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Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

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ABSTRACT

Ventilatory responses to hypoxia vary widely depending on the pattern and length of hypoxic exposure. Acute, prolonged, or intermittent hypoxic episodes can increase or decrease breathing for seconds to years, both during the hypoxic stimulus, and also after its removal. These myriad effects are the result of a complicated web of molecular interactions that underlie plasticity in the respiratory control reflex circuits and ultimately control the physiology of breathing in hypoxia. Since the time domains of the physiological hypoxic ventilatory response (HVR) were identified, considerable research effort has gone toward elucidating the underlying molecular mechanisms that mediate these varied responses. This research has begun to describe complicated and plastic interactions in the relay circuits between the peripheral chemoreceptors and the ventilatory control circuits within the central nervous system. Intriguingly, many of these molecular pathways seem to share key components between the different time domains, suggesting that varied physiological HVRs are the result of specific modifications to overlapping pathways. This review highlights what has been discovered regarding the cell and molecular level control of the time domains of the HVR, and highlights key areas where further research is required. Understanding the molecular control of ventilation in hypoxia has important implications for basic physiology and is emerging as an important component of several clinical fields. © 2016 American Physiological Society. Compr Physiol 6:1345‐1385, 2016.

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Figure 1. Figure 1. Time domains of the HVR. Ventilation (V·I), tidal volume (VT), and respiratory frequency (fR) as a function of time during normoxia (dotted baseline) and different durations and patterns of hypoxia (solid baseline). (A) The acute HVR is followed by STP and STD during brief (seconds to minutes) hypoxic exposures. (B) Ventilatory responses during and after sustained (minutes to days) hypoxic exposures include HVD, VAH, and VDH described in later sections; HD is not shown.) (C) Ventilatory responses during and after intermittent hypoxic exposures include PA and LTF (described in later sections).
Figure 2. Figure 2. Molecular mechanisms of the acute HVR. Acute hypoxia of seconds to minutes causes increased ventilation during the hypoxic stimulus. (A) During short‐term hypoxia, decreased PaO2 is sensed by the peripheral chemoreceptors (carotid bodies). Hypoxia‐mediated excitatory ion (Na+ and Ca2+) influx induces depolarization of the carotid bodies, which leads to the generation of action potentials that then propagate along the carotid sinus nerve. (B) Excitatory glutamatergic carotid body afferent neurons along with SP and inhibitory GABAergic neurons synapse at the NTS. If the summation of these opposing signals is net‐excitatory, action potentials are generated in the NTS neurons that communicate to the respiratory motorneurons and increase ventilation via excitation of the phrenic nerve. (C) At the synapse between carotid sinus nerve afferent neurons and the NTS, pre‐synaptic release of SP, glutamate, and GABA induce opposing effects on the excitability of the NTS postsynaptic second‐order neurons and induce excitatory signal propagation that increases downstream respiratory drive (i.e., the acute HVR). (D) This increased drive manifests as an increase in ventilation (raw data is from rats acutely breathing normoxic or hypoxic gas mixtures (Pamenter and Powell, unpublished).
Figure 3. Figure 3. Molecular mechanisms of STP. Acute hypoxia of several minutes increases ventilatory drive and normoxic (baseline) ventilation remains elevated for several minutes poststimulus. (A) During short‐term hypoxia: (i) carotid sinus nerve activity is elevated, which leads to (ii) sustained glutamate (glut) release from carotid body afferent neurons that stimulates NMDARs in postsynaptic NTS second‐order neurons. Maintained activation of postsynaptic glutamate receptors causes (iii) intracellular Ca2+ accumulation, which (iv) binds with calmodulin and activates CaMKII. CaMKII then (v) modifies membrane‐dissociated nNOSs, stimulating production of NO, which rapidly defuses back across the synaptic cleft and (vi) stimulates guanalyl cyclase‐mediated production of cGMP. cGMP then enhances presynaptic glut release and thus enhances the excitatory signal propagation that increases downstream respiratory drive (i.e., STP). (B) Physiologically, STP manifests as an increase in breathing frequency; reprinted with permission ().
Figure 4. Figure 4. Molecular mechanisms of STD. Acute hypoxia of seconds to minutes can lead to a short‐term decrease in breathing frequency via an incompletely understood pathway. (A) Acute hypoxia induces activation of serotonin (5‐HT) type 2A and 2C receptors and/or α2‐adrenoreceptors within the noradrenergic A5 cell group. Activation of 5‐HT2A/2C or α2‐adrenoreceptors modulates glutamatergic NMDARs via an unknown pathway, and presumably decreases NMDAR activation. (B) Physiologically, activation of this pathway leads to decreased phrenic nerve activity and decreased ventilation (due to reduced breathing frequency); reprinted with permission ().
Figure 5. Figure 5. HVD in humans involves a rapid decrease in O2 sensitivity followed by larger decreases in ventilation without changes in O2 sensitivity. (Upper panel) The slope of the HVR between baseline in mild hyperoxia and SaO2 = 85% for 3 min is significantly greater than the slope between SaO2 = 75% and 85% after 25 min of hypoxia (SaO2 = 85%). (Lower panel) However, most of the decrease in ventilation during sustained hypoxia is explained by a significant decrease in ventilation without a change in O2 sensitivity; the slope of the HVR between SaO2 = 90% and 80% is not significantly different after 8 versus 14 min of hypoxia (SaO2 = 90%), but there is significant HVD (illustrated as a decrease in the Y intercept predicting ventilation at SaO2 = 100%). We propose a more accurate way to quantify HVD is the decrease in ventilation predicted within the range of sustained hypoxia studied, for example, the change in ventilation predicted at SaO2 = 85% between the two HVR measurements in the lower panel; reprinted with permission ().
