Astrocytes play an active role in persistence of respiratory augmentation in the recovery phase after hypoxic exposure

Abstract

Hypoxia induces shortness of breath, and augments respiration, and the respiratory augmentation persists for a while even in the post‐hypoxic recovery phase. However, the mechanism of posthypoxic persistent respiratory augmentation has not been fully elucidated. We propose a hypothesis that astrocytes are involved in the central mechanism of post‐hypoxic persistent respiratory augmentation. To investigate this hypothesis, we conducted two kinds of experimental analyses. First, we examined astrocytic involvement in hypoxic ventilatory responses in the in vitro experiments. In this experiment, we used the medulla‐spinal cord preparation isolated from newborn rats. Briefly, the medulla and spinal cord were together isolated from neonatal rats under anesthesia. The preparations were fixed in a recording chamber and superfused firstly with oxygenated (95% O2, 5% CO2) artificial cerebrospinal fluid (aCSF), secondly with hypoxic (95% N2, 5% CO2) aCSF for 5 min, and thirdly again with oxygenated aCSF for 20 min. We compared respiratory frequencies in the post‐hypoxic recovery phase in preparations without and with administration of arundic acid (500 μM), a blocker of astrocytic activation. Second, we examined astrocytic involvement in hypoxic ventilatory responses in the in vivo experiments. In these experiments, unanesthetized adult mice were exposed to various levels of hypoxia, and ventilatory responses were analyzed by whole body plethysmography. Effects of arundic acid on ventilation were investigated. In results, in in vitro experiments, hypoxia increased respiratory frequency in both groups. During superfusion with oxygenated aCSF after hypoxic exposure, respiratory frequency in the group without arundic acid was still persistently increased. On the other hand, respiratory frequency in the group with arundic acid was gradually decreased in the post‐hypoxic phase, and it was eventually depressed and less than that of the pre‐hypoxic phase in the later post‐hypoxic phase. In in vivo experiments, moderately strong hypoxia increased ventilation, and ventilatory augmentation persisted even after cessation of hypoxia loading. Arundic acid blocked persistence of post‐hypoxic ventilatory augmentation. Stronger hypoxia induced biphasic responses, i.e., initial ventilatory augmentation followed by ventilatory depression. Arundic acid strengthened hypoxic ventilatory depression. We conclude that astrocytes play an important role in persistence of post‐hypoxic respiratory augmentation.Support or Funding InformationJSPS KAKENHI numbers 17H05540, 17K08559 and 18K17783