Long-Term Recurrent Hypoxia in Developing Rat Attenuates Respiratory Responses to Subsequent Acute Hypoxia

Abstract

Whereas definitive treatment of pediatric conditions associated with hypoxemia reverses many pathologic symptoms, some physiologic dysfunctions appear to persist. These abnormalities are attributed to long-lasting central effects of prior hypoxia. To investigate such effects in an animal model, male rats were exposed to FiO 2 ϭ 0.12 continuously for 7 h daily from postnatal day (p) 17 (representing early childhood) through p33 (representing adolescence), defined as recurrent hypoxia. Respiratory responses during and following 20 min FiO 2 ϭ 0.12 were measured on p35 and p47. To control for early weaning on p15 (normal weaning ϭ p21), male rats were weaned on either p15 or p21, raised in normoxia, and also tested for respiratory responsiveness to acute hypoxia. To assess sex differences, female rats were assigned to similar groups and protocols. Minute ventilation, respiratory frequency, tidal volume, and respiratory drive were measured in unsedated animals using whole-body plethysmography. After recurrent hypoxia, male rats displayed an attenuation of ventilation, frequency, and drive during hypoxia, and of all functions after hypoxia on both p35 and p47. There were no differences between test days during hypoxia, and greater attenuation of tidal volume and respiratory drive on p47 during recovery from hypoxia. Respiratory responses displayed no effect of sex on p35, and occasional effects of early weaning on p35 and p47. Thus, recurrent hypoxia produces long-lasting attenuation in respiratory responsiveness to subsequent acute hypoxia. Such long-lasting attenuation, if present in humans, may diminish the protection of children with a history of recurrent hypoxemia against future hypoxic events. H ypoxemia of varying duration, pattern, and timing is an important feature in many clinical conditions in pediatrics. A strong association or causality between hypoxemia and developmental, behavioral, and/or cognitive dysfunctions has been documented, primarily for sleep-disordered breathing and congenital heart disease (1). With regard to sleepdisordered breathing, the dysfunctions also include sleep fragmentation, diminished arousability, diminished responsiveness to respiratory chemical stimuli, fatigue, failure to thrive, hypertension, and cor pulmonale (2-6).Whereas adenotonsillectomy, a definitive treatment for sleep-disordered breathing associated with enlarged adenoids and/or tonsils, reverses the upper airway obstruction and many sleep-related symptoms in children, recent studies suggest that abnormalities in cardiorespiratory control, arousability, learning, and behavior can persist beyond the relief of such obstruction (4,7-9). These studies have attributed the lingering dysfunctions to long-term central effects of prior hypoxemia associated with more severe obstructive sleep apnea.It is important to establish in controlled animal studies whether there indeed are long-lasting effects of an antecedent hypoxia. It is also important to determine whether such effects, if present, are particular to a spe...

Ventilatory responses during and following exposure to a hypoxic challenge in conscious mice deficient or null in S-nitrosoglutathione reductase

“…Parameters were frequency of breathing (f R ); tidal volume (V T ); ventilation (V̇); inspiratory time (T I ); expiratory time (T E ); V T /T I , an index of respiratory drive (Moss et al, 2006); peak inspiratory flow (PIF), and peak expiratory flow (PEF). The provided software constantly corrected digitized values for changes in chamber temperature and humidity.…”

“…This short-term facilitation (STF), which occurs in humans (Dahan et al, 1995), rats (Moss et al, 2006), and mice (Kline and Prabhakar, 2001; Kline et al, 2002), is due to a central neural mechanism that drives ventilation independently of peripheral or central chemoreceptor inputs (Millhorn et al, 1980). Although little is known about the underlying neurochemical processes, STF is markedly diminished in nNOS knock-out mice (Kline and Prabhakar, 2001; Kline et al, 2002), suggesting a role for excitatory SNOs rather than NO per se .…”

Hypoxia-induced ventilatory responses in conscious mice: Gender differences in ventilatory roll-off and facilitation

“…Provided software constantly corrected digitized values for changes in chamber temperature and humidity and a rejection algorithm excluded motion-induced artifacts. Due to the minor differences in body weights between the males and females, parameters such as V T , PIF and PEF, often corrected for body weight (Moss et al, 2006) are presented without corrections.…”

“…Cessation of exposure to hypoxia often results in ventilatory parameters increasing or remaining above baseline for a substantial period of time. This “short-term facilitation (STF)” of ventilation, first detailed in anesthetized cats (Wagner and Eldridge, 1991), also occurs in awake or sleeping humans (Dahan et al, 1995) and rats (Moss et al, 2006), and is activated by a central neural mechanism with slow dynamics that drives ventilation independently of peripheral or central chemoreceptor inputs (Millhorn et al, 1980). …”

Intermittent Hypoxia in Childhood: The Harmful Consequences Versus Potential Benefits of Therapeutic Uses

“…However, the neural structures, neurotransmitters, and downstream signaling pathways underlying such biphasic changes in HVR induced by IH are unknown. Using an immature rat model simulating OSA, Moss et al investigated effects of chronic IH (12% O 2 , 7 h daily) on rats from postnatal day 17 (representing early childhood) through day 33 (representing adolescence) and day 47 (adult) ( 55 ). They reported that chronic IH produced long-lasting attenuation in respiratory responsiveness to subsequent acute hypoxia.…”