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Control of Breathing During Exercise

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Abstract

During exercise by healthy mammals, alveolar ventilation and alveolar‐capillary diffusion increase in proportion to the increase in metabolic rate to prevent PaCO2 from increasing and Pao2 from decreasing. There is no known mechanism capable of directly sensing the rate of gas exchange in the muscles or the lungs; thus, for over a century there has been intense interest in elucidating how respiratory neurons adjust their output to variables which can not be directly monitored. Several hypotheses have been tested and supportive data were obtained, but for each hypothesis, there are contradictory data or reasons to question the validity of each hypothesis. Herein, we report a critique of the major hypotheses which has led to the following conclusions. First, a single stimulus or combination of stimuli that convincingly and entirely explains the hyperpnea has not been identified. Second, the coupling of the hyperpnea to metabolic rate is not causal but is due to of these variables each resulting from a common factor which link the circulatory and ventilatory responses to exercise. Third, stimuli postulated to act at pulmonary or cardiac receptors or carotid and intracranial chemoreceptors are not primary mediators of the hyperpnea. Fourth, stimuli originating in exercising limbs and conveyed to the brain by spinal afferents contribute to the exercise hyperpnea. Fifth, the hyperventilation during heavy exercise is not primarily due to lactacidosis stimulation of carotid chemoreceptors. Finally, since volitional exercise requires activation of the CNS, neural feed‐forward (central command) mediation of the exercise hyperpnea seems intuitive and is supported by data from several studies. However, there is no compelling evidence to accept this concept as an indisputable fact. © 2012 American Physiological Society. Compr Physiol 2:743‐777, 2012.

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Figure 1. Figure 1.

Schematic depicting multiple structures contributing to the control of breathing. It is hypothesized that respiratory rhythm originates within a brainstem oscillator which activates brainstem pattern generating neurons that provide for the proper sequential activation of respiratory pump (diaphragm, intercostal, and abdominal) and airway (laryngeal and pharyngeal) muscles. These brainstem neurons receive excitatory and inhibitory input from multiple sources including hypothesized supramedullary central command and mecho/metaboreceptor initiated spinal afferents from limb and respiratory skeletal muscles. In addition, the brainstem controller neurons receive carotid and intracranial chemoreceptor (retrotrapezoid nucleus, RTN) and vagal mechanoreceptor input critical to meet the proper ventilatory response to exercise. The figure is, with permission, from Dempsey et al. .

Figure 2. Figure 2.

Steady‐state arterial blood gas and pH status during spontaneous exercise in humans and ponies. Exercise intensity is depicted by heart rate rather than metabolic rate to avoid use of a mask or breathing valve which that can affect the ventilatory response. Note in humans arterial homeostasis is maintained from rest to a heart rate of about 150 and thereafter pH and PaCO2 decrease. In ponies, PaCO2 is inversely related to exercise intensity from rest to maximum irrespective of initially an alkaline but then an acid pH. In both species, Pao2 homeostasis is maintained throughout exercise. Data are, with permission, from Forster et al. .

Figure 3. Figure 3.

Effect of steady‐state exercise intensity (expressed as CO2 excretion, ) in humans on pulmonary (E) and alveolar (A) ventilation, breathing frequency (fb), tidal volume (VT), and dead space (VD) to VT ratio. Note E and A increase linearly as increases to about 2.5 l/min but thereafter E and A increase relatively more than . Adapted, with permission, from Dempsey et al. .

Figure 4. Figure 4.

Temporal pattern of ventilatory responses during and after exercise by healthy humans. Panel A shows the normal fast (phase I) and slow (phase II) responses to mild exercise and also shows that occlusion of blood flow to the muscles during the recovery hastens the return of ventilation to control levels [data, with permission, from Dejours ]. In panel B are data during and after heavy constant work rate cycloergometer exercise. Between the two arrows, cuffs around the legs were inflated to occlude blood flow (open symbols) and these data are compared to unoccluded flow (closed symbols). Note again that the ventilatory decline during recovery was increased during cuff occlusion despite expected accumulation of metabolites in the muscle circulation [data, with permission, from Haouzi et al. ].

