; Baharav et al. 1995) have revealed that slow-wave sleep or quiet sleep is associated
with an increase in the vagal function and a decrease in the sympathetic function. Such alterations
are dramatically reversed during the rapid eye movement sleep or paradoxical sleep. Thus, it is
very important to distinguish the sleep–wake stages for the investigation of the autonomic functions
(Kuo et al. 2004a; Kuo and Yang 2004). Recently we developed a simple and quantitative analysis
to explore the interaction between cerebral cortical and autonomic functions during sleep (Yang
et al. 2002; Yang et al. 2003; Kuo et al. 2004b) that does not employ the specific terminology of
different waveforms used in conventional sleep staging. The methodology was based on
simultaneous power spectral analyses of the electroencephalogram (EEG), electromyogram (EMG),
and heart rate variability. With the application of such techniques, the present study was designed
to test whether zolpidem has an effect on sleep-related cardiac autonomic regulations.
Materials and methods
Preparation of animals
All experiments were carried out on adult male Wistar–Kyoto rats (n=10). The rats were raised
in a sound-attenuated room with a 12:12-h light–dark cycle (lights on 0600–1800 hours) as well
as with appropriate temperature (22±2°C), and humidity (40–70%) control. Detailed procedures
for the sleep study of the rats were described previously (Shaw et al. 2002; Kuo et al. 2004a, b).
On the day of electrode implantation, the rats were 12 to 15 weeks old. Under pentobarbital
anesthesia (50 mg/kg i.p.), each rat was placed in a standard stereotaxic apparatus where electrodes
for the parietal EEG, nuchal EMG, and electrocardiogram were implanted. After surgery, the rats
were given antibiotics (chlortetracycline) and individually housed in translucent cages for the
1-week recovery and subsequent experiments. To allow the rats to habituate to the experimental
apparatus, each animal was placed in the recording environment for at least two times (1 h/day)
before testing. During the day of the recording, a 30-min period was allowed for the rat to become
familiar with the surroundings. The rats were given distilled water (vehicle), zolpidem (Fujisawa,
3
Japan) at doses of 3 or 30 mg/kg, or triazolam (Pfizer, USA) at doses of 0.075 or 0.75 mg/kg via
gavage. At 30 min after the drug administration, both electrophysiological and video signals were
simultaneously recorded for 6 h (1030–1630 hours). Each animal of the group received all doses
of drugs and distilled water in a randomized protocol. Each dose of one drug was separated by a
48-h washout period with gavage of distilled water to avoid animals associating human handling
with drug effects. Recording of polysomnographic parameters during the washout period ensured
that physiological conditions of the animals returned to basal conditions. The experimental protocol
was approved by the Institutional Animal Care and Use Committee of Tzu Chi University.
Data acquisition and storage
The EEG, EMG, and electrocardiogram signals were amplified 1,000-fold, but with different
selections for filter bandwidths. The EEG was filtered with 0.32–40 Hz, the EMG with 32–320 Hz,
and the electrocardiogram with 0.64–320 Hz. These bioelectric signals were relayed to an 8-bit
analog–digital converter connected to an IBM PC-compatible computer. The EEG, EMG, and
electrocardiogram signals were synchronously digitized but at different sampling rates (256, 1,024,
and 1,024 Hz, respectively). The acquired data were analyzed on-line but were simultaneously
stored on a hard disk for subsequent off-line verification.
Digital signal processing
The digital signal processing of the bioelectric signals was similar to the procedures used in our
previous studies (Yang et al. 2003; Kuo et al. 2004a, b). The preprocessing of the electrocardiogram
signals was designed according to the recommended procedures (Task Force of the European
Society of Cardiology and the North American Society of Pacing and Electrophysiology 1996),
which were detailed in our previous reports (Kuo et al. 1999, 2004a; Yang et al. 2003). In brief,
the computer algorithm identified each normal ventricular discharge waveform and rejected each
ventricular premature complex or noise according to its likelihood in a standard template. Stationary
R–R intervals (RR) were resampled and interpolated at a rate of 64 Hz to provide continuity in
the time domain. The sampling rate of EEG signals was also reduced to 64 Hz.
