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J Appl Physiol 102: 350-357, 2007. First published September 21, 2006; doi:10.1152/japplphysiol.01463.2005
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GABAA and GABAB receptors differentially modulate volume and frequency in ventilatory compensation in obese Zucker rats

Ai-Lun Yang,1 Ming-Jae Lo,2 Hua Ting,3 Jwo-Sheng Chen,4 Chih-Yang Huang,5,* and Shin-Da Lee6,*

1Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Early Childhood Education, National Taichung University, Taichung, Taiwan; 3Department of Physical Medicine and Rehabilitation, Chung-Shan Medical University Hospital, Taichung, Taiwan; and 4Department of Physiology, 5Graduate Institute of Chinese Medical Science, and 6Department of Physical Therapy, China Medical University, Taichung, Taiwan

Submitted 21 November 2005 ; accepted in final form 16 August 2006


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 
The aim of this study was to investigate whether GABAA and/or GABAB receptor-mediated mechanisms contribute to the impaired ventilatory response and reduced maximal aerobic exercise capacity in obese Zucker rats. Ten lean and 10 obese Zucker rats were studied at 12 wk of age. Minute ventilation (VE), tidal volume (VT), and breathing frequency (f) during room air breathing and in response to 10 min of hypercapnia (8% CO2) and 30 min of hypoxia (10% O2) were measured by the barometric method, and peak oxygen consumption (VO2 peak) was measured by an enclosed metabolic treadmill following the randomized blinded subcutaneous administration of equal volumes of DMSO (vehicle), bicuculline (selective GABAA receptor antagonist, 1 mg/kg), and phaclofen (selective GABAB receptor antagonist, 1 mg/kg). Administration of bicuculline and phaclofen to lean animals had no effect on VE and VO2 peak. Similarly, phaclofen failed to alter VE and VO2 peak in obese rats, although it did significantly increase f after 5–20 min of hypoxia. In contrast, bicuculline increased VE and VT relative to DMSO during room air breathing and after 10–30 min of hypoxic exposure in obese rats, but it did not increase VE at 5 min of hypoxemia. Bicuculline increased VO2 peak relative to DMSO in obese Zucker rats. We conclude that endogenous GABA acting on GABAA receptors can modulate VE and VO2 peak in obese but not in lean Zucker rats, whereas endogenous GABA acting on GABAB receptors modulates f during hypoxia (5–20 min) in obese rats in a very different manner from that when acting on GABAA receptors.

gamma-aminobutyric acid; respiration; bicuculline; phaclofen; hypoxia

MORBID OBESITY IS OFTEN ASSOCIATED with alveolar hypoventilation resulting from excess respiratory demands and insufficient ventilatory output. Abnormal respiratory control in some forms of obesity may lead to a decrease in ventilatory compensation and, in time, to the development of chronic alveolar hypoventilation (hypoxemia and hypercapnia) (27, 37). The obese Zucker rat, a model of morbid obesity, presents many of the same respiratory deficits found in morbidly obese humans (8, 10), including abnormal respiratory control mechanisms (19–23). The underlying mechanisms responsible for these abnormal ventilatory responses in obesity are still unclear, but they are related to altered neuromodulation, which has been previously reported in obese Zucker rats (20, 21, 23, 28–30).

GABA is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS) and acts at ~25–40% of the synapses within the CNS (38). The endogenous GABA acting on ionotropic GABAA receptor and metabotropic GABAB receptor modulates ventilation in different manners. GABAA receptors have been shown to be involved in generating and modulating respiration (13, 17). During hypoxic challenges, brain GABA levels increase and exert an inhibitory effect on ventilation (26, 39). GABAB receptors may contribute essentially to the modulation of respiratory rhythm in adult mammals and may be involved in the control of respiratory neuronal discharge (33). GABAB receptors are also present in the carotid chemoreceptor reflex pathway in the commissural subnucleus of the nucleus tractus solitarii and modulate the chemoreceptor reflex in urethane- and chloralose-anesthetized rats (36).