Figure 6. Figure 6. Molecular mechanisms of the HVD. Acute hypoxia of 5 to 30 min leads to a decrease in ventilatory drive, or a hypoxic apnea. The underlying mechanism of this HVR is poorly understood but evidence indicates mediation at both the peripheral chemoreceptors (A) and within the CNS (B). (A) At the peripheral chemoreceptors, DA release may inhibit hypoxia‐mediated carotid body depolarization and reduce carotid sinus nerve activity and thus downstream phrenic nerve activity. (B) At the synapse between the carotid sinus nerve and NTS second‐order neurons, GABA accumulation due to chronic activation of GABAergic interneurons or conversion of excessive synaptic glutamate to GABA by GAD inhibits the electrical excitability and downstream phrenic nerve activation. DA may act on either the carotid sinus nerve afferent or GABAergic interneurons to decrease GABA accumulation via these putative pathways. Activation of adenosine and opioid receptors has also been implicated in this pathway, potentially via inhibition of glutamatergic NMDAR activity mediated by inhibitory g protein signaling. (C) Physiologically, STP manifests as decreased ventilation (data shown are from hypoxic chemodenervated dogs; adapted from () with permission.
Figure 7. Figure 7. Opposing effects of DA on carotid body chemoreceptor sensitivity and ventilation. Ventilation (V·I) and arterial chemoreceptor activity measured simultaneously in anesthetized cats with haloperidol (open symbols) versus control (filled symbols). Haloperidol blocks D2Rs (i) in carotid bodies, which increases chemoreceptor activity for a given PO2, and (ii) in the CNS, which decreases the CNS gain of the HVR so V·I is less for a given chemoreceptor activity. Reprinted with permission (); adapted from () with permission.
Figure 8. Figure 8. VAH involves increases in the CNS gain of the HVR. Neural output to respiratory muscles (left, phrenic burst frequency; right, phrenic burst frequency X integrated phrenic amplitude; analogous to fR and V·I, respectively) increases in chronically hypoxic (filled symbols) compared to normoxic control rats (open symbols) for any given level of electrical stimulation of the carotid sinus nerve; reprinted with permission ().
Figure 9. Figure 9. VAH is mediated by glutamatergic NMDAR, but not AMPAR receptors. (A) The acute HVR is abolished by blocking NMDARs with MK801 in the NTS of chronically hypoxic, awake rats (CSH) and has no effect on chronically normoxic (CON) rats. (B) Non‐NMDA glutamatergic receptors (blocked with NBQX) contribute to the ventilatory chemoreflex response all conditions (i.e., acute or chronic hypoxia (and also hypercapnia, not shown) and do not play a unique role in VAH; adapted from () with permission.
Figure 10. Figure 10. Hypoxic ventilatory drive is reduced in high altitude natives. Relationship between ventilation and arterial oxygen tension in low altitude control human subjects, high altitude (HA) residents (3‐39 years at altitude) and HA natives (born and live at altitude); reprinted with permission ().
Figure 11. Figure 11. High‐altitude natives from Tibet (upper panel) have greater and varied HVRs than high altitude native Andeans (Aymara; lower panel). Adapted from () with permission.
Figure 12. Figure 12. Putative molecular mechanism of PA at the carotid body. (A) AIH or repeated acute application of serotonin (5‐HT) to carotid bodies induces PKC‐mediated phosphorylation of carotid body NADPH oxidase (NOX) subunits and increased production or superoxide (O2). Superoxide production leads to enhanced carotid body membrane potential depolarization and increased afferent neuron firing. (B) This effect is manifested in progressive augmentation of phrenic nerve activity during the hypoxic episodes (or during 5‐HT application, arrows), followed by LTF of phrenic nerve activity in the normoxic period following the intermittent stimulus; adapted from () with permission.
Figure 13. Figure 13. Classic model of the molecular basis of phrenic LTF. Intermittent hypoxia (IH) increases ventilatory drive during acute hypoxia and normoxic (baseline) ventilation remains elevated for over an hour after IH. (A) Carotid body stimulation by IH releases 5‐HT from neuromodulatory Raphe neurons, which binds to 5‐HT type 1A and 2A receptors on phrenic motorneurons. 5‐HT activates Gq protein signaling cascades to activate protein kinase C (PKC) and induce the synthesis of BDNF. BDNF binds to tyrosine kinase receptors (TrkB) that activate phospho‐extracellular signal regulated kinase (pERK). In other systems, pERK has been shown to phosphorylate glutamatergic NMDARs in postsynaptic neurons and increase sensitivity to presynaptic glutamate release. (B) Physiologically, this increased sensitivity manifests as enhanced phrenic nerve activity and increased ventilation (primarily increased tidal volume); adapted from () with permission.
Figure 14. Figure 14. New model for phrenic LTF with multiple molecular pathways. The Gq pathway (blue arrows) proceeds as described in Figure , but can also be activated by α1‐adrenergic receptors (α1Rs). The Gs pathway (green arrows) can be induced by the activation of adenosine type 2A receptors (A2AR) or 5‐HT type 7 receptors (5‐HT7R), which are coupled to Gs proteins. Gs signaling activates protein kinase A (PKA), which stimulates immature TrkB to modulate phospho‐protein kinase B (pAkt). In other systems, this phosphorylates glutamatergic NMDARs and increases sensitivity to pre‐synaptic glutamate release. Recently, additional pathways (dashed arrows) have been described wherein vascular endothelial growth factor receptor‐2 (VEGFR‐2) or erythropoietin receptor (EPOR) induce LTF via phosphoinositide 3‐kinase (PI3K) and pAkt, and perhaps pERK.
Figure 15. Figure 15. Putative mechanism for ROS in phrenic LTF. Recent evidence supports a critical role for ROS produced from membrane‐bound NOX in the manifestation of LTF following AIH. (A) Activation of 5‐HT type 2 receptors in the post‐synaptic cell induces NOX activity and generation of O2. O2 acts to induce LTF, presumably via protein‐phosphatase (PP)‐mediated phosphorylation of NMDARs. (B) Application of the NOX inhibitor apocynin or ROS scavengers (not shown) abolish phrenic LTF following AIH; adapted from () with permission.


