Sympathetic dysregulation induced by postnatal intermittent hypoxia

Abstract

Study objectives Exposure to postnatal chronic intermittent hypoxia (pCIH), as experienced in sleep-disordered breathing, is a risk factor for developing cardiorespiratory diseases in adulthood. pCIH causes respiratory instability and motor dysfunction that persist until adult life. In this study, we investigated the impact of pCIH on the sympathetic control of arterial pressure in rats. Methods and Results Neonate male Holtzman rats (P0-1) were exposed to pCIH (6% O2 for 30 s, every 10 min, 8 h/day) during their first 10-15 days of life, while control animals were maintained under normoxia. In early adult life (P25-40), freely behaving pCIH animals (n=13) showed higher baseline arterial pressure levels linked to augmented sympathetic-mediated variability than control animals (n=12, P<0.05). Using decerebrated in situ preparations, we found that juvenile pCIH rats exhibited a two-fold increase in thoracic sympathetic nerve activity (n=14) and elevated firing frequency of ventromedullary presympathetic neurons (n=7) compared to control rats (n=6-7, P<0.05). This pCIH-induced sympathetic dysregulation was associated with increased HIF-1α (hypoxic inducible factor) mRNA expression in catecholaminergic pre-sympathetic neurons (n=5,P<0.05). At older age (P90-99), pCIH rats displayed higher arterial pressure levels and larger depressor responses to ganglionic blockade (n=6-8, P<0.05), confirming the sympathetic overactivity state. Conclusions pCIH facilitates the vasoconstrictor sympathetic drive by mechanisms associated with enhanced firing activity and HIF-1α expression in ventromedullary pre-sympathetic neurons. This excessive sympathetic activity persists until adulthood resulting in high blood pressure levels and variability, which contribute to developing cardiovascular diseases.

Carotid body hypersensitivity in intermittent hypoxia and obtructive sleep apnoea

“…Neurons in the NTS relay information to the hypothalamic paraventricular nucleus and sympathoexcitatory neurons in the RVLM (Herman & Cullinan, 1997;Sawchenko et al, 1996). A recent study reported that IH increases RVLM neuronal activity linked to presympathetic neurons (Karlen-Amarante et al, 2023). On the one hand, Zoccal et al (2011) believe that IH enhances purinergic but not glutamatergic transmission in the RVLM.…”

Does Perinatal Intermittent Hypoxia Affect Cerebrovascular Network Development?

“…While animal models cannot fully recapitulate the complexity of the clinical scenario, CIH models do produce an injury profile similar to that seen in humans, with respect to white matter loss, neurodevelopmental delay, and functional deficits [[11], [13]]. Very recently, it has been suggested that postnatal CIH might be a risk factor for developing cardiorespiratory diseases in adulthood as well [[64]]. The models generally involve several daily sessions of intermittent hypoxia over various days [[65]].…”

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

“…In rats, CIH increases sympathetic activity and disrupts respiratory-sympathetic coupling resulting in hypertension ( Zoccal et al, 2008 ; Simms et al, 2009 ; Zoccal et al, 2009 ; Molkov et al, 2011 ). Furthermore, when exposure to CIH occurs postnatally, elevated arterial pressure levels and baroreflex dysfunctions can persist into adulthood ( Soukhova-O'Hare et al, 2006 ; Karlen-Amarante et al, 2023 ). The cardiopulmonary effects of CIH have been attributed to the overexcitation of rostral ventrolateral medulla (RVLM) presympathetic neurons ( Karlen-Amarante et al, 2023 ) via excitatory and inhibitory inputs from respiratory rhythmogenic networks ( Lipski et al, 1996 ; Molkov et al, 2011 ; Moraes et al, 2012 , 2013 ).…”

“…Furthermore, when exposure to CIH occurs postnatally, elevated arterial pressure levels and baroreflex dysfunctions can persist into adulthood ( Soukhova-O'Hare et al, 2006 ; Karlen-Amarante et al, 2023 ). The cardiopulmonary effects of CIH have been attributed to the overexcitation of rostral ventrolateral medulla (RVLM) presympathetic neurons ( Karlen-Amarante et al, 2023 ) via excitatory and inhibitory inputs from respiratory rhythmogenic networks ( Lipski et al, 1996 ; Molkov et al, 2011 ; Moraes et al, 2012 , 2013 ). However, the exact neuronal mechanisms underlying respiratory modulation of sympathetic activity remain to be characterized.…”