Figure 5. Figure 5.

Temporal pattern of PaCO2 in humans (n = 10) from rest to work and work‐to‐work submaximal levels of exercise. All data were obtained without the subjects encumbered by a breathing valve system. Note the transient hypocapnia in the exercise transitions. The data are, with permission, from Forster et al. .

Figure 6. Figure 6.

Temporal pattern of PaCO2 in normal and carotid body denervated (CBD) ponies in rest to work and work‐to‐work transitions. The data were obtained without a mask needed to measure ventilatory parameters. Note the hypocapnia in rest to work transitions with some but not complete recovery, the changes in work‐to‐work transitions, and the exacerbation of the PaCO2 disruptions after CBD. The data are, with permission, from Pan et al. .

Figure 7. Figure 7.

Recording of inspiration (upward deflection) and expiration in a human subject at rest and during moderate bicycle exercise. Onset of exercise indicated by x. Volume change indicated on right side and marks on the bottom indicate seconds. Adapted, with permission, from Krogh and Linehard .

Figure 8. Figure 8.

The ventilatory (E/) response to exercise is increased as muscle strength is progressively weakened (decrease in handgrip strength) by injection of tubocurare. Adapted, with permission, from Asmussen et al. .

Figure 9. Figure 9.

Data supporting concept that suprapontine mechanisms “central command” stimulates breathing. Shown (panel a) is a decorticate cat preparation used in studies when respiration (phrenic nerve activity) was measured during spontaneous locomotion and locomotion was induced by stimulation in the subthalamic locomotor region (panel b). Shown in panel c is decorticate paralyzed preparation used for spontaneous fictive locomotion which as shown in panel d elicited a respiratory response. Data are, with permission, from Eldridge et al. .

Figure 10. Figure 10.

Effect of voluntary (circles) and electrically (x) induced exercise on pulmonary ventilation (vent) and alveolar PCO2 (PCO2 alv) relative to metabolic rate (l O2 min). Note the near identical responses to the two exercise tasks interpreted as indicating “central command” is not obligatory for ventilatory response to exercise. Data are, with permission, from Asmussen et al. .

Figure 11. Figure 11.

Schematics depicting multiple supramedullary structures potentially contributing to cardiovascular and respiratory control during exercise. The cardiovascular schematic was developed by Green and Paterson and presented here with their permission. To our knowledge, no comparable schematic has been published for respiratory control; thus, since the cardiovascular and respiratory responses to exercise are usually qualitatively the same, we assume the supramedullary components are the same or at least similar for both responses. As detailed in the text, evidence suggests medullary respiratory neurons receive excitatory exercise‐related inputs from suprapontine pathways that include the cortex, anterior (AHN) and lateral (LHA) hypothalamic nuclei, paraventricular nucleus (PVN), and periaqueductal gray (PAG). The respiratory rhythm originates within a brainstem oscillator which activates pattern generating neurons that provide for proper sequential activation of respiratory pump and airway muscles. The pre‐Bötzinger (PBC) is the core site of rhythm and pattern generation with important contributions from the parafacial respiratory group (pFRG)/retrotrapezoid nucleus (RTN) as well as the pontine respiratory group including the lateral parabrachial nucleus (LPBN) .

Figure 12. Figure 12.

Anatomical distribution of the afferent innervation of the cat skeletal muscle. Most of the group III and IV afferents fibers are found in association with arterioles (a.) and the venous and venular structures (v.) of the muscles. Data are, with permission, from Stacey et al. .

Figure 13. Figure 13.

Exercise activates group III and group IV muscles afferents. Shown are cumulative histograms for 24 group III afferents (A) and 10 group IV afferents (B) before, during, and after time that cats performed dynamic exercise, which was induced by stimulation of mesencephalic locomotor region. Exercise period is denoted by horizontal bars. Note maintained response to dynamic exercise by both group III and group IV afferent impulses. Data are, with permission, from Adreani et al. .

Figure 14. Figure 14.

