Chapter 4 - Adaptive cardiorespiratory changes to chronic continuous and intermittent hypoxia

Abstract

This chapter reviews cardiorespiratory adaptations to chronic hypoxia (CH) experienced at high altitude and cardiorespiratory pathologies elicited by chronic intermittent hypoxia (CIH) occurring with obstructive sleep apnea (OSA). Short-term CH increases breathing (ventilatory acclimatization to hypoxia) and blood pressure (BP) through carotid body (CB) chemo reflex. Hyperplasia of glomus cells, alterations in ion channels, and recruitment of additional excitatory molecules are implicated in the heightened CB chemo reflex by CH. Transcriptional activation of hypoxia-inducible factors (HIF-1 and 2) is a major molecular mechanism underlying respiratory adaptations to short-term CH. High-altitude natives experiencing long-term CH exhibit blunted hypoxic ventilatory response (HVR) and reduced BP due to desensitization of CB response to hypoxia and impaired processing of CB sensory information at the central nervous system. Ventilatory changes evoked by long-term CH are not readily reversed after return to sea level. OSA patients and rodents subjected to CIH exhibit heightened CB chemo reflex, increased hypoxic ventilatory response, and hypertension. Increased generation of reactive oxygen species (ROS) is a major cellular mechanism underlying CIH-induced enhanced CB chemo reflex and the ensuing cardiorespiratory pathologies. ROS generation by CIH is mediated by nontranscriptional, disrupted HIF-1 and HIF-2-dependent transcriptions as well as epigenetic mechanisms.