Intermittent but not sustained hypercapnic hypoxia induces ventilatory long‐term facilitation in awake rats

Obstructive sleep apnea (OSA) patients experience hypercapnia as well as hypoxemia during their recurrent apnea events. However, respiratory long‐term facilitation (LTF), which may play a role in stabilizing upper airway patency in OSA patients as some postulated, has so far been studied almost exclusively using intermittent hypoxia alone. In anesthetized rats, intermittent, but not sustained, hypoxia induces LTF, whereas neither intermittent nor sustained hypercapnia induces LTF. The aim of this study was to systematically examine the effectiveness of either intermittent or sustained exposure to hypoxia and/or hypercapnia in inducing ventilatory LTF in awake rats. Thus adult male Sprague‐Dawley rats were exposed to 9 different protocols: 10 episodes of 2‐min hypercapnic hypoxia (HH: 5% CO 2 plus 10% O 2 ), hypoxia (HX: 10% O 2 ) or hypercapnia (HC: 5% CO 2 ) with 3‐min normoxia intervals, and sustained HH, HX or HC with 47‐min (entire protocols) or 20‐min (accumulative stimuli) duration. LTF, measured by plethysmography, was successfully induced by intermittent HH (23% above baseline) and intermittent HX (20%), but not by intermittent HC (3%) or any of the sustained protocols (HH: 2% and 3%, HX: 2% and −1%, HC: −5% and −3%). These results indicate that intermittent HH, which more closely mimics sleep apneas compared with intermittent HX, induces a similar, if not greater, ventilatory LTF in awake rats. These data also confirm in awake rats that neither intermittent nor sustained HC induces LTF, and that the pattern of intermittent stimuli is essential since sustained HH or HX fails to induce LTF even with relatively longer durations. (Supported by NIH HL64912)