The obese Zucker rat shows accelerated synthesis of GABA in the brain stem (31) and possesses altered brain GABAergic mechanisms that contribute to their overeating (7, 31). One of our laboratory's previous investigations found important links between GABAA receptors mechanisms and impaired breathing control in obesity (21). That study showed that endogenous GABA acting on GABAA receptors modulates both ventilation during room air breathing and ventilatory response to sustained hypoxia in obese but not in lean Zucker rats by acting specifically on GABAA receptors located within the CNS but not in the peripheral nervous system (21). Increased GABAA receptor-related activity appears to generally depress ventilation and impair exercise capacity in obese Zucker rats (21, 24). However, it is not clearly known whether GABA acting on GABAB receptors modulates minute ventilation (VE) and peak oxygen consumption (VO2 peak). Therefore, GABAA vs. GABAB receptor-mediated modulation of ventilation and exercise capacity in obese Zucker rats needs to be clarified.

The purpose of this study therefore, was to investigate whether GABA acting on GABAA or GABAB receptors modulates the ventilatory response to acute (5 min) and sustained (10–30 min) hypoxia, ventilatory response to hypercapnia, and peak aerobic exercise capacity in morbidly obese Zucker rats. We hypothesized that endogenous GABA acting on GABAA or GABAB receptors modulates ventilation during room air breathing as well that the ventilatory response to acute and sustained hypoxia, the ventilatory response to hypercapnia and modulated VO2 peak in obese but not in lean Zucker rats. In the present study, a parallel study design was used, with lean, age-matched Zucker rats serving as controls.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals.   The studies were performed on 10 lean (Fa/Fa or Fa/fa) and 10 obese (fa/fa) age-matched 12-wk-old male Zucker rats. Animals were born by female (Fa/fa) and male (Fa/fa) breeders purchased from Charles River Laboratory in France. One lean and one obese rat were obtained from the same breeder and were housed in one cage. Ambient temperature was maintained at 25°C, and the animals were kept on an artificial 12:12-h light-dark cycle. The light period began at 7:00 AM. Rats were provided with standard laboratory chow (Lab Diet 5001, PMI Nutrition International, Brentwood, MO) and water ad libitum. All protocols were approved by the Institutional Animal Care and Use Committee of Chang Shan Medical University, Taichung, Taiwan.

VE.   Breathing patterns were recorded using the barometric technique, of which complete details have previously been provided (23). Briefly, a cylindrical Plexiglas chamber with a volume of 4 liters was used to measure metabolic rate and breathing pattern. Gas flow through the chamber was provided from pressurized gas tanks. To measure ventilation, the chamber was completely sealed after momentarily interrupting the flow through it, and the pressure oscillations caused by breathing were recorded for <1 min by a sensitive pressure transducer (Biopac System, Goleta, CA). The pressure signal was amplified by a preamplifier and displayed on the Biophysical Monitoring System (model MP 100, Biopac). Injection and withdrawal of 0.3 ml of air with a 1-ml syringe were performed at least 12 times during the recording for calibration. From the pressure oscillations due to breathing, tidal volume (VT) was computed using the formula described by Drorbaugh and Fenn (9), incorporating the analytic modification suggested by Jacky (16). For each condition, VT and breathing frequency (f) were calculated over a period corresponding to at least 30 successive breaths. VE was also calculated (VE = VT x f), and it was expressed at body temperature-atmospheric pressure-saturation (ml BTPS·kg–1·min–1). Colonic temperature was measured continuously from a digital rectal thermoprobe and was taken as representative of body temperature (Tb).