Power spectral analysis
The sleep pattern and autonomic functions were analyzed for 2 h after vehicle or drug gavage.
The EEG and RR signals to be analyzed were truncated into successive 16-s (1,024 points) time
4
segments (windows or epochs) with 50% overlapping. A Hamming window was applied to each
time segment to attenuate the leakage effect (Kuo and Chan 1993). Our algorithm then estimated
the power density of the spectral components based on the fast Fourier transform. The resulting
power spectrum was corrected for attenuation resulting from sampling and application of the
Hamming window (Kuo et al. 1999). The EMG signals to be analyzed were truncated into successive
2-s (2,048 points) time segments without overlapping. They consequently underwent fast Fourier
transform after application of the Hamming window. Eight successive EMG spectra (a total of
16 s) were averaged to achieve synchronization between the EEG and RR spectra.
For each 16-s time segment, we quantified the high-frequency (HF, 0.6–2.4 Hz) and
low-frequency power (LF, 0.06–0.6 Hz) of the RR spectrogram (Yang et al. 2003; Kuo et al.
2004a), the α (6.8–13 Hz), β power (13–32 Hz), θ power (4–6.8 Hz), and δ power (0.5–4 Hz) of
the EEG spectrogram (Shaw et al. 2002), and the power of the EMG spectrogram (200–500 Hz).
The LF to HF ratio (LF/HF) was also calculated. HF indicates cardiac vagal activity whereas
LF/HF reflects cardiac sympathetic modulations or sympathovagal balance (Task Force of the
European Society of Cardiology and the North American Society of Pacing and Electrophysiology
1996). To determine whether EEG was in an arousal state or not, a subjective rating was hard to
accomplish without considering the whole frequency contents of the EEG, including the α, β, θ,
and δ components. Thus, we calculated the mean power frequency of the EEG spectrogram (MPF)
which covered all the components using the following equation (Kuo et al. 2004a, b):
where f is any given frequency, fo is the lower cutoff frequency, fc is the upper cutoff frequency,
and PSD(f) is the power spectral density of a given frequency. In this study, the fo was the low-cut
frequency of the δ power, whereas the fc was the high-cut frequency of the β power.
Sleep pattern analysis
The detailed procedures for the sleep pattern analysis have been reported previously (Kuo et al.
2004a, b). For each time segment, we defined its sleep–wake stage as active waking (AW) if the
corresponding MPF was greater than the threshold of MPF (TMPF) and the EMG power was greater
than the threshold of EMG power (TEMG); as quiet sleep (QS) if the corresponding MPF was less
than TMPF and the EMG power was less than TEMG; and as paradoxical sleep (PS) if the corresponding
5
MPF was greater than TMPF and the EMG power was less than TEMG. If the corresponding MPF
was less than TMPF and the EMG power was greater than TEMG, the sleep–wake stage was undefined
and the data of this epoch were not used in subsequent statistical analyses. The TMPF and TEMG of
each animal were defined manually by an operator and were constant for the whole recording
period. Visual observations of the behavior were used as an aid in defining the thresholds. Using
random samples from experimental sessions, we made several comparisons between this
semiautomatic sleep classifications and assessment by another operator who observed the raw
signal tracings and video recordings. The man–machine agreement of AW, QS, and PS
classifications was greater than 90%.
A mature sleep–wake stage was defined as any stage that persisted unchanged for at least six
epochs (approximately 56 s), and any sleep–wake stage that persisted for less than six epochs was
regarded a transient interruption (Kuo et al. 2004b).
