Contribution of Acid‐Sensing Ion Channels to Hypoxia‐ and Hypercapnia‐Induced Ventilatory Drive in Conscious Unrestrained Mice
Authors: Detweiler Neil D , Vigil Kenneth G , Yan Simin , Resta Thomas C , Walker Benjimen R , Jernigan Nikki L 
Published: November 2023

Arterial O2 and CO2 tensions (PaO‐2 and PaCO2) are primarily monitored by peripheral and central chemoreceptors, respectively. This information is integrated by the respiratory control center in the brain, which stimulates the appropriate level of breathing (ventilatory drive) to maintain PaO2 and PaCO2 homeostasis in the blood. Acid‐sensing ion channels (ASICs) are voltage‐independent cation channels of varying cation selectivity that are members of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily and arise from four genes (ASIC1‐4). Previous reports have revealed roles for ASICs in both central and peripheral chemoreception. For example, phrenic nerve output in response to arterial hypercapnia was decreased by local pan‐ASIC inhibition in the nucleus tractus solitarius in anesthetized rats. In another study, ASIC3 was specifically observed to play a role in acid‐induced calcium responses in isolated carotid body glomus cells. However, the contributions of ASICs to ventilatory drive have not been assessed in conscious, unrestrained animals. The objective of this study was to test the hypothesis that ASIC3 contributes to reflex increases in ventilation caused by acute exposure to hypoxia and/or hypercapnia in vivo. We utilized whole‐body plethysmography to assess isocapnic hypoxia (7% O2, 3.2% CO2)‐ and hypercapnia (21% O2, 6% CO2)‐ induced changes in respiratory frequency, tidal volume, and minute ventilation in ASIC3−/−, and wild‐type (WT) mice. Additionally, we assessed changes in oxygen and carbon dioxide tensions in arterial blood samples obtained via chronically implanted femoral artery catheters. Isocapnic hypoxia decreased PaO2 and caused statistically significant increases in respiratory frequency, tidal volume, and minute ventilation in both groups of mice. Hypercapnia increased both PaO‐2 and PaCO‐2 and caused statistically significant increases in respiratory frequency, tidal volume, and minute ventilation in both groups of mice. Surprisingly, despite the existing evidence for ASIC3 involvement in chemoreception, we did not observe any statistically significant differences between ASIC3−/− and WT mice in any of the responses measured. For example, exposure to hypercapnia significantly increased minute ventilation from 2.7 ± 0.2 to 7.0 ± 0.3 ml/min/g in WT mice, and similarly, from 2.6 ± 0.3 to 7.1 ± 0.3 ml/min/g in ASIC3−/− mice. These results bring into question the physiological relevance of ASIC3 to ventilatory control in vivo. In future experiments, we will assess these responses in mice lacking ASIC1, another ASIC that has been implicated in ventilatory drive. Results are reported as mean ± standard error, statistical comparisons were made using a 2‐way ANOVA with a Sidak's multiple comparison test, and p < 0.05 was the threshold for statistical significance.Support or Funding InformationSupported by National Heart, Lung, and Blood Institute Grants R01 HL‐111084 (to N.L. Jernigan), T32 HL007736 (to T.C. Resta), and National Institute of General Medical Science R25 GM060201 (to M.C. Werner‐Washburne)