VO2 peak.   The exercise test to elicit VO2 peak was performed in a metabolic treadmill. To maintain a constant flow rate, airflow through the metabolic treadmill was provided from pressurized air tanks. Flow was controlled by a flowmeter (Dwyer Instruments) and maintained at 5 l/min throughout the exercise test. Because the lean and obese animals had different exercise capacities (23), the exercise protocols used to elicit VO2 peak were slightly different for lean and obese rats. The treadmill slope was set at 20% for lean animals and 10% for obese animals and remained constant throughout the exercise test. After being injected with one of three solutions (DMSO, bicuculline, or phaclofen), each rat was placed into the metabolic treadmill where it started exercising for 30 min. The protocol for lean animals consisted of an initial speed of 10 m/min followed by a 3 m/min increases in speed every 2 min until the animal could no longer to run. Obese rats began at 10 m/min followed by a 3 m/min increases every 3 min.

O2 consumption and CO2 production.   O2 consumption (VO2) and CO2 production (VCO2) were measured from the inlet and outlet of the barometric chamber. The concentrations of CO2 and O2 entering and exiting the chamber were monitored with a CO2 gas analyzer (model O2 100C, Biopac) and an O2 analyzer (model CO2 100C, Biopac) arranged in a series. The calibrations and linearities of the gas analyzers were checked twice daily using certified calibration gases. Data were presented at standard temperature and pressure under dry conditions (STPD), corrected for the effective body mass (EBM) exponent according to Refinetti (34), and were expressed in kilograms to the power of 0.75 (ml O2 STPD·kg–0.75·min–1). EBM was calculated as 1.00 M0.75 and 0.86 M0.75 for lean and obese Zucker rats, respectively [M is total body mass (kg)] (34). EBM was used to minimize metabolic differences in adipose tissue mass between lean and obese rats.

Experimental protocol.   Animals were retested at 3-day intervals following a subcutaneous injection of equal volumes of either DMSO (vehicle; 1 ml/kg), phaclofen (1 mg/kg, GABAB receptors antagonist), or bicuculline hydrochloride (1 mg/kg, GABAA antagonist) (Sigma Chemical, St. Louis, MO). All three solutions were prepared daily and placed in vials labeled as solutions I, II, or III. The agents were administered in a blinded, randomized design with 72 h elapsing between successive tests. The investigators involved in the testing were blinded to the contents of the vials and remained so until both the ventilatory tests were completed and the data were analyzed. After the test agent was administered and the rectal thermoprobe was inserted, the rat was placed into the barometric chamber within the restrainer. All animals were exposed to room air for 30 min, hypoxic exposure (10% O2-balance N2) for 30 min, room air for 10 min, and hypercapnic exposure (8% CO2-23% O2-balance N2). Ventilatory and metabolic data were collected at 20 and 30 min after drug administration during room air breathing; at 35, 40, 50, and 60 min after drug administration during hypoxia; at 70 min after drug administration during room air; and at 80 min after drug administration during hypercapnia. Ventilation and exercise tests were performed on six separate occasions with no less than a 72-h recovery period between successive tests. Five lean and five obese Zucker rats underwent ventilatory tests on days 1, 4, and 7, followed by exercise tests on days 10, 13, and 16, whereas the remaining five pairs underwent exercise test on days 2, 5 and 8, followed by ventilatory test on days 11, 14, and 17. Thus, ventilatory and exercise tests were completed within a 17-day period. In an attempt to minimize the stress level during the study, all animals were habituated to a restrainer with a rectal probe for 3 days/wk for 1 mo and to an experimental protocol inside the chamber for 2 days before the first study. To minimize any potential differences related to circadian rhythms, each rat was injected and tested at approximately the same time of day.

Statistical analysis.   Body weights of lean and obese rats were averaged over the 7-day experimental period, and differences between the two groups were tested by unpaired Student's t-test. The other parameters [VE, VT, f, VO2, VCO2, ventilatory equivalent for O2 (VE/VO2), ventilatory equivalent for CO2 (VE/VCO2), and Tb] were analyzed by analysis of variance using the general linear model in a one-between (lean and obese) and two-within (gases exposures over time, drugs) design. Differences in ventilatory and metabolic parameters among vehicle, phaclofen, and bicuculline were subsequently tested as single-group repeated measures with contrast transformation during room air and during hypoxic or hypercapnic exposure in lean vs. obese rats, separately. The contrast transformation is useful when one level of the repeated measures effect is a control level, DMSO, against which the other level, phaclofen, or bicuculline, is compared. In all cases, P < 0.05 was considered statistically significant. All data presented in the text, tables, and figures are means ± SE.


