Postnatal intermittent hypoxia enhances phrenic and reduces vagal upper airway motor activities in rats by epigenetic mechanisms

Abstract

Periods of apnoea, commonly observed in prematures and newborns, are an important risk factor for the development of cardiorespiratory diseases in adulthood. In the present study, we evaluated changes in pulmonary ventilation and respiratory motor pattern in juvenile and adult rats exposed to postnatal chronic intermittent hypoxia (pCIH). Newborn male Holtzman rats (P1) were submitted to pCIH (6% O 2 for 30 s, every 9 min, 8 h a day (09.30-17.30 h)) during their first 10 days of life, while control animals were maintained under normoxic conditions (20.8% O 2). Thereafter, animals of both groups were maintained under normoxia until the experiments. Unanaesthetized juvenile pCIH rats (n = 27) exhibited elevated tidal volume and respiratory irregularities (P < 0.05) compared to control rats (n = 7). Decerebrate, arterially perfused in situ preparations of juvenile pCIH rats (n = 11) displayed augmented phrenic nerve (PN) burst amplitude and reduced central vagus nerve activity in comparison to controls (n = 10). At adulthood, pCIH rats (n = 5) showed enhanced tidal volume (P < 0.05) and increased respiratory variability compared to the control group (n = 5). The pCIH-induced changes in ventilation and respiratory motor outputs were prevented by treatment with the DNA methyltransferase inhibitor decitabine (1 mg kg −1 , I.P.) during the exposure to pCIH. Our data demonstrate that pCIH in rats impacts, in a persistent way, control of the respiratory pattern, increasing PN activity to the diaphragm and reducing the vagal-related activity to laryngeal muscles, which, respectively, may contribute to improve resting pulmonary ventilation and predispose to collapse of the upper airways during quiet breathing.

Postinspiratory and preBötzinger complexes contribute to respiratory-sympathetic coupling in mice before and after chronic intermittent hypoxia

“…Specifically, the current results support the interpretation that CIH causes a cascade of events which begin with an overactive carotid body (Nanduri et al, 2012) and lead to RLVM hyperactivity that is exacerbated by an increased excitatory drive from PiCo and preBötC. However, it is unlikely that these respiratory complexes are the only contributing factors to the RVLM overactivity, given that CIH is known to cause a variety of other changes in the respiratory network (Zoccal et al, 2008;Molkov et al, 2011;Moraes et al, 2012Moraes et al, , 2013Bazilio et al, 2019;Zoccal et al, 2019;Bittencourt-Silva et al, 2020;Karlen-Amarante et al, 2023). These findings are consistent with the pathogenesis of obstructive sleep apnea related hypertension, which is a risk factor for developing lifethreatening cardiovascular diseases.…”

Epigenetic silencing by early‐life hypoxic stress programmes respiratory motor control

“…In conclusion, Bittencourt‐Silva et al. () confirm and extend previous work drawing focus to epigenetic modulation of respiratory motor control arising from postnatal exposure to intermittent hypoxia. An increased understanding of the complex relationship between DNA methylation and site‐specific modifications in respiratory neural control networks will advance our appreciation of the notably deleterious impact of early‐life exposures to hypoxic stress on cardiorespiratory control.…”

“…However, consistent with the potential for impaired control of upper airway patency after exposure to intermittent hypoxia, Bittencourt‐Silva et al. () observed reduced vagal motor inspiratory and postinspiratory activity in rats exposed to neonatal intermittent hypoxia compared with sham animals.…”

“…In this issue of Experimental Physiology,Bittencourt-Silva, Furtado Menezes, Mondonça-Junior, Karlen-Amarante, and Zoccal (2020) extend work in this important and topical area of investigation,focusing on the lasting consequences of exposure to intermittent hypoxia during postnatal development on respiratory motor activity and breathing. Male rat pups (together with their dams) were exposed to intermittent hypoxia for the first 10-15 days of life.…”

Hypoxia sensing in the body: An update on the peripheral and central mechanisms

“…However, adult animals that experienced CIH during the postnatal period exhibit increased expression of the transcription factor hypoxia‐inducible factor 1 alpha in the ventrolateral medulla (Karlen‐Amarante et al., 2023 ), suggesting plasticity in hypoxia‐sensitive mechanisms in the CNS. The sustained alterations in the peripheral and central pathways induced by postnatal CIH contribute to development of arterial hypertension and breathing irregularities in adulthood by epigenetic‐related mechanisms affecting sensory activity and neuronal excitability (Bittencourt‐Silva et al., 2020 ; Karlen‐Amarante et al., 2023 ; Nanduri et al., 2012 ). Additional experiments are required to explore these mechanisms further.…”