Increased muscle blood flow activates group III and group IV afferents. Shown in the top panel are the temporal profiles of cumulative histogram of the activity of 15 group IV (open bars) and 3 group III (solid bars) fibers of the cat triceps surae, responding to papaverine (top) and mean popliteal blood flow (bottom). Shown in the bottom are the effects of venous obstruction on the discharge of a group IV muscle afferent fiber originating in the triceps surae of the cat at different flow levels after an injection of isoproterenol. The higher the level of flow before occlusion the greater the neural response to venous distension. Data are, with permission, from Haouzi et al. .

Figure 15. Figure 15.

The time course of pulmonary ventilation (E), oxygen consumption (), and the E/ ration (EO2) in an anesthetized (neural) dog when the hindlimb muscles were induced electrically to contract and the venous blood from the hindlimbs was delivered to another non exercise (humoral) dog. Note the brisk hyperpnea at the onset of contraction in the neural dog and the delayed response in the humoral dog. Data are, with permission, from Kao et al. .

Figure 16. Figure 16.

Blood flow in muscles has an effect on ventilation. Shown in panel A are the effects of the occlusion of the iliac arteries on the E and responses at the onset of electrically induced muscle contractions in anesthetized dogs. The arrow indicates the onset of exercise. The arterial occlusion was maintained during the period depicted by the horizontal bar. Responses in control condition are depicted with open symbols while the responses to occlusion and release are shown using closed symbols. Note that impediment of the arterial supply to the contracting muscles prevented the normal increase in and reduced dramatically the magnitude of the normal E response to exercise. Shown in panel B are the E effects of the occlusion of the lower abdominal aorta and inferior vena cava at the cessation of electrically induced hindlimb muscle contractions in an anesthetized dog. At the cessation of the contractions (second vertical arrow), both the arterial and venous balloons were inflated (first and second horizontal bar, respectively). The arterial balloon was deflated at the first vertical line, whereas venous return from the hindlimb remained blocked. This change caused E to increase despite the drop in PETCO2 and the lack of sustained change in systemic blood pressure (BP). When the venous balloon was deflated, note that E decreased despite the ensuing hypercapnia. Data are, with permission, from Huszczuk et al. .

Figure 17. Figure 17.

Rapid muscle blood flow response to exercise. Shown are oxygen consumption (dotted line, ) and leg blood flow (solid line) response to constant work rate exercise in supine position (40 W). Note the immediate increase in blood flow (as soon as the exercise starts) and the exponential increase in blood flow preceding phase II and reaching a steady state within 2 min. The ventilatory responses have been added based on the characteristics presented by MacDonald et al. .

Figure 18. Figure 18.

The isocapnic ventilatory response (right panel) to exercise does not correlate with changes in cardiac output and mixed venous CO2 content (left panel) during ramp‐like exercise in healthy humans. Note that as cardiac output and ventilation increase dramatically, there is only a small change in mixed venous CO2 content; thus, it is unlikely CO2 content provides a major signal for the blood flow and ventilatory responses. Data are, with permission, from Sun et al. .

Figure 19. Figure 19.

Effect of blockage of μ‐opioid sensitive type III‐IV muscle afferents via intrathecal Fentanyl on the steady‐state ventilatory response to 3 min of cycling exercise at each of four work rates. (*P<0.05, P<0.8). The Fentanyl‐induced hypoventilation was due to a reduced breathing frequency. Heart rate and mean arterial blood pressure (data not shown) along with E were significantly reduced at each work rate. Taking into account the reduced exercise E with Fentanyl plus the ventilatory equivalent of the concomitant rise in PETCO2, it is estimated that the partial blockage of muscle afferents accounted for 47%, 45%, and 15% of the total exercise hyperpnea at 100, 150, and 325 W, respectively. Data adapted, with permission, from Amann et al. .

Figure 20. Figure 20.

Example of changes in oxygen consumption (O2), CO2 excretion (), and ventilation when the period of sinusoidal changes in treadmill speed is shortened from 5 to 2 and then to 1 min. The fundamental component of the responses computed by Fourier analysis is superimposed on the raw data. Note that the changes in walking frequency are in phase with the sinusoidal changes in the speed of the treadmill and that there is no reduction in amplitude when the frequency of oscillations of the treadmill speed increases. There is a clear reduction in amplitude of both pulmonary gas exchange and ventilation when the oscillation period decreases whereas the phase lag between walking frequency and the respiratory parameters increases. Data are, with permission, from Haouzi et al. .