Statistical analysis
Total power (TPEEG), α, β, θ, and δ powers of EEG spectrogram and total power (TPHRV), HF, and
LF/HF of RR spectrogram were quantified. These parameters were logarithmically transformed
to correct for the skewness of the distribution (Kuo et al. 1999). Effects of the drugs (vehicle,
3 mg/kg zolpidem, 30 mg/kg zolpidem, 0.075 mg/kg triazolam, and 0.75 mg/kg triazolam) on the
physiological parameters were assessed using one-way analysis of variance (ANOVA) with
repeated measures. When indicated by a significant F statistic, regional differences were isolated
using post hoc comparisons with Fisher’s least significant difference test. Statistical significance
was assumed for P
30 mg/kg, resulted in more accumulated QS time and less accumulated AW time as compared
with the vehicle control group (Fig. 2a). The 30-mg/kg zolpidem group exhibited less accumulated
PS time, whereas the 3-mg/kg zolpidem group did not. The triazolam administration, either 0.075
or 0.75 mg/kg, resulted in more accumulated QS time, less accumulated AW time, and less
accumulated PS time (Fig. 2a). Although 0.075 mg/kg triazolam achieved similar QS time as
3 mg/kg zolpidem did, it significantly suppressed PS time, whereas 3 mg/kg zolpidem did not.
The 0.75 mg/kg triazolam group had the longest QS time among all groups. The stage number of
AW, QS, or PS during the recording period was generally decreased in all the zolpidem and
triazolam groups (Fig. 2b). The average QS duration was increased in all the zolpidem and triazolam
groups, in which the 0.75-mg/kg triazolam group had the longest QS duration (Fig. 2c).
Fig. 1 Continuous and simultaneous analysis of polysomnograms during 0 to 2-h window of daytime sleep
after gavage application of vehicle, 3 mg/kg zolpidem (ZP3) and 30 mg/kg zolpidem (ZP30) at 0 min in
one rat. The EEGs and 3-D power spectrograms show the successive power spectral density of the EEG
(EPSD). Temporal alterations in the mean power frequency (MPF) of the EEG and the power of
electromyogram (EMG) are also shown. The sleep stage, including active waking (AW), quiet sleep (QS),
and paradoxical sleep (PS), as well as interruptions (ticks) are denoted. Averaged mean of the R–R intervals
(RR), corresponding 3-D power spectrograms of RR (HPSD), total power (TP), high-frequency power (HF),
7
low-frequency power (LF), and LF-to-HF ratio (LF/HF) were likewise monitored. Right, ranges of frequency
for the α, β, θ, and δ power of EEG and HF and LF of RR. ln natural logarithm
Fig. 2 Dosage effects of zolpidem and triazolam on accumulated time (a), number (b), and average duration
(c) during whole recording (Mixed), active waking (AW), quiet sleep (QS), and paradoxical sleep (PS) during
0 to 2 h window of daytime recording after gavage application in rats. ZP3, 3 mg/kg zolpidem; TZ0.075,
0.075 mg/kg triazolam; ZP30, 30 mg/kg zolpidem; TZ0.75, 0.75 mg/kg triazolam. Data are expressed as
means±SEM of ten rats per group. *P
Fig. 3 Dosage effects of zolpidem and triazolam on total power TPEEG (a), δ (b), θ (c), α (d), and β power
magnitude (e) of EEGs during whole recording (Mixed), active waking (AW), quiet sleep (QS), and paradoxical
sleep (PS) during 0 to 2-h window of daytime recording after gavage application in rats. ZP3, 3 mg/kg
zolpidem; TZ0.075, 0.075 mg/kg triazolam; ZP30, 30 mg/kg zolpidem; TZ0.75, 0.75 mg/kg triazolam. Data
are expressed as means±SEM of ten rats per group. *P
Fig. 4 Dosage effects of zolpidem and triazolam on δ (a), θ (b), α (c), and β power percentage (d) of EEGs
during whole recording (Mixed), active waking (AW), quiet sleep (QS), and paradoxical sleep (PS) during
0 to 2-h window of daytime recording after gavage application in rats. ZP3, 3 mg/kg zolpidem; TZ0.075,
0.075 mg/kg triazolam; ZP30, 30 mg/kg zolpidem; TZ0.75, 0.75 mg/kg triazolam. Data are expressed as
means ± SEM of ten rats per group. *P
during AW, QS, or PS. By contrast, the high-dose triazolam administration (0.75 mg/kg)
significantly decreased LF/HF during AW, QS, and PS.
