Altered carotid body function by intermittent hypoxia in neonates and adults: Relevance to recurrent apneas

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Abstract

Chronic intermittent hypoxia (CIH) is associated with recurrent apneas in adults and premature infants. It has been proposed that reflexes arising from the carotid bodies contribute to the autonomic abnormalities associated with CIH. The purpose of this review is to summarize recent studies on the effects of CIH on adult and neonatal carotid bodies. CIH exerts two major effects on the adult carotid body that includes sensitization of the hypoxic sensory response and induction of sensory long-term facilitation (LTF). In neonates CIH leads to sensitization of the hypoxic response but does not induce sensory LTF. The effects of CIH on carotid bodies develop over time and could be reversed in adults but not in neonates. CIH-evoked changes in the carotid body involve reactive oxygen species (ROS)-mediated signaling and transcriptional activation by hypoxia-inducible factor-1. Augmented chemoreceptor sensitivity to hypoxia increases the likelihood of unstable breathing perpetuating the effects of CIH, whereas sensory LTF may contribute to increased sympathetic tone and systemic hypertension associated with recurrent apneas.

Introduction

Systemic hypoxia occurs under many different circumstances and affects physiological systems in unique ways. For instance, continuous systemic hypoxia is experienced during sojourns at high altitude. On the other hand, for people who reside at or near sea level, recurrent episodes of hypoxia are encountered more frequently than continuous hypoxia in life. Transient episodes of hypoxia are associated with pathophysiological situations including sleep-disordered breathing manifested as recurrent apneas (obstructive or central apneas). Recurrent apneas are prevalent in 50% of premature infants (Poets et al., 1994), 5% of middle-aged men and 2% of women after menopause (Nieto et al., 2000, Shahar et al., 2001). In severely affected patients, the frequency of apneas may exceed 60 episodes/h and arterial blood O2 saturation can be reduced to as low as 50%. As a consequence of cessation of breathing, patients with recurrent apneas experience not only chronic intermittent hypoxia (CIH) but also chronic intermittent hypercapnia (i.e., elevations in arterial CO2). A major advance in the field of apnea research is the demonstration that exposing experimental animals to CIH alone is sufficient to result in physiological changes similar to that described in recurrent apnea patients (Fletcher, 2001). Although both continuous and intermittent hypoxia results in decreases in arterial O2, physiological responses to both forms of hypoxia differ quite considerably. Whilst continuous hypoxia leads to adaptations of the physiological systems, CIH associated with recurrent apneas result in morbidity including development of hypertension, myocardial infarctions and stroke (Nieto et al., 2000, Shahar et al., 2001).

Physiological responses to systemic hypoxia depend on the O2-sensing ability of the peripheral arterial chemoreceptors, especially the carotid bodies. It is being increasingly appreciated that reflexes arising from the carotid bodies play more important roles in chronic hypoxia (days to months) than in acute hypoxia (Prabhakar and Peng, 2004). For instance, role of carotid bodies in ventilatory adaptations during high altitude acclimatization is well documented (Bisgard, 2000). On the other hand, little is known on the effects of CIH on the carotid body. In recent years, development of animal models of CIH mimicking the hypoxic patterns encountered during recurrent apneas provided new insights in to the carotid body function. The purpose of this article is to summarize what is known about the effects of CIH on the O2 sensing ability of the neonatal and adult carotid bodies, how they differ from continuous hypoxia and the potential contribution of altered carotid body function to the morbidity associated with recurrent apneas.

Section snippets

Evidence for altered carotid body function during chronic intermittent hypoxia (CIH)

Much of the earlier information on the role of carotid bodies during CIH has come from studies on patients with recurrent apneas (obstructive or central apneas). It has been suggested that carotid bodies constitute the “frontline” defense system for detecting systemic hypoxia associated with apneas (Cistulli and Sullivan, 1994). Patients with recurrent apneas exhibit augmented hypoxic ventilatory response (Narkiewicz et al., 1999) which was attributed to enhanced peripheral chemoreceptor

Effects of CIH on adult carotid body activity

Direct evidence for altered carotid body function by CIH has come from recent studies on carotid bodies from CIH exposed rats (Peng et al., 2003, Peng and Prabhakar, 2004), cats (Rey et al., 2004) and mice (Peng et al., 2006a, Peng et al., 2006b). The following section summarizes the findings from these studies.

