Effect of the GABAA agonist gaboxadol on nocturnal sleep and hormone secretion in healthy elderly subjects

Marike Lancel, Thomas C. Wetter, Axel Steiger, and Stefan Mathias

Max Planck Institute of Psychiatry, 80804 Munich, Germany


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Aging is associated with a dramatic decrease in sleep intensity and continuity. The selective GABAA receptor agonist gaboxadol has been shown to increase non-REM sleep and the duration of the non-REM episodes in rats and sleep efficiency in young subjects and to enhance low-frequency activity in the electroencephalogram (EEG) within non-REM sleep in both rats and humans. In this double-blind, placebo-controlled study, we investigated the influence of an oral dose of 15 mg of gaboxadol on nocturnal sleep and hormone secretion (ACTH, cortisol, prolactin, growth hormone) in 10 healthy elderly subjects (6 women). Compared with placebo, gaboxadol did not affect endocrine activity but significantly reduced perceived sleep latency, elevated self-estimated total sleep time, and increased sleep efficiency by decreasing intermittent wakefulness and powerfully augmented low-frequency activity in the EEG within non-REM sleep. These findings indicate that gaboxadol is able to increase sleep consolidation and non-REM sleep intensity, without disrupting REM sleep, in elderly individuals and that these effects are not mediated by a modulation of hormone secretion.

gamma -aminobutyric acidA receptor; growth hormone; hypothalamic-pituitary-adrenocortical axis; sleep-electroencephalogram spectral analysis; aging


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

INSOMNIA, WHICH COMPRISES a dissatisfaction with the quantity or quality of sleep, is particularly common in the elderly (9, 19, 26). Polysomnographic studies demonstrated that sleep quality deteriorates as a function of age. With advancing age, sleep intensity decreases, as indexed by progressive reductions in the amount of slow-wave sleep (SWS; stages 3 and 4) and in low-frequency activity in the electroencephalogram (EEG) during non-rapid-eye-movement (non-REM) sleep, which are most pronounced during the first half of the night. Moreover, sleep efficiency (total sleep time relative to time in bed) declines due to an increase in the number and duration of nocturnal awakenings, especially during the second half of the night (reviewed in Refs. 1, 20). These age-related sleep changes are associated with alterations in neuroendocrine activity. It is assumed that the efficacy of the sleep-promoting growth hormone (GH)-releasing hormone (GHRH) is reduced in the aged (reviewed in Ref. 28). Compared with young individuals, the nocturnal release of GH is drastically blunted (30), and pulsatile GHRH infusions evoke a diminished increase in the amount of SWS and GH concentrations and a decrease in cortisol plasma levels in elderly subjects (11). Furthermore, there is a lot of evidence indicating that the hypothalamic-pituitary-adrenocortical (HPA) system changes with age (reviewed in Ref. 29). In the young, plasma concentrations of the wake-related corticotropic hormones are minimal during the first half of the night and steadily increase during the rest of the sleep period. In elderly individuals, cortisol levels are relatively high during the beginning of the night, start to rise at an earlier time point, and display dampened diurnal fluctuations.

To improve their sleep, many elderly insomniacs use hypnotics occasionally or habitually. Most hypnotics, such as benzodiazepines, are so-called agonistic modulators of gamma -aminobutyric acidA (GABAA) receptors in that they allosterically potentiate the response of GABAA receptors to GABA (reviewed in Ref. 25). These compounds reliably shorten sleep onset latency and increase sleep continuity, but they suppress REM sleep and deep sleep, as reflected by a decrease in SWS and/or an attenuation of low-frequency activity in the EEG within non-REM sleep (reviewed in Ref. 15). Although the data are inconsistent, benzodiazepine hypnotics seem to affect hormonal secretions. Various studies have found a suppression of cortisol or, less desirable, of GH and a stimulation of prolactin (4, 12, 27).

