OBJECTIVE: To determine whether altered central and/or peripheral gamma-aminobutyric acid (GABA)ergic mechanisms acting in GABAA receptors contribute to the abnormal ventilatory response to acute and sustained hypoxia in obese Zucker rats. METHODS: In all, 10 lean and 10 obese Zucker rats were studied at 12 weeks of age. Ventilation (V̇E), tidal volume (VT), and breathing frequency (f) during room air breathing and in response to sustained (30 min) hypoxic (10% O2) challenges were measured on three separate occasions by the barometric method following the randomized blinded administration of equal volumes of DMSO (vehicle), bicuculline methiodide (BM, 1 mg/kg, peripheral GABAA receptor antagonist), or bicuculline hydrochloride (BHCl, 1 mg/kg, peripheral and central GABAA receptor antagonist). RESULTS: Administration of BM and BHCl in lean animals had no effect on ventilation either during room air breathing or 30 min of sustained exposure to hypoxia. Similarly, BM failed to alter ventilation in obese rats. In contrast, BHCl significantly (P < 0.05) increased V̇E and VT during room air breathing and 10-30 min of hypoxic exposure in obese rats. During 5 min of acute hypoxic exposure, V T remained elevated with BHCl in obese rats, but the V̇E appeared not to be increased with BHCl due to a decrease in f. CONCLUSION: Thus, endogenous GABA modulates both ventilation during room air breathing and ventilatory response to sustained hypoxia in obese, not in lean, Zucker rats by acting specifically on GABAA receptors located within the central, not peripheral, nervous system. However, endogenous GABA does not modulate ventilation but the pattern of breathing during acute hypoxia in obesity in a different manner from that during sustained hypoxia.
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