Figure 1. Time domains of the HVR. Ventilation (V·I), tidal volume (VT), and respiratory frequency (fR) as a function of time during normoxia (dotted baseline) and different durations and patterns of hypoxia (solid baseline). (A) The acute HVR is followed by STP and STD during brief (seconds to minutes) hypoxic exposures. (B) Ventilatory responses during and after sustained (minutes to days) hypoxic exposures include HVD, VAH, and VDH described in later sections; HD is not shown.) (C) Ventilatory responses during and after intermittent hypoxic exposures include PA and LTF (described in later sections).


Figure 2. Molecular mechanisms of the acute HVR. Acute hypoxia of seconds to minutes causes increased ventilation during the hypoxic stimulus. (A) During short‐term hypoxia, decreased PaO2 is sensed by the peripheral chemoreceptors (carotid bodies). Hypoxia‐mediated excitatory ion (Na+ and Ca2+) influx induces depolarization of the carotid bodies, which leads to the generation of action potentials that then propagate along the carotid sinus nerve. (B) Excitatory glutamatergic carotid body afferent neurons along with SP and inhibitory GABAergic neurons synapse at the NTS. If the summation of these opposing signals is net‐excitatory, action potentials are generated in the NTS neurons that communicate to the respiratory motorneurons and increase ventilation via excitation of the phrenic nerve. (C) At the synapse between carotid sinus nerve afferent neurons and the NTS, pre‐synaptic release of SP, glutamate, and GABA induce opposing effects on the excitability of the NTS postsynaptic second‐order neurons and induce excitatory signal propagation that increases downstream respiratory drive (i.e., the acute HVR). (D) This increased drive manifests as an increase in ventilation (raw data is from rats acutely breathing normoxic or hypoxic gas mixtures (Pamenter and Powell, unpublished).


