GABAA and GABAB receptors differentially modulate volume and frequency in ventilatory compensation in obese Zucker rats

Abstract

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 (V̇e), 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 (V̇o2 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 V̇e and V̇o2 peak. Similarly, phaclofen failed to alter V̇e and V̇o2 peak in obese rats, although it did significantly increase f after 5–20 min of hypoxia. In contrast, bicuculline increased V̇e 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 V̇e at 5 min of hypoxemia. Bicuculline increased V̇o2 peak relative to DMSO in obese Zucker rats. We conclude that endogenous GABA acting on GABAA receptors can modulate V̇e and V̇o2 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.