Chronic Intermittent Hypoxia Blunts the Expression of Ventilatory Long Term Facilitation in Sleeping Rats.

We have previously reported that chronic intermittent hypoxia (CIH), a central feature of human sleep-disordered breathing, causes respiratory instability in sleeping rats (Edge D, Bradford A, O'halloran KD. Adv Exp Med Biol 758:359-363, 2012). Long term facilitation (LTF) of respiratory motor outputs following exposure to episodic, but not sustained, hypoxia has been described. We hypothesized that CIH would enhance ventilatory LTF during sleep. We examined the effects of 3 and 7 days of CIH exposure on the expression of ventilatory LTF in sleeping rats. Adult male Wistar rats were exposed to 20 cycles of normoxia and hypoxia (5 % O(2) at nadir; SaO(2) ~ 80 %) per hour, 8 h per day for 3 or 7 consecutive days (CIH, N = 7 per group). Corresponding sham groups (N = 7 per group) were subjected to alternating cycles of air under identical experimental conditions in parallel. Following gas exposures, breathing during sleep was assessed in unrestrained, unanaesthetized animals using the technique of whole-body plethysmography. Rats were exposed to room air (baseline) and then to an acute IH (AIH) protocol consisting of alternating periods of normoxia (7 min) and hypoxia (FiO(2) 0.1, 5 min) for 10 cycles. Breathing was monitored during the AIH exposure and for 1 h in normoxia following AIH exposure. Baseline ventilation was elevated after 3 but not 7 days of CIH exposure. The hypoxic ventilatory response was equivalent in sham and CIH animals after 3 days but ventilatory responses to repeated hypoxic challenges were significantly blunted following 7 days of CIH. Minute ventilation was significantly elevated following AIH exposure compared to baseline in sham but not in CIH exposed animals. LTF, determined as the % increase in minute ventilation from baseline following AIH exposure, was significantly blunted in CIH exposed rats. In summary, CIH leads to impaired ventilatory responsiveness to AIH. Moreover, CIH blunts ventilatory LTF. The physiological significance of ventilatory LTF is context-dependent but it is reasonable to consider that it can potentially destabilize respiratory control, in view of the potential for LTF to give rise to hypocapnia. CIH-induced blunting of LTF may represent a compensatory mechanism subserving respiratory homeostasis. Our results suggest that CIH-induced increase in apnoea index (Edge D, Bradford A, O'halloran KD. Adv Exp Med Biol 758:359-363, 2012) is not related to enhanced ventilatory LTF. We conclude that the mature adult respiratory system exhibits plasticity and metaplasticity with potential consequences for the control of respiratory homeostasis. Our results may have implications for human sleep apnoea.