Figure 3. Molecular mechanisms of STP. Acute hypoxia of several minutes increases ventilatory drive and normoxic (baseline) ventilation remains elevated for several minutes poststimulus. (A) During short‐term hypoxia: (i) carotid sinus nerve activity is elevated, which leads to (ii) sustained glutamate (glut) release from carotid body afferent neurons that stimulates NMDARs in postsynaptic NTS second‐order neurons. Maintained activation of postsynaptic glutamate receptors causes (iii) intracellular Ca2+ accumulation, which (iv) binds with calmodulin and activates CaMKII. CaMKII then (v) modifies membrane‐dissociated nNOSs, stimulating production of NO, which rapidly defuses back across the synaptic cleft and (vi) stimulates guanalyl cyclase‐mediated production of cGMP. cGMP then enhances presynaptic glut release and thus enhances the excitatory signal propagation that increases downstream respiratory drive (i.e., STP). (B) Physiologically, STP manifests as an increase in breathing frequency; reprinted with permission ().


Figure 4. Molecular mechanisms of STD. Acute hypoxia of seconds to minutes can lead to a short‐term decrease in breathing frequency via an incompletely understood pathway. (A) Acute hypoxia induces activation of serotonin (5‐HT) type 2A and 2C receptors and/or α2‐adrenoreceptors within the noradrenergic A5 cell group. Activation of 5‐HT2A/2C or α2‐adrenoreceptors modulates glutamatergic NMDARs via an unknown pathway, and presumably decreases NMDAR activation. (B) Physiologically, activation of this pathway leads to decreased phrenic nerve activity and decreased ventilation (due to reduced breathing frequency); reprinted with permission ().


Figure 5. HVD in humans involves a rapid decrease in O2 sensitivity followed by larger decreases in ventilation without changes in O2 sensitivity. (Upper panel) The slope of the HVR between baseline in mild hyperoxia and SaO2 = 85% for 3 min is significantly greater than the slope between SaO2 = 75% and 85% after 25 min of hypoxia (SaO2 = 85%). (Lower panel) However, most of the decrease in ventilation during sustained hypoxia is explained by a significant decrease in ventilation without a change in O2 sensitivity; the slope of the HVR between SaO2 = 90% and 80% is not significantly different after 8 versus 14 min of hypoxia (SaO2 = 90%), but there is significant HVD (illustrated as a decrease in the Y intercept predicting ventilation at SaO2 = 100%). We propose a more accurate way to quantify HVD is the decrease in ventilation predicted within the range of sustained hypoxia studied, for example, the change in ventilation predicted at SaO2 = 85% between the two HVR measurements in the lower panel; reprinted with permission ().


Figure 6. Molecular mechanisms of the HVD. Acute hypoxia of 5 to 30 min leads to a decrease in ventilatory drive, or a hypoxic apnea. The underlying mechanism of this HVR is poorly understood but evidence indicates mediation at both the peripheral chemoreceptors (A) and within the CNS (B). (A) At the peripheral chemoreceptors, DA release may inhibit hypoxia‐mediated carotid body depolarization and reduce carotid sinus nerve activity and thus downstream phrenic nerve activity. (B) At the synapse between the carotid sinus nerve and NTS second‐order neurons, GABA accumulation due to chronic activation of GABAergic interneurons or conversion of excessive synaptic glutamate to GABA by GAD inhibits the electrical excitability and downstream phrenic nerve activation. DA may act on either the carotid sinus nerve afferent or GABAergic interneurons to decrease GABA accumulation via these putative pathways. Activation of adenosine and opioid receptors has also been implicated in this pathway, potentially via inhibition of glutamatergic NMDAR activity mediated by inhibitory g protein signaling. (C) Physiologically, STP manifests as decreased ventilation (data shown are from hypoxic chemodenervated dogs; adapted from () with permission.


Figure 7. Opposing effects of DA on carotid body chemoreceptor sensitivity and ventilation. Ventilation (V·I) and arterial chemoreceptor activity measured simultaneously in anesthetized cats with haloperidol (open symbols) versus control (filled symbols). Haloperidol blocks D2Rs (i) in carotid bodies, which increases chemoreceptor activity for a given PO2, and (ii) in the CNS, which decreases the CNS gain of the HVR so V·I is less for a given chemoreceptor activity. Reprinted with permission (); adapted from () with permission.


