Changes in the autonomic and respiratory patterns of mice submitted to short‐term sustained hypoxia

Abstract

Short-term sustained hypoxia (SH) in rats induces changes in sympathetic-respiratory coupling and sympathetic overactivity, which seems to be linked to hypertension. However, there is no previous experimental data about the effects of SH on the autonomic and respiratory pattern in mice. In the present study we tested the hypothesis that mice submitted to SH present autonomic and respiratory changes similarly to rats. To reach this goal we evaluated the effects of 24-hour SH exposure on cardiovascular, respiratory and autonomic parameters in baseline conditions and upon chemoreflex activation.C57BL/6J mice (7-8 weeks old, ~25g) were deeply anesthetized for femoral artery and jugular vein catheterization. Four days later, they were submitted to SH (24h, FiO2 0.1) or normoxia. At the end of SH protocol, arterial pressure, heart rate and ventilation were recorded in vivo. Peripheral chemoreflex was activated via KCN injection (0.16 mg/Kg, i.v.). In another experimental group, we performed in situ recordings of phrenic (PN), abdominal, (AbN), cervical vagus (cVN) and thoracic sympathetic (tSN) nerves activities of SH mice using the working heart-brainstem preparation. All experimental protocols were approved by the Institutional Ethics Committee (#140/2019 and #163/2019). In the in vivo approach, although SH mice (n=13) presented a significant decrease in baseline HR (510 ± 22 vs 633 ± 16 beats min-1; P = 0.002) compared with the controls (n=17), no differences were observed in mean arterial pressure levels (109 ± 2 vs 106 ± 2 mmHg; P=0.443). SH mice (n=14) also showed significantly increased respiratory frequency [(fR) 277 ± 8 vs 203 ± 6 breaths.min-1; P <0.0001], tidal volume [(VT) 14 ± 1 vs. 12 ± 1mL.Kg1; P = 0.0019)], and ventilation [(VE) 3927 ± 164 vs 2390 ± 104 mL.Kg-1.min-1; P < 0.0001)] compared with controls (n=17). The magnitudes of bradycardic responses to chemoreflex activation were greater in SH mice (n=8) than in controls (n=11; -329 ± 36 vs -210 ± 30 beats min-1, P=0.02). In the in situ approach, baseline PN discharge (PND) frequency was significantly reduced in SH mice (n=11) in relation to controls (n=26) (0.69 ± 0.06 vs 1.13 ± 0.10 Hz, P=0.0154). The incidence of Late-E bursts in AbN activity in SH mice (n=10) was significantly increased in relation to controls (n=20) (83.3 ± 7.7 vs 24.3 ± 8.0%, P<0.0001). The duration of expiration in SH mice (n=11) was longer than in controls (n=22) (1.13 ± 0.16 vs 0.67 ± 0.07s, P= 0.0002) due to an increase in the duration of post-inspiration (0.78 ± 0.12 vs 0.35 ± 0.04s, P= 0.0032). tSNA in the SH group (n=10) was significantly reduced during late-expiration (E2) compared with the control group (n=16) (19.0 ± 4.3 vs 39.7 ± 4.2%, P= 0.0203). The data are showing that 24-h SH protocol in mice produces: a) an increase in parasympathetic tone to the heart, which seems to be related to changes in their breathing pattern; and b) prolonged expiration and active expiration associated with a reduction in sympathetic activity during E2. This autonomic imbalance favoring the parasympathetic componente may explain why mice, different of rats, do not develop hypertension after SH.