Recent experiments have demonstrated that the selective GABAA receptor agonist gaboxadol [4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol; THIP], which is currently developed by H. Lundbeck for the treatment of insomnia, exerts effects on sleep that differ markedly from those of agonistic modulators of GABAA receptors. In rats, gaboxadol dose dependently increases time in non-REM sleep, lengthens the duration of the non-REM episodes, and elevates the slow-frequency components (<9 Hz) in the EEG within non-REM sleep (14, 16). In contrast to hypnotic benzodiazepines, these effects are sustained during a 5-day chronic treatment (17). In young men, a single oral dose of 20 mg of gaboxadol taken at bedtime appeared to significantly increase sleep efficiency and the amount of SWS and to augment low-frequency activity (<8 Hz), while depressing activity in the frequency range of sleep spindles in the EEG within non-REM sleep (7). Intriguingly, these findings indicate that gaboxadol is able to increase sleep consolidation as well as sleep intensity without inhibiting REM sleep. If gaboxadol exerts comparable effects in older people, it counteracts the typical age-related changes in sleep and possibly also in nocturnal hormone secretion.

In the present double-blind and placebo-controlled study, we investigated the influence of gaboxadol, taken orally shortly before retiring during two consecutive nights, on undisturbed sleep during the first night and on sleep-related hormonal profiles during the second night in 10 healthy elderly subjects without sleep complaints.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects. Ten healthy volunteers (age range 61-78 yr), six women (mean age 68.0 ± 6.7 yr) and four men (mean age 68.3 ± 2.8 yr), participated in the study after being subjected to extensive psychiatric, physical, and laboratory examinations. Criteria for exclusion from the study were subjective sleep disturbances, substance abuse, medical illness, aberrancies in blood chemistry, waking EEG or electrocardiogram, a personal or family history of psychiatric disorders, recent stressful life events, a transmeridian flight during the previous 3 mo, and shift work. Additionally, the subjects underwent a two-night polysomnographic examination in the sleep laboratory to rule out specific sleep disorders such as sleep-associated breathing disorders or periodic leg movement disorder. Written informed consent was obtained from all subjects after procedures and possible side effects were explained to them. The subjects were requested to maintain regular bedtimes and to abstain from alcohol before and during the study.

Study design. The experiment was approved by the local ethics committee. The subjects participated in two experimental sessions that were separated by at least 1 wk. Each session consisted of three consecutive nights in our sleep laboratory beginning at 2100. Night 1 served for adaptation to the laboratory conditions. On nights 2 and 3, the subjects took a gelatin capsule at 2230 containing a placebo (lactose) in one session and 15 mg of gaboxadol (Lundbeck, Copenhagen, Denmark) in the other session, according to a randomized double-blind schedule (5 subjects started with placebo). On night 2, electrodes were placed to record EEGs (C3-A2 and C4-A1), the submental electromyogram (EMG), and a vertical and horizontal electrooculogram (EOG). On night 3, an indwelling forearm catheter was inserted, which was connected to a plastic tube that ran through a soundproof lock to a neighboring laboratory. To measure the circulating levels of adrenocorticotropic hormone (ACTH), cortisol, GH, and prolactin, blood samples were taken from the intravenous cannula every 30 min between 2100 and 0700, except at 2230. On all nights, the subjects went to bed at 2300 (lights off). They were allowed to sleep until 0700 during the adaptation night. To assess possible effects on total sleep time, bedtime was unrestricted during nights and 3. On the morning after night 2, 15-30 min after rising, the subjects completed a questionnaire consisting of open and multiple choice questions assessing subjective sleep quality and monitoring whether, and if so which, physical or psychological side effects they had noticed. The rationale for measuring sleep and hormone levels during separate nights is that blood sampling is well known to disrupt sleep.