Figure 21. Figure 21.

Ventilatory sensitivity to increases in PaCO2 at rest and during two levels of bicycle exercise in a normal human. Note that exercise did not change the slope of the relationship indicating an unchanged sensitivity to CO2 during exercise. Data are, with permission, from studies by Asmussen et al, .

Figure 22. Figure 22.

Effect of exercise on ventilatory (E) sensitivity to hypoxia in a normal human. The closed symbols were obtained at rest and the additional data were obtained during two levels of submaximal exercise. Note that exercise increased the response to hypoxia. Data are, with permission, from Asmussen et al. .



Figure 1.

Schematic depicting multiple structures contributing to the control of breathing. It is hypothesized that respiratory rhythm originates within a brainstem oscillator which activates brainstem pattern generating neurons that provide for the proper sequential activation of respiratory pump (diaphragm, intercostal, and abdominal) and airway (laryngeal and pharyngeal) muscles. These brainstem neurons receive excitatory and inhibitory input from multiple sources including hypothesized supramedullary central command and mecho/metaboreceptor initiated spinal afferents from limb and respiratory skeletal muscles. In addition, the brainstem controller neurons receive carotid and intracranial chemoreceptor (retrotrapezoid nucleus, RTN) and vagal mechanoreceptor input critical to meet the proper ventilatory response to exercise. The figure is, with permission, from Dempsey et al. .



Figure 2.

Steady‐state arterial blood gas and pH status during spontaneous exercise in humans and ponies. Exercise intensity is depicted by heart rate rather than metabolic rate to avoid use of a mask or breathing valve which that can affect the ventilatory response. Note in humans arterial homeostasis is maintained from rest to a heart rate of about 150 and thereafter pH and PaCO2 decrease. In ponies, PaCO2 is inversely related to exercise intensity from rest to maximum irrespective of initially an alkaline but then an acid pH. In both species, Pao2 homeostasis is maintained throughout exercise. Data are, with permission, from Forster et al. .



Figure 3.

Effect of steady‐state exercise intensity (expressed as CO2 excretion, ) in humans on pulmonary (E) and alveolar (A) ventilation, breathing frequency (fb), tidal volume (VT), and dead space (VD) to VT ratio. Note E and A increase linearly as increases to about 2.5 l/min but thereafter E and A increase relatively more than . Adapted, with permission, from Dempsey et al. .



Figure 4.

Temporal pattern of ventilatory responses during and after exercise by healthy humans. Panel A shows the normal fast (phase I) and slow (phase II) responses to mild exercise and also shows that occlusion of blood flow to the muscles during the recovery hastens the return of ventilation to control levels [data, with permission, from Dejours ]. In panel B are data during and after heavy constant work rate cycloergometer exercise. Between the two arrows, cuffs around the legs were inflated to occlude blood flow (open symbols) and these data are compared to unoccluded flow (closed symbols). Note again that the ventilatory decline during recovery was increased during cuff occlusion despite expected accumulation of metabolites in the muscle circulation [data, with permission, from Haouzi et al. ].



Figure 5.

Temporal pattern of PaCO2 in humans (n = 10) from rest to work and work‐to‐work submaximal levels of exercise. All data were obtained without the subjects encumbered by a breathing valve system. Note the transient hypocapnia in the exercise transitions. The data are, with permission, from Forster et al. .



Figure 6.

Temporal pattern of PaCO2 in normal and carotid body denervated (CBD) ponies in rest to work and work‐to‐work transitions. The data were obtained without a mask needed to measure ventilatory parameters. Note the hypocapnia in rest to work transitions with some but not complete recovery, the changes in work‐to‐work transitions, and the exacerbation of the PaCO2 disruptions after CBD. The data are, with permission, from Pan et al. .



Figure 7.

