Central-peripheral respiratory chemoreflex interaction changes with acclimatization to high altitude

Background: With chronic exposure to hypobaric hypoxia, the medullary (central) and arterial (peripheral) respiratory chemoreflexes become sensitized (i.e., ventilatory acclimatization). Whether the interaction between chemoreceptors is also altered has not been assessed. PURPOSE & HYPOTHESIS: We investigated the peripheral chemoreflex response to hypoxia at increasing arterial and central CO 2 tensions in humans at 1100 m (low altitude: Calgary, Canada) and after 7 days at 3800 m (high altitude: La Paz, Bolivia). We hypothesized that ventilatory acclimatization alters central and peripheral chemoreceptor interaction. METHOD: Seventeen participants (8 females; mean±SD age: 27±5 years) completed two repetitions of modified rebreathing with end-tidal PO 2 (P ET O 2 ) clamped at 150, 60, and 45 mmHg over two visits at each location. End-tidal PCO 2 (P ET CO 2 ), P ET O 2 , ventilation (V· E ), and saturation (S p O 2 ) were measured breath-by-breath by dual gas analyser, volume turbine, and pulse oximeter. The V· E vs. P ET CO 2 relationship in the hyperoxic test gave the central chemoreflex response to PCO 2 and the hypoxic tests provided combined central-peripheral chemoreflex responses. ANALYSIS: The slope of the V· E vs. P ET CO 2 (V· E S, L·min -1 ·mmHg -1 ) of each iso-oxic condition was obtained by fitting a piecewise model. Linear regression was used to determine peripheral chemoreflex sensitivity (PChS: L·min -1 ·mmHg -1 ·% S c O 2 -1 ) at each P ET CO 2 as previously described (Guluzade et al. 2023). These steps were repeated every 1 mmHg of P ET CO 2 to build a PChS vs. PCO 2 relationship for each participant. Individual PChS-P ET CO 2 relationships were fit with linear (additive) and polynomial (non-additive) functions. Akaike Information Criterion identified the best-fit model. Results: Two-way (isoxic condition x location) repeated measures analysis of variance revealed that V· E S rose from low-to-high altitude (p<0.001) and with isoxic PO 2 (p<0.001) from 4.0±2.1 to 7.2±5.4 L·min -1 ·mmHg -1 at 150 mmHg, 6.3±3.5 to 9.7±4.9 L·min -1 ·mmHg -1 at 60 mmHg, and 7.7±4.8 to 11.5±5.1 L·min -1 ·mmHg -1 at 45 mmHg. The PChS vs. P ET CO 2 relationship was best described by an additive (linear) model in 12 and 13 of 17 participants at low and high altitude, respectively. At low altitude, five participants had a hypo-additive interaction (decelerating polynomial), and, at high altitude, four participants exhibited hyper-additivity (accelerating polynomial). All five hypo-additive individuals became additive after a week at 3800 m and four additive participants became hyper-additive. Conclusion: Findings support differential between-participant respiratory chemoreflex interaction that is modified with acclimatization at high altitude in a hypo-to-hyper-additive manner. NSERC Discovery (D.A.K, RGPIN-2021-03980; T.A.D., RGPIN-2024-04182; R.J.A.W., RGPIN-2020-05312), UCalgary Transdisciplinary Connector and HBI RHISE grants. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.