Sleep-EEG analysis. Throughout night 2 (from 2300 until the subject wanted to rise), EEGs (time constant 0.3 s, amplification 70 µV/cm, high- and low-pass filtering 0.53 and 70 Hz, -3 dB, and -12 dB/octave), EMG, and EOGs were recorded on a Schwartzer ED 24 polygraph. Sleep stages were visually scored per 30-s epoch according to conventional criteria (22) by experienced raters who were unaware of the treatment. The variables computed included total time in bed, total sleep time, sleep efficiency (total sleep time/time in bed), sleep onset latency (time between lights off and the first occurrence of stage 2), the latency to REM sleep (time between sleep onset latency and the first epoch of REM sleep), absolute time spent in each sleep stage, intermittent wakefulness (wakefulness between sleep onset latency and the last sleep epoch), and the number of awakenings (>= 30-s epoch and >= 1 min).

By use of a personal computer, the signals were sampled at 100 Hz by an 8-bit analog-digital converter and stored on disk. The C3-A2 EEG derivation was submitted to a fast Fourier transformation. EEG power spectra were computed for consecutive rectangular windows of 256 samples (approx 2.56 s), resulting in a frequency resolution of approx 0.39 Hz between 0 and 50 Hz. EEG spectra were averaged over epochs of 12 consecutive windows (approx 30.72 s). For the following epoch, the procedure stepped back 72 samples (0.72 s) to permit synchronization with the 30-s epochs of the visual scores. Epochs containing visually identified EEG artifacts, as well as epochs scored as movement time, were eliminated. Average power in 49 frequency bins (0.39-19.14 Hz, 0.39-Hz bins), slow-wave activity (SWA; 0.78-4.29 Hz), and sigma -activity (12.5-14.84 Hz) within non-REM sleep (stages 2, 3, and 4) were computed for the first four 2-h intervals. To avoid missing values, average power in each of the 49 frequency bins was computed per 4-h interval for REM sleep. Because of large interindividual differences in absolute power, EEG power densities within non-REM and REM sleep were normalized by their being expressed as a percentage of the average power in the same frequency band and sleep state during the entire placebo night.

Hormone analysis. After heparinization and centrifugal separation, the plasma samples taken during night 3 were immediately frozen at -25°C (cortisol, GH, and prolactin) or -80°C (ACTH). For technical reasons, the blood samples of only nine subjects could be analyzed. The plasma levels of ACTH and cortisol were determined by commercial radioimmunoassay kits (Nichols Institute, San Juan Capistrano, CA and ICN Biomedicals, Carson, CA, respectively). The detection limits were 3 pg/ml for ACTH and 1.5 ng/ml for cortisol. GH was measured using Nichols Luma Tag human GH and chemiluminescence immunometric assay (Nichols Institute), which has a sensitivity limit of 0.2 ng/ml. Prolactin concentrations were detected with a two-site immunoluminometric assay (Liaison, Prolactin, Byk-Sangtec Diagnostica, Dietzenbach, Germany) with a detection limit of 0.5 ng/ml. Intra- and interassay coefficients of variation were <10% for all hormones. For each hormone, all samples were analyzed in the same assay. Average plasma levels were determined, and area under the curve was calculated using Simpson's rule (trapezoidal integration) for the presleep period (samples taken between 2100 and 2200) and for the first and second halves of the sleep period (samples taken between 2300 and 0230 and from 0300 to 0700, respectively).

Statistical evaluation. Because of the ordinal data structure of the subjective sleep parameters and endocrine variables, differences between the treatments were analyzed with the nonparametric Wilcoxon matched-pairs signed-rank test. To approach normality in the visually scored sleep parameters, the data were log transformed [y = log10(x + 1)]. Differences in visually scored sleep parameters and in EEG power density measures were identified by a one- or two-factorial repeated-measures analysis of variance (ANOVA; Greenhouse-Geisser correction), with treatment (2 levels) and time (2 or 4 levels) as within-subjects factors. Where appropriate, ANOVA was followed by two-sided paired t-tests.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Subjective sleep quality. Compared with placebo, gaboxadol significantly reduced self-estimated sleep onset latency and increased the subjective assessment of total sleep time (Table 1). It did not influence the other aspects of subjective sleep quality or the perceived state upon awakening.