Fig. 5 Dosage effects of zolpidem and triazolam on mean of R–R intervals (RR, a), total power (TPHRV, b),
high-frequency power (HF, c), and LF-to-HF ratio (LF/HF, d) of heart rate variability during whole recording
(Mixed), active waking (AW), quiet sleep (QS), and paradoxical sleep (PS) during 0 to 2-h window of daytime
recording after gavage application in rats. ZP3, 3 mg/kg zolpidem; TZ0.075, 0.075 mg/kg triazolam; ZP30,
30 mg/kg zolpidem; TZ0.75, 0.75 mg/kg triazolam. Data are expressed as means±SEM of ten rats per group.
*P
30 mg/kg zolpidem were also diminished except the increase of accumulated QS time, the increase
of TPEEG during AW and QS, and the decrease of HF during QS and PS. For the triazolam, the
high-dose (0.75 mg/kg) group still had an increase of accumulated QS time. The suppressive
effects on HF during QS and PS persisted in both the low- (0.075 mg/kg) and high-dose
(0.75 mg/kg) groups.
DiscussionIn the present study, we demonstrated that zolpidem may not only prolong the sleep time and
promote sleep depth, but also prominently affect the autonomic functions. Two different doses of
zolpidem induced disparity changes in heart rate variability despite similar changes in the EEG.
The lower dose (3 mg/kg) increased RR and HF, whereas the higher dosage (30 mg/kg) decreased
RR during PS and decreased HF during sleep. By contrast, equivalent dosages of triazolam
(0.075 mg/kg), which induced a similar hypnotic effect as 3 mg/kg zolpidem, did not produce any
facilitative effect on RR or HF, but they produced only suppressive effects. A larger dose of
triazolam (0.75 mg/kg) produced even more significant suppressions on RR, HF, and LF/HF.
These results indicated that the lower dosage of zolpidem induced significantly hypnotic as well
as cardiac vagotonic effects. We inferred that this newly generated hypnotic may produce less
stress on the cardiovascular system; however, the dosage should be paid more attention. Our results
also suggested that sleep-related autonomic effects might be considered in the evaluation of the
therapeutic or side effects of hypnotics.
It is well known that the autonomic nervous system monitors and regulates many aspects of the
body’s functions. When humans are under various kinds of stress, autonomic disturbances may
occur (Uchino et al. 1999). Myocardial infarction patients with severe vagal withdrawal are even
prone to enter a cycle that may result in a tendency toward lethal tachyarrhythmia (Huikuri et al.
1996). It has been hypothesized that the sleep-state-dependent fluctuations in autonomic activity,
e.g., vagal withdrawal and sympathetic activation, may trigger the onset of major cardiovascular
events, such as myocardial infarction, ventricular tachyarrhythmias, and even sudden cardiac death
(Muller et al. 1985; Vanoli et al. 1995; Lavery et al. 1997; Viola et al. 2002). Patients with chronic
sleep disorder also frequently have severe autonomic disturbances. The evidence for this
combination of conditions includes longer or shorter sleeping period (Kripke et al. 2002), insomnia
(Irwin et al. 2003), sleep deprivation (Franco et al. 2003), and sleep apnea (Belozeroff et al. 2003;
Spicuzza et al. 2003). Other studies (Frisina et al. 1998) demonstrated that hypertensive subjects
12
failed to exhibit a normal decrease of blood pressure during sleep. Our previous study (Kuo et al.