   RESULTS
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 RESULTS
DISCUSSION
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Obese rats weighed ~40% (265 ± 4 vs. 385 ± 8 g; P < 0.01) more than age-matched lean animals. Obese Zucker rats had a lower VE (ml·min–1·kg–1) and a lower VT (ml/kg) than lean rats during room air breathing and adopted a breathing strategy with a higher f (Table 1). There was a significant interaction in VE between lean and obese rats (P < 0.01). There was a significant interaction in VE among three factors (phenotypes, time courses, and drugs) (P < 0.01).


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  		Table 1. Ventilatory and metabolic parameters in room air

 
Room air.   The changes of ventilatory patterns were similar under room air exposure at the three different time points of postinjection (20, 30, and 70 min) after phaclofen or bicuculline administration relative to DMSO. In lean Zucker rats, VE, VT, f, VO2, VCO2, VE/VO2, and VE/VCO2, and Tb under room air exposure were unaffected by the administration of either phaclofen or bicuculline (Table 1, Fig. 1). Phaclofen had no effect on all parameters during room air breathing (f, VT, VE, VE/VO2,VE/VCO2, VO2, VCO2, and Tb) in obese Zucker rats. In sharp contrast, bicuculline injection increased VT, VE, VE/VO2, and VE/VCO2 but it did not increase f, VO2, VCO2, and Tb in obese Zucker rats during room air breathing (Table 1, Fig. 1).


Figure 1
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  		Fig. 1. Effects of DMSO (vehicle; {circ}), phaclofen ({blacktriangleup}), and bicuculline (bullet) administration on minute ventilation (VE), tidal volume (VT), and breathing frequency (f) of lean (left, n = 10) and obese (right, n = 10) Zucker rats during 20th to 30th min of room air, during 30th to 60th min of 10% O2 exposure and during 60th to 70th min of room air. Injection time of DMSO, phaclofen, or bicuculline is at 0 min (not shown). Values are means ± SE. *P < 0.05, **P < 0.01, significant difference between DMSO and bicuculline at the same time point. #P < 0.05, significant difference between DMSO and phaclofen at the same time point.

 
Hypoxia.   In lean Zucker rats, during acute hypoxic exposure (5 min), neither phacolfen nor bicuculline brought about a changes in any of the parameters (f, VT, VE, VE/VO2, VE/VCO2, VO2, VCO2, and Tb), compared with those treated with DMSO (Table 2). In obese Zucker rats, phaclofen administration increased f during acute hypoxic exposure for 5 min and during sustained hypoxia for 10 and 20 min (Table 2, Fig. 1), whereas VE, VT, and other parameters were not altered relative to DMSO. (Table 3, Fig. 1). During acute hypoxic exposure, obese Zucker rats treated with bicuculline exhibited both a significant (P < 0.05) elevation in VT and a decrease in f (5 min) relative to DMSO, which resulted in no change in VE at 5 min hypoxic exposure (Table 2, Fig. 1). At the same time, bicuculline pretreatment did not alter other parameters (VE/VO2, VE/VCO2, VO2, VCO2, and Tb) in obese Zucker rats, compared with DMSO (Table 2). In contrast, obese rats treated with bicuculline exhibited significant elevations relative to DMSO in VT, VE, VE/VO2, and VE/VCO2 but not in f, VO2, VCO2, and Tb during 10–30 min of hypoxia (Fig. 1).