                              
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Table 1.   Subjective sleep quality

With regard to the question of whether the subjects had experienced physical or psychological side effects, one subject reported "unpleasant dreams" during the night of placebo treatment.

Visually scored sleep parameters. Gaboxadol significantly increased sleep efficiency (Table 2; see legend for results of ANOVA) on average by 4.5%, which was caused mainly by a tendential increase in total sleep time. Although gaboxadol did not affect sleep onset latency, it significantly decreased intermittent wakefulness and reduced the number of awakenings. Although gaboxadol increased stage 2 and SWS in 8 of the 10 subjects, none of the non-REM sleep stages was significantly affected by it. Gaboxadol neither altered the latency to REM sleep nor total time in REM sleep.

                              
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Table 2.   Visually scored all-night sleep variables

Accumulation of the stages over 2-h intervals shows that gaboxadol decreased wakefulness throughout the night (Fig. 1). This seems to be related to a nonsignificant increase in SWS during the first half and to an increase in stage 2 during the second half of the night. In contrast, the temporal evolution of REM sleep was practically identical during the placebo and gaboxadol nights.


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Fig. 1.   Cumulation of intermittent wakefulness, stage 2, slow-wave sleep and rapid eye movement (REM) sleep after administration of placebo and gaboxadol. Values are means ± SE (n = 10) and are plotted at the upper limit of each 2-h interval. *P <=  0.05 (two-sided paired t-tests).

EEG power spectra within non-REM and REM sleep. Analysis of SWA within non-REM sleep yielded a significant effect of treatment (F1,9 = 16.9, P = 0.003) and of time (F3,27 = 59.6, P < 0.0001). Compared with placebo, gaboxadol powerfully elevated SWA during the entire night, most prominently during the first 4 h (Fig. 2). Irrespective of the treatment, SWA declined monotonically over consecutive 2-h intervals. For sigma -activity, ANOVA found only a significant time effect (F3,27 = 7.4, P = 0.004), which was due to a treatment-independent decline across the first two 2-h intervals (Fig. 2).


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Fig. 2.   Time course of slow-wave and sigma -activity within non-REM sleep (stages 2, 3, and 4) after administration of placebo and gaboxadol. Values are means ± SE (n = 10) and are plotted in the middle of the 2-h intervals. For each subject, data were expressed as a percentage of the average SWA and sigma -activity within non-REM sleep during the entire placebo night. *P < 0.05 (two-sided paired t-tests).

Analysis of EEG power densities in each of the 0.39-Hz bins yielded a significant (P < 0.05) treatment effect for all frequencies <7.5 Hz. Over the first 8 h of the sleep period, gaboxadol prominently enhanced power in all affected frequency bands (Fig. 3), which was evident throughout the recording period (Fig. 4). Furthermore, ANOVA found a significant time effect for all frequency bands <8 Hz and between 9 and 17 Hz, reflecting a steady decline in low-frequency activity and a transient decrease in high-frequency activity that were not affected by the treatment.


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Fig. 3.   Effect of gaboxadol on electroencephalogram (EEG) power densities within non-REM sleep (stages 2, 3, and 4) and REM sleep during the first 8 h of the sleep period. Values are means ± SE (n = 10). For plotting purposes, data of each subject were expressed as a percentage of the corresponding placebo value. Lines at the bottom of the graphs indicate frequency bands for which ANOVA yielded a significant (P < 0.05) effect of treatment.



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Fig. 4.   EEG power densities in the frequencies between 0.39 and 19.14 Hz within non-REM sleep (stages 2, 3, and 4) per 2-h interval after administration of placebo and gaboxadol. Values are means ± SE (n = 10). For plotting purposes, data of each subject were expressed as a percentage of the average power in the same frequency band within non-REM sleep during the entire placebo night. Lines at the bottom of the graphs indicate frequency bands in which power differed significantly between the treatments (P < 0.05, two-sided paired t-tests).

