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

Abstract

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 ( . 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). 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 (Po0.05) 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. 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.

GABA-mediated neurotransmission in the nucleus of the solitary tract alters resting ventilation following exposure to chronic hypoxia in conscious rats

“…2). On the other hand, Lin et al (18) demonstrated that bicuculline treatment (sc) had no effect on resting ventilation (while breathing room air) or the HVR (30 min of hypoxia) in conscious lean Zucker rats. Furthermore, in obese Zucker rats, bicuculline treatment caused a reduction in fR and an elevation in VT during exposure to acute hypoxia.…”

GABAAand GABABreceptors differentially modulate volume and frequency in ventilatory compensation in obese Zucker rats

“…That study showed that endogenous GABA acting on GABA A 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 GABA A receptors located within the CNS but not in the peripheral nervous system (21). Increased GABA A 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 GABA B receptors modulates minute ventilation (V E) and peak oxygen consumption (V O 2 peak ).…”

More Activated Cardiac Mitochondrial‐dependent Apoptotic Pathway in Obese Zucker Rats

“…The obese Zucker rat, a genetic model of severe obesity, presents many of the same cardiopulmonary deficits as noted in obese humans, including respiratory control dysfunction (1, 2, 3, 4), chest wall limitations (5), upper airway narrowing (6), hypertension (7), myocardial hypertrophy (8), and poor exercise capacity (9, 10). Severe obesity in humans has long been recognized as causing a form of cardiomyopathy characterized by increased rates of hypertension, chronic volume overload, left ventricular hypertrophy, and the development of heart failure (11, 12, 13, 14).…”