Recording of inspiration (upward deflection) and expiration in a human subject at rest and during moderate bicycle exercise. Onset of exercise indicated by x. Volume change indicated on right side and marks on the bottom indicate seconds. Adapted, with permission, from Krogh and Linehard .



Figure 8.

The ventilatory (E/) response to exercise is increased as muscle strength is progressively weakened (decrease in handgrip strength) by injection of tubocurare. Adapted, with permission, from Asmussen et al. .



Figure 9.

Data supporting concept that suprapontine mechanisms “central command” stimulates breathing. Shown (panel a) is a decorticate cat preparation used in studies when respiration (phrenic nerve activity) was measured during spontaneous locomotion and locomotion was induced by stimulation in the subthalamic locomotor region (panel b). Shown in panel c is decorticate paralyzed preparation used for spontaneous fictive locomotion which as shown in panel d elicited a respiratory response. Data are, with permission, from Eldridge et al. .



Figure 10.

Effect of voluntary (circles) and electrically (x) induced exercise on pulmonary ventilation (vent) and alveolar PCO2 (PCO2 alv) relative to metabolic rate (l O2 min). Note the near identical responses to the two exercise tasks interpreted as indicating “central command” is not obligatory for ventilatory response to exercise. Data are, with permission, from Asmussen et al. .



Figure 11.

Schematics depicting multiple supramedullary structures potentially contributing to cardiovascular and respiratory control during exercise. The cardiovascular schematic was developed by Green and Paterson and presented here with their permission. To our knowledge, no comparable schematic has been published for respiratory control; thus, since the cardiovascular and respiratory responses to exercise are usually qualitatively the same, we assume the supramedullary components are the same or at least similar for both responses. As detailed in the text, evidence suggests medullary respiratory neurons receive excitatory exercise‐related inputs from suprapontine pathways that include the cortex, anterior (AHN) and lateral (LHA) hypothalamic nuclei, paraventricular nucleus (PVN), and periaqueductal gray (PAG). The respiratory rhythm originates within a brainstem oscillator which activates pattern generating neurons that provide for proper sequential activation of respiratory pump and airway muscles. The pre‐Bötzinger (PBC) is the core site of rhythm and pattern generation with important contributions from the parafacial respiratory group (pFRG)/retrotrapezoid nucleus (RTN) as well as the pontine respiratory group including the lateral parabrachial nucleus (LPBN) .



Figure 12.

Anatomical distribution of the afferent innervation of the cat skeletal muscle. Most of the group III and IV afferents fibers are found in association with arterioles (a.) and the venous and venular structures (v.) of the muscles. Data are, with permission, from Stacey et al. .



Figure 13.

Exercise activates group III and group IV muscles afferents. Shown are cumulative histograms for 24 group III afferents (A) and 10 group IV afferents (B) before, during, and after time that cats performed dynamic exercise, which was induced by stimulation of mesencephalic locomotor region. Exercise period is denoted by horizontal bars. Note maintained response to dynamic exercise by both group III and group IV afferent impulses. Data are, with permission, from Adreani et al. .



Figure 14.

Increased muscle blood flow activates group III and group IV afferents. Shown in the top panel are the temporal profiles of cumulative histogram of the activity of 15 group IV (open bars) and 3 group III (solid bars) fibers of the cat triceps surae, responding to papaverine (top) and mean popliteal blood flow (bottom). Shown in the bottom are the effects of venous obstruction on the discharge of a group IV muscle afferent fiber originating in the triceps surae of the cat at different flow levels after an injection of isoproterenol. The higher the level of flow before occlusion the greater the neural response to venous distension. Data are, with permission, from Haouzi et al. .



Figure 15.

The time course of pulmonary ventilation (E), oxygen consumption (), and the E/ ration (EO2) in an anesthetized (neural) dog when the hindlimb muscles were induced electrically to contract and the venous blood from the hindlimbs was delivered to another non exercise (humoral) dog. Note the brisk hyperpnea at the onset of contraction in the neural dog and the delayed response in the humoral dog. Data are, with permission, from Kao et al. .



Figure 16.