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  		Table 2. Ventilatory and metabolic parameters to hypoxia at 5 min

 

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  		Table 3. Ventilatory and metabolic parameters to hypoxia at 30 min

 
Hypercapnia.   Ventilatory parameters measured in response to the hypercapnic gas challenge were unaffected relative to DMSO in the obese Zucker rats following the administration of either phaclofen or bicuculline (Table 4). In addition, the administration of phaclofen or bicuculline had no significant effect on any metabolic parameter and Tb during CO2 exposure in obese Zucker rats, compared with DMSO (Table 4).


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  		Table 4. Ventilatory parameters during hypercarpnic exposure in lean and obese Zucker rats treated with vehicle, phaclofen, and bicuculline

 
VO2 peak.   Obese rats had a reduced VO2 peak (ml·kg–0.75·min–1) compared with lean rats (P < 0.01; 1-way ANOVA) (Table 5). VO2 peak (expressed either ml/kg, ml·kg–1·min–1, or ml·kg–0.75·min–1) was unaltered relative to DMSO following either phaclofen or bicuculline administration in lean animals compared with DMSO (Table 5, Fig. 2). The average of VO2 peak was significantly increased (60.0 ± 4.8 vs. 66.1 ± 3.6 ml·kg–0.75·min–1; P < 0.05) following bicuculline administration compared with controls. In contrast, VO2 peak was not changed relative to DMSO by phaclofen administration (Table 5, Fig. 2).


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  		Table 5. VO2 peak in lean and obese Zucker rats treated with vehicle, phaclofen, and bicuculline

 

Figure 2
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  		Fig. 2. Effects of phaclofen (top, {blacksquare}) and bicuculline (bottom, bullet) administration on mean peak O2 consumption normalized by effective body mass (VO2 peak/EMB) response across the percentage of exercise time to peak in lean (left, n = 10) vs. obese (right, n = 10) Zucker rats, comparing with DMSO administration ({circ}). Values are means ± SE. *P < 0.05, Significant difference from the value of vehicle, DMSO, at the same time point.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Our findings can be summarized as follows: 1) endogenous GABA acting on either GABAA or GABAB receptors did not modulate VE and VO2 peak in lean Zucker rats; 2) in obese rats, ventilation during room air breathing was depressed by endogenous GABAergic activity via GABAA receptors; 3) in obese rats, the pattern of breathing during acute hypoxia was altered by GABAA or GABAB blockade, each in quite different manners; 4) during sustained hypoxic exposure, ventilation (via VT) was persistently elevated via inhibition of GABAA not GABAB receptors in obese rats; and 5) the reduced aerobic exercise capacity in obese Zucker rats may be attributed to altered GABAA receptor-mediated not GABAB receptor-mediated mechanisms. Therefore, the data in the present study support our hypothesis that endogenous GABA acting on GABAA receptors and GABAB receptors modulates ventilation and exercise in very different ways.

GABA is the major inhibitory neurotransmitter in the mammalian CNS and acts at ~25–40% of the synapses within the CNS (6). GABA can exert its effect via either ionotropic (GABAA and GABAC) receptors, to produce fast synaptic inhibition, or via metabotropic GABAB receptors, to produce slow, prolonged inhibitory signals (6).

GABA is inhibitory neurotransmitter acting on GABAA and GABAB receptors located in many sites (2, 6). Previous studies have suggested that systemic administration of phaclofen is able to cross the blood-brain barrier and has effects on the CNS (2). For example, phaclofen (2 mg/kg sc) has been found to antagonize the effects of 6 mg/kg baclofen in dorsal striatum via electrophysiological and microdialysis studies (2). In the present study, phaclofen and bicuculline were injected systemically such that there would be widespread antagonistic actions (6). Thus specific locations where these agents act are not clear from the present study. GABA and other inhibitory neuromodulators play an important role in neuronal regulation of breathing (13, 17). GABA may be involved in a neurotransmitter in the modulation of respiratory neural activities (12, 14, 18). GABAB receptors are present in the commissural subnucleus of the nucleus tractus solitarii and modulate the chemoreflex (36). Our first goal was rather to distinguish the relative role of GABAA vs GABAB receptor-mediated mechanisms in contributing to altered ventilatory response or reduced VO2 peak in obese Zucker rats. Besides, because of a different GABAergic mechanism between normoxic and hypoxic ventilation, we had to draw our conclusions by observing the absolute values comparing bicuculline vs. DMSO or phaclofen vs. DMSO instead of observing the changes in ventilation comparing normoxia vs. hypoxia. Further experiments using microinjections into specific brain regions will be required to identify those areas that are directly responsible for the ventilatory responses.