For EEG power densities within REM sleep, ANOVA found a significant effect of treatment for all frequency bands <12 Hz and of time for nearly all frequencies >3 Hz. Gaboxadol augmented power in the lower frequencies, most prominently in the frequency bands between 5 and 9 Hz (Fig. 3), which subsided during the course of the sleep period (Fig. 5). Irrespective of the treatment, power in most frequency bands declined over the night.


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Fig. 5.   EEG power densities in the frequencies between 0.39 and 19.14 Hz within REM sleep per 4-h interval after administration of placebo and gaboxadol. Values are means ± SE (n = 10). For plotting purposes, data of each subject were expressed as a percentage of the average power in the same frequency band within REM sleep during the entire placebo night. Lines at the bottom of the graphs indicate frequency bands in which power differed significantly between the treatments (P < 0.05, two-sided paired t-tests).

Endocrine variables. Plasma concentrations of ACTH, cortisol, prolactin, and GH did not differ significantly between the placebo and gaboxadol conditions (Table 3 and Fig. 6).

                              
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Table 3.   Endocrine variables



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Fig. 6.   Time course of the levels of ACTH, cortisol, prolactin, and growth hormone. Values are means ± SE (n = 9).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Placebo night. The questionnaire revealed that the subjects were satisfied with their sleep during the placebo condition. Nevertheless, the polysomnographically derived parameters showed that sleep quality was in general rather poor. In agreement with most previous reports on nocturnal sleep in the elderly (1, 20), sleep efficiency was low, on average 81.5%, caused by frequent and partially long-lasting arousals. Moreover, the subjects displayed little SWS, which was due to a relatively low amount of stage 3 and the complete absence of stage 4. Other studies demonstrated that the age-related decline of SWS is associated with a reduction in the amplitude (8) and density (6) of slow waves and, consequently, with a decrease of spectral power density in the lower frequency bands (5, 6, 18). Conforming with these reports, the temporal changes in SWS and SWA across the night were qualitatively identical to the patterns in young subjects: SWS was concentrated in the first part of the night, and SWA decayed monotonically in the course of the sleep period. Coupled with the fact that extended previous wakefulness increases SWS (3, 23, 31) and SWA (21) in older as in younger subjects, sleep intensity clearly remains a function of sleep-wake-dependent processes. Reportedly, age-related decreases in EEG power are not confined to SWA but also encompass theta - as well as sigma -frequency bands (5, 18), whereby the latter is related to a reduction in the number, duration, and amplitude of sleep spindles (10, 32). In contrast to slow-frequency components, the time course of sigma -activity changes profoundly with age. Whereas sigma -activity tends to increase over consecutive non-REM episodes in the young, it hardly fluctuates in middle-aged individuals (5, 18) and even declines across the first half of the night in our senior subjects.

