Episode Frequency Determines the Impact of Chronic Intermittent Hypoxia on Phrenic Long Term Facilitation

Abstract

Acute intermittent hypoxia (AIH) elicits a form of spinal, phrenic motor plasticity known as phrenic long‐term facilitation (pLTF). Preconditioning with chronic intermittent hypoxia (CIH) as might be experienced during sleep disordered breathing, has conflicting effects on pLTF. For example, preconditioning with CIH consisting of 5 min hypoxic episodes with 5 min intervals (12 hours per night; 7 days) enhances AIH induced pLTF (Ling et al., 2001). Conversely, 8 hours of intermittent hypoxia consisting of 2 min episodes with 2 min intervals 16 hours prior to AIH abolishes pLTF through a mechanism that requires systemic inflammation and spinal p38 MAP kinase activation (Huxtable et al., 2015). We hypothesized that this differential response resulted from differences in the frequency hypoxic episodes (6 versus 15 per hour), versus the cumulative duration (1 versus 7 days) or timing (day versus night) of intermittent hypoxia. Thus, we compared the impact of intermittent hypoxia presented for 7 consecutive days, 8 hours per day (IH‐7). The three experimental groups were: 1) 5 min episodes of 10.5% O2 with 5 min normoxic intervals (6 episodes/hour, 8 hours/day, 7 days; IH‐7‐5min); 2) 2 min hypoxic episodes (10.5% O2) with 2 minute normoxic intervals (15 episodes/hour, 8 hours/day, 7 days; IH‐7‐2 min); and 3) naïve rats exposed to normoxia (21% O2; 8hrs/day, 7 days; sham). Neurophysiology experiments conducted 16 hours after the final day of IH‐7 enabled assessment of AIH‐induced phrenic and hypoglossal long‐term facilitation. In comparison with sham rats, rats preconditioned with IH‐7‐5 exhibited normal pLTF expression (45% baseline; p < 0.05). In rats preconditioned with IH‐7‐2, pLTF was abolished (7% baseline; p> 0.05). Mean arterial pressure was elevated in rats exposed to IH‐7‐2 (10mmHg), but not IH‐7‐5. Thus, the impact of CIH on pLTF and arterial blood pressure is highly dependent on the frequency of hypoxic episodes. An important transition in impact of CIH from pro‐plasticity to pro‐inflammatory/pathogenic (Dale et al., 2014) occurs between 6 and 15 episodes per hour, consistent with previous literature reports (Navarette‐Opazo et al., 2014).Support or Funding InformationSupported by: K12HD055929 (EGR), 1R01HL69084 (GSM); 1R01HL511198 (GSM)