The frequency and amplitude of the activity recorded from the phrenic and hypoglossal nerves have been reported to be reduced after administering the agonists of GABAA and GABAB receptors (12). Similar effects were observed following the infusion of bicuculline (0.05–0.2 µM) and phaclofen (0.1–0.2 mM), both of which increased the frequency and amplitude of inspiratory bursts (12). Generally, respiratory neural activities are potentially inhibited by GABA acting on either GABAA and GABAB receptors. In the present study, a GABAA receptor antagonist significantly increased VT and VE during room air breathing in obese, but not in age-matched lean, Zucker rats; the same increases, however, were not observed after a GABAB receptor antagonist was administered. Therefore, during the breathing of room air, GABAA receptor mediated VE in obese rats, whereas GABAB receptor did not mediate VE under the same conditions. When treated with bicuculline, obese Zucker rats increased in VE, VE/VO2, and VE/VCO2, but they had no changes in surrounding CO2 level, metabolic rate (VO2, VCO2), and Tb. The administration of phaclofen, however, had no effect on metabolic rate or Tb in lean and obese Zucker rats. In a previous study, Kneussl and colleagues (18) showed that metabolic rate was independent of the effects of GABA on respiration. Similarly, our results appear to support the idea that GABAergic modulation of ventilation, regardless of whether it acts on GABAA or GABAB, is independent of metabolic rate or Tb.

We found a significant interaction in VE between lean and obese rats. Lean Zucker rats exhibited an abrupt increase in VE in response to acute (5 min) hypoxic exposure followed by a gradual decline with sustained (20 and 30 min) hypoxia. Obese Zucker rats, however, have been reported to exhibit an initial increase in VE in response to acute hypoxia that plateaus during chronic hypoxia (19, 20, 22, 29). The initial rise in VE in response to acute hypoxia originates from peripheral receptors, located mainly in the carotid body, which project to the nucleus tractus solitarius in the brain stem (11). The gradual decline in VE as hypoxia continues, which has been noted in lean animals, is thought to be mediated by central ventilatory depression in response to hypoxic depression of central neurons (17).

Lean rats treated with either bicuculline or phaclofen exhibited no changes in VE, compared with those treated with the vehicle (DMSO), during acute and sustained hypoxic responses, suggesting that endogenous GABA acting on GABAA or GABAB receptors does not contribute to either the early or the late hypoxic ventilatory responses. In contrast, obese Zucker rats treated with bicuculline did not increase VE during 5 min hypoxic exposure, because VT increased and f decreased. During 10- to 30-min hypoxic exposure, obese rats treated with bicuculline, but not phaclofen, did exhibit significant elevations in VT, VE, VE/VO2, VE/VCO2 but not in f, VO2, VCO2, and Tb. GABA acting on GABAB receptors modulated f during acute and sustained hypoxia in obese but not in lean Zucker rats. These findings indicate that GABA acting on GABAA receptors modulates ventilatory response to sustained hypoxic exposure in obesity, which is independent of metabolic rate or Tb, whereas GABA acting on GABAB receptors modulates the patterns of breathing during acute hypoxia and early sustained hypoxia. Endogenous GABA acting on GABAA and GABAB receptors did modulate ventilation and/or the pattern of breathing in a very different manners during hypoxic exposure.