Figure 8. VAH involves increases in the CNS gain of the HVR. Neural output to respiratory muscles (left, phrenic burst frequency; right, phrenic burst frequency X integrated phrenic amplitude; analogous to fR and V·I, respectively) increases in chronically hypoxic (filled symbols) compared to normoxic control rats (open symbols) for any given level of electrical stimulation of the carotid sinus nerve; reprinted with permission ().


Figure 9. VAH is mediated by glutamatergic NMDAR, but not AMPAR receptors. (A) The acute HVR is abolished by blocking NMDARs with MK801 in the NTS of chronically hypoxic, awake rats (CSH) and has no effect on chronically normoxic (CON) rats. (B) Non‐NMDA glutamatergic receptors (blocked with NBQX) contribute to the ventilatory chemoreflex response all conditions (i.e., acute or chronic hypoxia (and also hypercapnia, not shown) and do not play a unique role in VAH; adapted from () with permission.


Figure 10. Hypoxic ventilatory drive is reduced in high altitude natives. Relationship between ventilation and arterial oxygen tension in low altitude control human subjects, high altitude (HA) residents (3‐39 years at altitude) and HA natives (born and live at altitude); reprinted with permission ().


Figure 11. High‐altitude natives from Tibet (upper panel) have greater and varied HVRs than high altitude native Andeans (Aymara; lower panel). Adapted from () with permission.


Figure 12. Putative molecular mechanism of PA at the carotid body. (A) AIH or repeated acute application of serotonin (5‐HT) to carotid bodies induces PKC‐mediated phosphorylation of carotid body NADPH oxidase (NOX) subunits and increased production or superoxide (O2). Superoxide production leads to enhanced carotid body membrane potential depolarization and increased afferent neuron firing. (B) This effect is manifested in progressive augmentation of phrenic nerve activity during the hypoxic episodes (or during 5‐HT application, arrows), followed by LTF of phrenic nerve activity in the normoxic period following the intermittent stimulus; adapted from () with permission.


Figure 13. Classic model of the molecular basis of phrenic LTF. Intermittent hypoxia (IH) increases ventilatory drive during acute hypoxia and normoxic (baseline) ventilation remains elevated for over an hour after IH. (A) Carotid body stimulation by IH releases 5‐HT from neuromodulatory Raphe neurons, which binds to 5‐HT type 1A and 2A receptors on phrenic motorneurons. 5‐HT activates Gq protein signaling cascades to activate protein kinase C (PKC) and induce the synthesis of BDNF. BDNF binds to tyrosine kinase receptors (TrkB) that activate phospho‐extracellular signal regulated kinase (pERK). In other systems, pERK has been shown to phosphorylate glutamatergic NMDARs in postsynaptic neurons and increase sensitivity to presynaptic glutamate release. (B) Physiologically, this increased sensitivity manifests as enhanced phrenic nerve activity and increased ventilation (primarily increased tidal volume); adapted from () with permission.


Figure 14. New model for phrenic LTF with multiple molecular pathways. The Gq pathway (blue arrows) proceeds as described in Figure , but can also be activated by α1‐adrenergic receptors (α1Rs). The Gs pathway (green arrows) can be induced by the activation of adenosine type 2A receptors (A2AR) or 5‐HT type 7 receptors (5‐HT7R), which are coupled to Gs proteins. Gs signaling activates protein kinase A (PKA), which stimulates immature TrkB to modulate phospho‐protein kinase B (pAkt). In other systems, this phosphorylates glutamatergic NMDARs and increases sensitivity to pre‐synaptic glutamate release. Recently, additional pathways (dashed arrows) have been described wherein vascular endothelial growth factor receptor‐2 (VEGFR‐2) or erythropoietin receptor (EPOR) induce LTF via phosphoinositide 3‐kinase (PI3K) and pAkt, and perhaps pERK.


Figure 15. Putative mechanism for ROS in phrenic LTF. Recent evidence supports a critical role for ROS produced from membrane‐bound NOX in the manifestation of LTF following AIH. (A) Activation of 5‐HT type 2 receptors in the post‐synaptic cell induces NOX activity and generation of O2. O2 acts to induce LTF, presumably via protein‐phosphatase (PP)‐mediated phosphorylation of NMDARs. (B) Application of the NOX inhibitor apocynin or ROS scavengers (not shown) abolish phrenic LTF following AIH; adapted from () with permission.
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Matthew E. Pamenter, Frank L. Powell. Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis. Compr Physiol 2016, 6: 1345-1385. doi: 10.1002/cphy.c150026