Gaboxadol night. The employed dose of 15 mg of gaboxadol was well tolerated; none of the subjects reported negative side effects. As earlier observed in young subjects (7), gaboxadol did not affect sleep onset latency. Because this substance is absorbed rapidly after oral administration (24), this finding indicates that gaboxadol does not influence sleep initiation in subjects without difficulties in falling asleep; yet gaboxadol significantly shortened self-estimated sleep latency. Intriguingly, subjective sleep latency exceeded objective sleep onset latency during placebo, whereas they matched closely during the gaboxadol night. It is well established that elderly individuals tend to perceive sleep latency as being of longer duration (reviewed in Ref. 30). The gaboxadol-evoked reduction may be explained by its known weak anxiolytic properties (13). Moreover, gaboxadol significantly increased subjectively assessed total sleep time and tended to increase objective total sleep time. Although time in bed was unchanged, gaboxadol reduced the number of awakenings and persistently decreased intermittent wakefulness. Consequently, sleep efficiency was increased by approx 4.5%. The decrease in wakefulness was associated with a tendential increase in SWS during the first half and with an increase in stage 2 during the second half of the night. Gaboxadol did not promote SWS to the extent that it does in younger subjects. It is well established that many manipulations that increase SWS in young individuals, including sleep deprivation and the pulsatile administration of GHRH or cortisol, evoke only minor changes in SWS in aged subjects (2, 11, 21). These findings suggest that the flexibility to change the sleep pattern decreases with age. However, analysis of the EEG within non-REM sleep revealed that gaboxadol powerfully elevated SWA as well as the activity in the theta -frequency bands. The elevations were most prominent during the first part of the sleep period but were still evident at the end of the night. Qualitatively similar yet shorter-lasting effects have been observed in young subjects (7). Thus the elimination half-life of gaboxadol, which is 1.5-2 h in young individuals (24), may increase as a function of age. Although it is at present unclear whether the augmented power in the lower-frequency bands is caused by increases in the number and/or amplitude of slow waves, these observations indicate that gaboxadol increases non-REM sleep intensity. Unlike its influence in young subjects, gaboxadol did not depress sigma -activity, which may be a consequence of age-related changes in the neuronal processes underlying the generation and synchronization of sleep spindles. Concurrent with previous findings in young subjects, gaboxadol did not alter the distribution of REM sleep but persistently enhanced power in all frequency bands <12 Hz, most prominently in high theta , in the EEG within this stage. Because an earlier study found that middle-aged subjects exhibit less power in the delta -, theta -, and alpha -frequencies during REM sleep than young people (5), the present observation suggests that gaboxadol reverses most age-related EEG alterations in both non-REM and REM sleep. Finally, gaboxadol did not affect the hormone levels, which demonstrates that the sleep changes evoked by it are not mediated by or associated with altered activity of the hypothalamic-somatotrophic or HPA systems. Thus the GABAA agonist gaboxadol and benzodiazepine-agonistic modulators of GABAA receptors not only differ in their effects on the sleep EEG but also on sleep-related endocrine activity. With regard to the observation that various compounds that increase SWS or SWA, such as GHRH and gamma -hydroxybutyrate, also increase GH secretion (reviewed in Ref. 29), the absence of such an effect of gaboxadol may be unexpected. However, it has recently been shown that sleep deprivation does not elevate GH levels in elderly subjects either (21), which indicates that increases in SWS and/or SWA are not necessarily associated with concomitant changes in GH.

Previous reports demonstrated that the sleep profile evoked by gaboxadol in rats and young subjects largely resembles recovery sleep after prolonged wakefulness. A recent study examined the influence of a 40-h sleep deprivation on sleep, EEG power densities within non-REM sleep, and hormonal secretion in a group of subjects >60 yr old. Unlike gaboxadol, sleep deprivation slightly elevated the levels of prolactin, prominently reduced sleep onset latency, and attenuated EEG activity in some frequency bands in the range of sleep spindles. Similar to gaboxadol, it did not influence GH and cortisol concentrations, decreased intermittent wakefulness, moderately increased SWS, and augmented EEG activity in the frequency bands <8 Hz (21). Thus gaboxadol pharmacologically mimics various aspects of sleep homeostatic processes in elderly as well as in young individuals.

In conclusion, the present pilot study demonstrates that, upon acute administration, gaboxadol has marked effects on nocturnal sleep in elderly subjects (it increases sleep efficiency, by decreasing intermittent wakefulness, and robustly enhances low-frequency activity in the EEG within non-REM sleep, which suggests an increase in sleep intensity) that counteract typical age-related sleep changes. Coupled with the finding that tolerance to its sleep effects does not seem to develop rapidly in rats (17), gaboxadol shows promise as a treatment strategy for the chronic sleep disturbances that are most common in the elderly population.


    ACKNOWLEDGEMENTS

We thank Dr. Manfred Uhr and Alexandra Rippl for the hormone analyses.


    FOOTNOTES

This study was supported by H. Lundbeck A/S, Copenhagen, Denmark.

Address for reprint requests and other correspondence: M. Lancel, Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 Munich, Germany (E-mail: lancel{at}mpipsykl.mpg.de)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 18 October 2000; accepted in final form 15 February 2001.


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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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Am J Physiol Endocrinol Metab 281(1):E130-E137
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