2004a) confirmed that spontaneously hypertensive rats had a sympathovagal imbalance with an
increased sympathetic modulation during sleep. Thus, the treatment of sleep disorders faces the
challenge of not only the recovery of sleep states but also the restoration of the autonomic functions.
Unfortunately, evidence has indicated that many traditional hypnotics not only encourage sleep
but also produce tachycardia and vagolytic effects (Farmer et al. 2003; Shi et al. 2003). Thus, it
is not very surprising that people who had used sleeping pills had 1.5 times the mortality rate of
those who had never used them (Kripke et al. 1979). In addition, long-term use of sleeping pills
is especially dangerous for a person who already has ischemic heart disease. In this study, our
results suggested that zolpidem did not act like other traditional hypnotics such as triazolam when
applied in a low dosage. The 3 mg/kg zolpidem induced sleep while increasing cardiac vagal
activity. We thought that a proper dosage of zolpidem might be suitable for treatment of sleep
disorders with particular consideration of cardiovascular problems.
To the best of our knowledge, the vagotonic effect of zolpidem has not yet been reported. One
possible reason is that zolpidem is a relatively new hypnotic. The other possible reason is that
combining the analysis of the EEG and autonomic functions at the same time is relatively difficult.
Not only zolpidem but also other hypnotics with possible effects on sleep-related autonomic
functions have rarely been evaluated. Some studies indicated that zolpidem had little effect on
heart rate and blood pressure in healthy rats (Mailliet et al. 2001) and humans (Mccann et al. 1993).
The present study, however, revealed that a large dose (30 mg/kg) of zolpidem produced significant
suppression of heart period and cardiac vagal activity. Thus, we considered that the differences
between our study and others might be associated with the differences in dosage, route of
application, analysis time window, and analytical methodology. Zolpidem is known to reduce the
frequency of EEG rhythms. Since the MPF was used in our sleep–wake staging, we wondered
whether zolpidem may interfere with our staging system. The thresholds of the MPF were defined
according to the histogram of the accumulated MPF values. Thus, even if the MPF distribution
was altered, the threshold could still be traced. Finally, each MPF threshold was validated by the
rater with the assistance of video recordings, which ensured a high man–machine agreement.
Triazolam belongs to the benzodiazepine family. Previous evidence revealed that the traditional
hypnotics, such as benzodiazepines, prolonged QS time effectively while raising some undesirable
effects, including a prolongation of stage 2 non-rapid eye movement sleep, a reduction of rapid
eye movement sleep (Kanno et al. 2000), a suppression of vagal function (Farmer et al. 2003),
and others (Chouinard 2004). Our data essentially confirmed these observations. By contrast, like
13
those in previous studies (Kanno et al. 2000), our results revealed that a proper dose of zolpidem
significantly increased QS time as well as magnitude and percentage of EEG δ power, but showed
relatively no effects on PS time.
Previous studies have revealed that QS is associated with an increase in vagal function and a
decrease in sympathetic function. Such alternations are dramatically reversed during the PS stage
(Zemaityte et al. 1984; Cajochen et al. 1994; Baharav et al. 1995; Vaughn et al. 1995; Yang et al.
2002). The vagal activity of humans before going to bed may predict their chance of falling asleep
(Delamont et al. 1998). A poorer vagal activity of the spontaneously hypertensive rat was associated
with less sleep time and poorer sleep quality (Kuo et al. 2004b). Our data showed that the HF was
increased by low dosage of zolpidem but decreased by triazolam or high dosage of zolpidem. It
was noteworthy that the effects of these hypnotics on the HF appeared independent of the
sleep–wake states. The decrease in LF/HF upon high dosage of triazolam was also independent
of the sleep–wake states. In the long history of sleep research, there have been various
sleep–wake-promoting nuclei or centers hypothesized in the brain (Jouvet 1967; Gottesmann 1999;
Saper et al. 2001). A wake-to-sleep transition may be achieved from a suppression of the
wake-promoting system or from an activation of the sleep-promoting system (Jouvet 1967). The
comparison of the autonomic effects of the hypnotics may reveal the differences in their hypnotizing
mechanisms. The increased vagal index supported that zolpidem may have a facilitative effect on
the sleep-promoting system, whereas the decreased sympathetic index supports that triazolam may
have a suppressive effect on the wake-promoting system. The vagolytic effect of high-dose zolpidem
may be due to a nonspecific suppressive effect, which is not uncommon in high doses of anesthetics
and hypnotics. Detailed underlying mechanisms are interesting and warrant further investigations.
