GABAergic modulation of ventilatory response to acute and sustained hypoxia in obese Zucker rats

OBJECTIVE: To determine whether altered central and/or peripheral gamma-aminobutyric acid (GABA)ergic mechanisms acting in GABA_A 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 (V̇_E), tidal volume (V_T), 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 (B_M, 1 mg/kg, peripheral GABA_A receptor antagonist), or bicuculline hydrochloride (B_HCl, 1 mg/kg, peripheral and central GABA_A receptor antagonist). RESULTS: Administration of B_M and B_HCl in lean animals had no effect on ventilation either during room air breathing or 30 min of sustained exposure to hypoxia. Similarly, B_M failed to alter ventilation in obese rats. In contrast, B_HCl significantly (P < 0.05) increased V̇_E and V_T 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 B_HCl in obese rats, but the V̇_E appeared not to be increased with B_HCl 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 GABA_A 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.