Shorter hypoxic and inter-hypoxic intervals enhance acute intermittent hypoxia-induced phrenic long-term facilitation

Phrenic long-term facilitation (pLTF) is a form of respiratory motor plasticity evoked by repeated exposure to low oxygen (acute intermittent hypoxia; AIH). AIH has emerged as a promising therapeutic approach to restore lost respiratory and non-respiratory function in people with spinal cord injury and other clinical disorders that compromise movement. Optimal AIH protocols ( e.g. episode severity/duration and number of hypoxic episodes) to elicit plasticity (and therapeutic benefit) have not yet been established. Three, 5-minute moderate hypoxic episodes with 5-minute intervals have been used most often to study pLTF. New data suggest that the same cumulative duration of hypoxia ( i.e. 15 min), when presented in shorter episodes, enhances pLTF by minimizing hypoxia-evoked adenosine release. Although the “standard” AIH protocol can be improved by reducing the duration of hypoxic episodes, little attention has yet been given to the duration of inter-hypoxic intervals. Thus, we began investigations concerning the impact of interval duration and episode number in moderate AIH protocols (mAIH; arterial P O2 = 40-55mmHg). pLTF was assessed in anesthetized, paralyzed, vagotomized and ventilated male Sprague-Dawley rats exposed to mAIH consisting of: 1) 3, 1 minute hypoxic episodes (3x1) with either 5-, 2- or 1-minute inter-hypoxic intervals; or 2) 2, 5-minute hypoxic episodes with a single 15-minute interval, compared with the conventional protocol (3, 5 minute hypoxic episodes, 5 minute intervals). mAIH consisting of 3x1, 5-min intervals elicit similar pLTF versus 3, 5 min episodes with 5-min intervals (64 ± 7% and 64% ± 1%, respectively; both n=3) at 60 minutes post-hypoxia. Thus, shorter intervals in an otherwise similar mAIH protocol consisting of 3x1 minute hypoxic episodes significantly enhance pLTF (1-minute: 146 ± 15%, n=5; 2 minute: 92 ± 17%, n = 3). Two, 5-minute hypoxic episodes with a single 15-minute inter-hypoxic interval still elicited pLTF of 51 ± 26% (n=4). These preliminary findings suggest both the hypoxic episode and interval duration are important determinants of mAIH-induced pLTF. Optimizing AIH-induced motor plasticity is necessary as we harness its therapeutic potential to treat severe neuromuscular disorders that compromise breathing. Supported by: NIH HL147554, HL148030, T32HL134621 (ABM) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.