However, a higher vagal activity before and during QS might be beneficial for humans or animals
to achieve a smooth sleep. Compared with the significant vagolytic effects of triazolam and
high-dose zolpidem, low-dose zolpidem may provide a unique choice of treatment for insomnia.
In addition to achieving a deeper sleep, its vagatonic effect is harmonic with the normal
physiological rhythms.
People with sleep disorders usually also have autonomic disturbances or even cardiovascular
diseases. Appropriate restoration of autonomic function is necessary to maintain a balanced life.
Although the present hypnotics prolong sleep time effectively, most of them may suppress cardiac
vagal activity as in the case of triazolam (Farmer et al. 2003; Shi et al. 2003). Long-term use of
vagolytic hypnotics is potentially dangerous especially for patients with underlying cardiovascular
diseases. The present study indicated that a low dose of zolpidem effectively produced the hypnotic
14
effect while simultaneously increasing the cardiac vagal activity. We conclude that a proper dosage
of zolpidem may be suitable for treatment of sleep disorders with particular consideration of
cardiovascular problems. We also suggest that a study of the sleep pattern and related autonomic
functions may provide important clues for a proper selection of hypnotics to use. The effects of
zolpidem on the cerebral cortical and autonomic functions are unique and warrant further
investigations.
Acknowledgements H.Y. Chen and T.B J. Kuo contributed equally to this study. This study was
supported by National Science Council (Taiwan) through grants NSC-93-2314-B-320-008 and a
research grant (tcmrc-93-33a-01) from the Tzu Chi Charity Foundation. We thank Ms. Y.C. Lee
for her excellent technical support.
ReferencesBaharav A, Kotagal S, Gibbons V, Rubin BK, Pratt G, Karin J, Akselrod S (1995) Fluctuations in autonomicnervous activity during sleep displayed by power spectrum analysis of heart rate variability. Neurology45:1183–1187
Belozeroff V, Berry RB, Khoo MC (2003) Model-based assessment of autonomic control in obstructivesleep apnea syndrome. Sleep 26:65–73
Bonnet MH, Arand DL (1998) Heart rate variability in insomniacs and matched normal sleepers. PsychosomMed 60:610–615
Cajochen C, Pischke J, Aeschbach D, Borbely AA (1994) Heart rate dynamics during human sleep. PhysiolBehav 55:769–774
Chouinard G (2004) Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J ClinPsychiatry 65 Suppl 5:7–12
Declerck AC, Ruwe F, O’Hanlon JF, Vermeeren A, Wauquier A (1992) Effects of zolpidem and flunitrazepamon nocturnal sleep of women subjectively complaining of insomnia. Psychopharmacology 106:497–501
Delamont RS, Julu POO, Jamal GA (1998) Sleep deprivation and its effect on an index of cardiacparasympathetic activity in early nonREM sleep in normal and epileptic subjects. Sleep 21:493–498
Farmer MR, Ross HF, Chowdhary S, Osman F, Townend JN, Coote JH (2003) GABAergic mechanismsinvolved in the vagally mediated heart rate response to muscle contraction as revealed by studies withbenzodiazepines. Clin Auton Res 13:45–50
Franco P, Seret N, Van Hees JN, Lanquart JP Jr, Groswasser J, Kahn A (2003) Cardiac changes during sleepin sleep-deprived infants. Sleep 26:845–848
