| The underlying mechanisms responsible for the blunted ventilatory responses to hypoxia and hypercapnia in morbid obesity are unknown, but these blunted ventilatory responses are thought to represent part of the pathogenesis of the Obesity hypoventilation Syndrome (OHS) in obese humans. To investigate our hypothesis that altered neuromodulation contributes to the altered ventilatory responses in obesity, six independent studies were completed to evaluate the role of “Opioidergic, gamma-aminobutyric acid” (GABA)-ergic, N-methyl-D-aspartate (NMDA) receptor-mediated, nitroxidergic, dopaminergic, and adenosinergic ventilatory neuromodulatory systems in obese Zucker rats. Each study was performed on 14 or 16 male Zucker rats, half of the lean phenotype and half of the obese phenotype. Ventilation (VE) was measured on separate occasions by the barometric method following the randomized blinded administration of equal volumes of vehicle and specific antagonists to the various neurotransmitters/neuromodulators in question. Our findings can be summarized as: (1) resting ventilation in obese Zucker rats is modulated by increases in GABAergic and central opioidergic activity and by a decrease in nitroxidergic activity; (2) the ventilatory response to acute hypoxia in obese Zucker rats is modulated by increases in central opioidergic, peripheral dopaminergic, and central adenosinergic activities, and by decreases in NMDA receptor-mediated, nitroxidergic, and peripheral adenosinergic activities; (3) the ventilatory response to sustained (20∼30 min) hypoxia in obese Zucker rats is modulated by increases in GABAergic, and central adenosinergic activities, by decreases in nitroxidergic activities, and by changes in NMDA receptor-mediated and central opioidergic activity. These findings provide a potential link between various complex neural mechanisms and altered ventilatory drive in obesity, and implicates various neuromodulators as contributors to the depressed ventilation in obesity, thus providing valuable information both for sorting out the pathophysiology and for developing therapeutic methods to treat impaired ventilation in obesity. |