Effects of CIH on neonatal carotid body activity

Carotid bodies are immature at birth and respond poorly to hypoxia compared with adults (Blanco et al., 1984, Donnelly, 2000, Carroll, 2003). In rat pups, carotid body sensitivity to hypoxia develops during the first 7–10 days of life (Kholwadwala and Donnelly, 1992, Donnelly, 2000, Carroll, 2003). Several lines of evidence suggest that environmental O2 in the neonatal period profoundly influences maturation of carotid body sensitivity to hypoxia (Hanson, 1998; see Donnelly, 2000, Carroll, 2003

Mechanisms associated with CIH

Recent studies addressed potential mechanisms associated with the effects of CIH on the adult carotid body. CIH-induced sensitization of the hypoxic response as well as the sensory LTF could be elicited in ex vivo carotid bodies of rats as well as mice (Peng et al., 2003, Peng et al., 2006a, Peng et al., 2006b) suggesting that these effects are not secondary to cardiovascular changes such as elevated blood pressures seen in CIH exposed animals (Lesske et al., 1997, Kumar et al., 2006, Peng et

Cardio-respiratory consequences of CIH-induced carotid body changes

The CIH-induced sensitization of the hypoxic sensory response of the carotid body in neonates might be of considerable physiological significance in that in its absence apneas may lead to deleterious consequences on the central nervous system resulting in ventilatory depression. Consistent with such a possibility is the report that preterm infants with recurrent apneas exhibit greater HVR than control infants (Nock et al., 2004). In the adults, on the other hand, in the early stages of apnea

Acknowledgements

The research in author's laboratory is supported by grants from National Institutes of Health, Heart, Lung and Blood Institute, HL-25830 and HL-076537.

References (51)

  • S. Rey et al.

    Contribution of endothelin-1 to the enhanced carotid body chemosensory responses induced by chronic intermittent hypoxia

    Brain Res.

    (2006)
  • G. Yuan et al.

    Ca2+/calmodulin kinase-dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia

    J. Biol. Chem.

    (2005)
  • G.E. Bisgard et al.

    Adult carotid chemoafferent responses to hypoxia after 1, 2 and 4 wk of postnatal hyperoxia

    J. Appl. Physiol.

    (2003)
  • C.E. Blanco et al.

    The response to hypoxia of arterial chemoreceptors in fetal sheep and new-born lambs

    J. Physiol.

    (1984)
  • J.L. Carroll

    Developmental plasticity in respiratory control

    J. Appl. Physiol.

    (2003)
  • P.A. Cistulli et al.

    Pathophysiology of sleep apnea

  • D.F. Donnelly

    Developmental aspects of oxygen sensing by the carotid body

    J. Appl. Physiol.

    (2000)
  • E.C. Fletcher et al.

    Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea

    J. Appl. Physiol.

    (1992)
  • E.C. Fletcher

    Physiological consequences of intermittent hypoxia: systemic blood pressure

    J. Appl. Physiol.

    (2001)
  • R.D. Guzy et al.

    Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia

    Exp. Physiol.

    (2006)
  • N.V. Iyer et al.

    Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha

    Genes Dev.

    (1998)
  • N.L. Kanagy et al.

    Role of endothelin in intermittent hypoxia-induced hypertension

    Hypertension

    (2001)
  • T. Kara et al.

    Chemoreflexes—physiology and clinical implications

    Acta Physiol. Scand.

    (2003)
  • D. Kholwadwala et al.

    Maturation of carotid chemoreceptor sensitivity to hypoxia: in vitro studies in the newborn rat

    J. Physiol.

    (1992)
  • D.D. Kline et al.

    Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
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