Frisina N, Pedulla M, Mento G, Morano E, Lanuzza B, Buemi M (1998) Normotensive offspring withnon-dipper hypertensive parents have abnormal sleep pattern. Blood Press 7:76–80
Ganzoni E, Santoni JP, Chevillard V, Sebille M, Mathy B (1995) Zolpidem in insomnia: a 3-yearpost-marketing surveillance study in Switzerland. J Int Med Res 23:61–73
Gottesmann C (1999) Neurophysiological support of consciousness during waking and sleep. Prog Neurobiol59:469–508
Huikuri HV, Pikkujamsa SM, Airaksinen KE, Ikaheimo MJ, Rantala AO, Kauma H, Lilja M, KesaniemiYA (1996) Sex-related differences in autonomic modulation of heart rate in middle-aged subjects. Circulation94:122–125
Irwin M, Clark C, Kennedy B, Christian Gillin J, Ziegler M (2003) Nocturnal catecholamines and immunefunction in insomniacs, depressed patients, and control subjects. Brain Behav Immun 17:365–372
15
Jouvet M (1967) Neurophysiology of the states of sleep. Physiol Rev 47:117–177
Kanno O, Sasaki T, Watanabe H, Takazawa S, Nakagome K, Nakajima T, Ichikawa I, Akaho R, Suzuki M(2000) Comparison of the effects of zolpidem and triazolam on nocturnal sleep and sleep latency in themorning: a cross-over study in healthy young volunteers. Prog Neuro-psychopharmacol Biol Psychiatry24:897–910
Kripke DF, Simons RN, Garfinkel L, Hammond EC (1979) Short and long sleep and sleeping pills. Isincreased mortality associated? Arch Gen Psychiatry 36:103–116
Kripke DF, Garfinkel L, Wingard DL, Klauber MR, Marler MR (2002) Mortality associated with sleepduration and insomnia. Arch Gen Psychiatry 59:131–136
Kuo TBJ, Chan SHH (1993) Continuous, on-line, real-time spectral analysis of arterial blood pressure usinga personal computer. Am J Physiol 264:H2208–H2213
Kuo TBJ, Yang CCH (2004) Scatterplot analysis of EEG slow-wave magnitude and heart rate variability:an integrative exploration of cerebral cortical and autonomic functions. Sleep 27:648–656
Kuo TBJ, Lin T, Yang CCH, Li CL, Chen CF, Chou P (1999) Effect of aging on gender differences in neuralcontrol of heart rate. Am J Physiol 277:H2233–H2239
Kuo TBJ, Lai CJ, Shaw FZ, Lai CW, Yang CCH (2004a) Sleep-related sympathovagal imbalance in SHR.Am J Physiol 286:H1170–H1176
Kuo TBJ, Shaw FZ, Lai CJ, Lai CW, Yang CCH (2004b) Changes in sleep patterns in spontaneouslyhypertensive rats. Sleep 27:406–412
Lavery CE, Mittleman MA, Cohen MC, Muller JE, Verrier RL (1997) Nonuniform nighttime distributionof acute cardiac events: a possible effect of sleep states. Circulation 96:3321–3327
Mailliet F, Galloux P, Poisson D (2001) Comparative effects of melatonin, zolpidem and diazepam on sleep,body temperature, blood pressure and heart rate measured by radiotelemetry in Wistar rats.Psychopharmacology (Berl) 156:417–426
McCann CC, Quera-Salva MA, Boudet J, Frisk M, Barthouil P, Borderies P, Meyer P (1993) Effect ofzolpidem during sleep on ventilation and cardiovascular variables in normal subjects. Fundam Clin Pharmacol7:305–310
Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK, Passamani E, Roberts R,Robertson T et al (1985) Circadian variation in the frequency of onset of acute myocardial infarction. NEngl J Med 313:1315–1322
Peppard PE, Young T, Palta M, Skatrud J (2000) Prospective study of the association between sleep-disorderedbreathing and hypertension. N Engl J Med 342:1378–1384