Blood flow in muscles has an effect on ventilation. Shown in panel A are the effects of the occlusion of the iliac arteries on the E and responses at the onset of electrically induced muscle contractions in anesthetized dogs. The arrow indicates the onset of exercise. The arterial occlusion was maintained during the period depicted by the horizontal bar. Responses in control condition are depicted with open symbols while the responses to occlusion and release are shown using closed symbols. Note that impediment of the arterial supply to the contracting muscles prevented the normal increase in and reduced dramatically the magnitude of the normal E response to exercise. Shown in panel B are the E effects of the occlusion of the lower abdominal aorta and inferior vena cava at the cessation of electrically induced hindlimb muscle contractions in an anesthetized dog. At the cessation of the contractions (second vertical arrow), both the arterial and venous balloons were inflated (first and second horizontal bar, respectively). The arterial balloon was deflated at the first vertical line, whereas venous return from the hindlimb remained blocked. This change caused E to increase despite the drop in PETCO2 and the lack of sustained change in systemic blood pressure (BP). When the venous balloon was deflated, note that E decreased despite the ensuing hypercapnia. Data are, with permission, from Huszczuk et al. .



Figure 17.

Rapid muscle blood flow response to exercise. Shown are oxygen consumption (dotted line, ) and leg blood flow (solid line) response to constant work rate exercise in supine position (40 W). Note the immediate increase in blood flow (as soon as the exercise starts) and the exponential increase in blood flow preceding phase II and reaching a steady state within 2 min. The ventilatory responses have been added based on the characteristics presented by MacDonald et al. .



Figure 18.

The isocapnic ventilatory response (right panel) to exercise does not correlate with changes in cardiac output and mixed venous CO2 content (left panel) during ramp‐like exercise in healthy humans. Note that as cardiac output and ventilation increase dramatically, there is only a small change in mixed venous CO2 content; thus, it is unlikely CO2 content provides a major signal for the blood flow and ventilatory responses. Data are, with permission, from Sun et al. .



Figure 19.

Effect of blockage of μ‐opioid sensitive type III‐IV muscle afferents via intrathecal Fentanyl on the steady‐state ventilatory response to 3 min of cycling exercise at each of four work rates. (*P<0.05, P<0.8). The Fentanyl‐induced hypoventilation was due to a reduced breathing frequency. Heart rate and mean arterial blood pressure (data not shown) along with E were significantly reduced at each work rate. Taking into account the reduced exercise E with Fentanyl plus the ventilatory equivalent of the concomitant rise in PETCO2, it is estimated that the partial blockage of muscle afferents accounted for 47%, 45%, and 15% of the total exercise hyperpnea at 100, 150, and 325 W, respectively. Data adapted, with permission, from Amann et al. .



Figure 20.

Example of changes in oxygen consumption (O2), CO2 excretion (), and ventilation when the period of sinusoidal changes in treadmill speed is shortened from 5 to 2 and then to 1 min. The fundamental component of the responses computed by Fourier analysis is superimposed on the raw data. Note that the changes in walking frequency are in phase with the sinusoidal changes in the speed of the treadmill and that there is no reduction in amplitude when the frequency of oscillations of the treadmill speed increases. There is a clear reduction in amplitude of both pulmonary gas exchange and ventilation when the oscillation period decreases whereas the phase lag between walking frequency and the respiratory parameters increases. Data are, with permission, from Haouzi et al. .



Figure 21.

Ventilatory sensitivity to increases in PaCO2 at rest and during two levels of bicycle exercise in a normal human. Note that exercise did not change the slope of the relationship indicating an unchanged sensitivity to CO2 during exercise. Data are, with permission, from studies by Asmussen et al, .



Figure 22.

Effect of exercise on ventilatory (E) sensitivity to hypoxia in a normal human. The closed symbols were obtained at rest and the additional data were obtained during two levels of submaximal exercise. Note that exercise increased the response to hypoxia. Data are, with permission, from Asmussen et al. .

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How to Cite

Hubert V. Forster, Philippe Haouzi, Jerome A. Dempsey. Control of Breathing During Exercise. Compr Physiol 2012, 2: 743-777. doi: 10.1002/cphy.c100045