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

Abstract

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. In all, 10 lean and 10 obese Zucker rats were studied at 12 weeks of age. Ventilation (V(.-)(E)), tidal volume (V(T)), and breathing frequency (f) during room air breathing and in response to sustained (30 min) hypoxic (10% O(2)) 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). 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 V(.-)(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 V(.-)(E) appeared not to be increased with B(HCl) due to a decrease in f. 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.