During hypercapnia, the respiratory drive is primarily determined by central chemoreceptors, which respond to changes in H+ concentration. In the present study, bicuculline or phaclofen administration had no effect on VE during 8% hypercapnia in either lean or obese animals. It has been previously reported that intracerebroventricular administration of GABA did depress an increased ventilation during 10% CO2 exposure (13), indicating that the preexisting GABAergic modulation at rest was not directly mediated by GABAA or GABAB receptors but that it was compensated by central chemical drive or neutralized by increased CO2/H+ (15). VE during hypercapnic exposure in both lean and obese Zucker rats was not modulated by GABAA or GABAB receptors.

There was a greater reduction in relative VO2 peak (ml·kg–0.75min–1) in the obese animals than in the lean animals (Table 5, Fig. 2), mirroring findings in obese humans (3). The run time to exhaustion on a treadmill set at a speed of 25 m/min has been reported to be significantly increased in rats administered the GABAB receptor agonist baclofen (1). However, we did not find that phaclofen administration changed VO2 peak in either lean or obese animals. In contrast, bicuculline administration led to an increase in VO2 peak in obese animals, reducing the difference between lean and obese animals. Thus endogenous GABA acting on GABAA receptors, which tonically inhibit VO2 peak in obese animals, may partially contribute to their reduced capacity for aerobic exercise. The underlying mechanism of GABAA receptor-mediated inhibition on VO2 peak is unknown. Muscimol, a GABAA receptor agonist, injected directly into the posterior hypothalamus significantly decreased treadmill run time to exhaustion (32). Whether exercise contributes to an increase in brain GABA content is still unknown. Striatal GABA levels remain unchanged following short-term exercise in rats (25), whereas whole brain GABA content is reduced following prolonged exercise in rats (5). It is also unclear whether GABA levels are different during exercise in lean and obese rats. The increase in VO2 peak following bicuculline administration may be secondary to improved ventilatory function. Although the respiratory system is not normally considered a limiting factor to peak aerobic exercise, this may not be so in certain pathological situations that affect the respiratory system such as aging, lung disease, and obesity (3). In the obese rat, mass loading together with reduced ventilatory drive may limit ventilation during exercise. Thus we can speculate that once bicuculline is administered, the increased respiratory drive enables obese rats to attain a higher ventilation and a concomitant higher VO2 peak. Once phaclofen is administered, the obese rats were found to have no changes in respiratory drive and no changes in VO2 peak. However, although we presently have no means of measuring VE during maximal exercise in obese rats, we conclude that reduced exercise capacity in obese Zucker rats may be attributed to altered GABAA receptor-mediated but not to GABAB receptor-mediated mechanisms.

Clinical application.   The dysregulation of GABA mediated food intake and hypothalamic-pituitary-adrenal function had been reported in studies of human obesity (4, 35). The role of the GABAergic system in the pathophysiology of obese alveolar hypoventilation is not totally understood. Obesity hypoventilation syndrome may involve multiple factors, including impaired respiratory control, respiratory muscle weakness, abnormal respiratory load compensation, and chest wall limitations (27, 37). One recognized theory to explain the pathogenesis of obesity hypoventilation syndrome is depressed chemical ventilatory drive (37). Although no study as far as we know had implicated GABA in obesity hypoventilation syndrome, our study suggests that GABAA receptor-mediated tonic inhibition may be responsible for the impaired ventilatory control in obesity. Further clinical studies are required to clarify whether endogenous GABA acting on GABAA receptor plays an important role in the pathogenesis of obesity hypoventilation syndrome or in the impaired ventilatory control in obesity.


   GRANTS
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 ABSTRACT
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REFERENCES
 
The study was supported by National Science Council, Taiwan, Grant NSC 93-2314-B-040-002.


   FOOTNOTES
 

Address for reprint requests and other correspondence: S.-D. Lee, Dept. of Physical Therapy, College of Health Care, China Medical Univ., 91 Hsueh-Shih Rd., Taichung 40202, Taiwan (e-mail: shinda{at}mail.cmu.edu.tw)

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.

* C.-Y. Huang and S.-D. Lee contributed equally to this work. Back


   REFERENCES
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