The Ventilatory Response to Hypoxia in Mammals: Mechanisms, Measurement, and Analysis

Abstract

The respiratory response to hypoxia in mammals develops from an inhibition of breathing movements in utero into a sustained increase in ventilation in the adult. This ventilatory response to hypoxia (HVR) in mammals is the subject of this review. The period immediately after birth contains a critical time window in which environmental factors can cause long-term changes in the structural and functional properties of the respiratory system, resulting in an altered HVR phenotype. Both neonatal chronic and chronic intermittent hypoxia, but also chronic hyperoxia, can induce such plastic changes, the nature of which depends on the time pattern and duration of the exposure (acute or chronic, episodic or not, etc.). At adult age, exposure to chronic hypoxic paradigms induces adjustments in the HVR that seem reversible when the respiratory system is fully matured. These changes are orchestrated by transcription factors of which hypoxia-inducible factor 1 has been identified as the master regulator. We discuss the mechanisms underlying the HVR and its adaptations to chronic changes in ambient oxygen concentration, with emphasis on the carotid bodies that contain oxygen sensors and initiate the response, and on the contribution of central neurotransmitters and brain stem regions. We also briefly summarize the techniques used in small animals and in humans to measure the HVR and discuss the specific difficulties encountered in its measurement and analysis.

Hypoxia-Induced Changes in Protein S-Nitrosylation in Female Mouse Brainstem

“…Serial sections demonstrated the expression of GSNOR and nNOS in neurons within the brainstem ( Figure 1A). Moreover, both proteins were seen in neurons located in the NTS, a region of the brain known to be involved in respiratory control (2,4). Immunofluorescence studies demonstrated that a subset of neurons contained both GSNOR and nNOS ( Figure 1B).…”

“…Hypoxia increases minute ventilation (VM) by activation of carotid body chemoafferents and integration of these signals by brainstem structures, including the nucleus tractus solitarius (NTS) (1)(2)(3)(4). The neurochemical mechanisms mediating the initial increase in VM upon exposure to hypoxia include: (1) activation of N-methyl-D-aspartate (NMDA) receptors (NMDARs); (2) increased activity of neuronal nitric oxide synthase (nNOS) via NMDAR-induced increases in intracellular Ca 21 ; and (3) activation of phospholipase C, protein kinase (PK) C, and tyrosine kinase phosphorylation cascades (3,4).…”

“…The neurochemical mechanisms mediating the initial increase in VM upon exposure to hypoxia include: (1) activation of N-methyl-D-aspartate (NMDA) receptors (NMDARs); (2) increased activity of neuronal nitric oxide synthase (nNOS) via NMDAR-induced increases in intracellular Ca 21 ; and (3) activation of phospholipase C, protein kinase (PK) C, and tyrosine kinase phosphorylation cascades (3,4). With sustained hypoxia, VM diminishes-a phenomenon known as ventilatory roll-off (1)(2)(3)(4). The mechanisms involved in roll-off include production of neurotransmitters inhibitory to respiration, such as g-amino-butyric acid and adenosine, as well as inhibition of NMDAR function via activation of platelet-derived growth factor (PDGF)-BB/PDGF receptor (PDGFR)-b signaling pathways (4)(5)(6).…”

A paradigm shift in oxygen sensing with a twist in the tale!

“…The physiological response to whole-body hypoxic stress, observed for example at altitude, in pulmonary diseases, and in respiratory control disorders that commonly present during sleep, includes the archetypal reflex cardiorespiratory adjustments of increased ventilation (serving to better oxygenate the pulmonary blood), increased cardiac output (improving oxygen delivery to the systemic circuit), and systemic vasodilatation (enhancing local delivery and uptake of oxygen into peripheral tissues) that together protect against profound oxygen deficiency in the face of global hypoxic stress (Teppema and Dahan, 2010;Prabhakar and Semenza, 2012).…”

Input from a chemosensory organ, the osphradium, does not mediate aerial respiration in Lymnaea stagnalis

“…However, the mechanisms by which organisms detect hypoxic conditions can vary significantly (Taylor et al 1999). In mammals, respiratory control appears to be primarily internalised, with oxygen sensors located in the branches of the carotid arteries and the aortic arch (Lopez-Barneo et al 2010, Teppema & Dahan 2010, and carbon dioxide levels are monitored in the cerebrospinal fluid (Teppema & Dahan 2010). But because oxygen levels are fairly constant in environments for air-breathing animals, carbon dioxide receptors that measure the internal levels of this gas are of greater significance (Taylor et al 1999).…”