Rumble R, Morgan K (1992) Hypnotics, sleep, and mortality in elderly people. J Am Geriatr Soc 40:787–791
Salo TM, Jula AM, Piha JS, Kantola IM, Pelttari L, Rauhala E, Metsala TH, Jalonen JO, Voipio-Pulkki LM,Viikari JS (2000) Comparison of autonomic withdrawal in men with obstructive sleep apnea syndrome,systemic hypertension, and neither condition. Am J Cardiol 85:232–238
Saper CB, Chou TC, Scammell TE (2001) The sleep switch: hypothalamic control of sleep and wakefulness.Trends Neurosci 24:726–731
Schwartz S, McDowell Anderson W, Cole SR, Cornoni-Huntley J, Hays JC, Blazer D (1999) Insomnia andheart disease: a review of epidemiologic studies. J Psychosom Res 47:313–333
Shaw FZ, Lai CJ, Chiu TH (2002) A low-noise flexible integrated system for recording and analysis ofmultiple electrical signals during sleep–wake states in rats. J Neurosci Methods 118:77–87
Shi SJ, Garcia KM, Meck JV (2003) Temazepam, but not zolpidem, causes orthostatic hypotension inastronauts after spaceflight. J Cardiovasc Pharmacol 41:31–39
Spicuzza L, Bernardi L, Calciati A, Di Maria GU (2003) Autonomic modulation of heart rate duringobstructive versus central apneas in patients with sleep-disordered breathing. Am J Respir Crit Care Med167:902–910
Suka M, Yoshida K, Sugimori H (2003) Persistent insomnia is a predictor of hypertension in Japanese maleworkers. J Occup Health 45:344–350
16
Task Force of the European Society of Cardiology and the North American Society of Pacing andElectrophysiology (1996) Heart rate variability: standards of measurement, physiological interpretation andclinical use. Circulation 93:1043–1065
Trevor AJ, Way WL (2004) Sedative–hypnotic drugs. In: Katzung BG (ed) Basic and clinical pharmacology.McGraw Hill, New York, pp 351–366
Uchino BN, Uno D, Holt-Lunstad J, Flinders JB (1999) Age-related differences in cardiovascular reactivityduring acute psychological stress in men and women. J Gerontol B Psychol Sci Soc Sci 54:P339–P346
Vanoli E, Adamson PB, Lin B, Pinna GD, Lazzara R, Orr WC (1995) Heart rate variability during specificsleep stages. A comparison of healthy subjects with patients after myocardial infarction. Circulation91:1918–1922
Vaughn BV, Quint SR, Messenheimer JA, Robertson KR (1995) Heart period variability in sleep.Electroencephalogr Clin Neurophysiol 94:155–162
Viola AU, Simon C, Ehrhart J, Geny B, Piquard F, Muzet A, Brandenberger G (2002) Sleep processes exerta predominant influence on the 24-h profile of heart rate variability. J Biol Rhythms 17:539–547
Yang CCH, Lai C-W, Lai HY, Kuo TBJ (2002) Relationship between electroencephalogram slow-wavemagnitude and heart rate variability during sleep in humans. Neurosci Lett 329:213–216
Yang CCH, Shaw FZ, Lai CJ, Lai CW, Kuo TBJ (2003) Relationship between electroencephalogramslow-wave magnitude and heart rate variability during sleep in rats. Neurosci Lett 336:21–24
Zemaityte D, Varoneckas G, Sokolov E (1984) Heart rhythm control during sleep. Psychophysiology21:279–289
17
IntroductionMaterials and methodsPreparation of animalsData acquisition and storageDigital signal processingPower spectral analysisSleep pattern analysisStatistical analysis
ResultsDiscussionReferences