• rate and depth of breathing are regulated so that Pa_CO2 is maintained close to 40 mm Hg. We can use the assumption that Pa_CO2 = PA_CO2 (i.e. that arterial CO₂ is equivalent to alveolar CO₂ concentrations). When PA_CO2 is regulated, PA_O2 is automatically set to an appropriate value that depends on the ambient partial pressure of oxygen and the health of the lungs (V/Q distribution). The Pa_CO2 sensitive mechanism is the main controller of breathing. However, the Pa_CO2 controller can be overridden in systemic arterial hypoxemia (e.g., acclimatization to living at high altitude) by a PA_O2 sensitive controller. This happens when arterial oxygen tension decreases below 60 mm Hg.
• Thoracic mechanoreceptors, chiefly stretch receptors in the walls of the airways, set the breathing frequency. They are stimulated by lung inflation and deflation. Stretch receptor input (afferent impulses via vagus) mainly influences inspiration. Interruption of the stretch receptors by cutting or cooling the vagus nerves prolongs inspiration.
• Central and Peripheral chemoreceptors also play a role in control of breathing. Both respond to changes in the CO₂ and H⁺ concentrations. Elevation of Pa_CO2 up to 100 mm Hg cause a linear increase in ventilation. Also, at any level of Pa_CO2, ventilation is greater when acidosis prevails and less when alkalosis prevails. It is also important to note that the central chemoreceptors contribute ~75% of the total ventilatory response to CO₂.
• Although CO₂ is the main controlled variable in breathing, when Pa_O2 decreases sufficiently, O₂ sensors in the carotid body (peripheral chemoreceptors) are stimulated and ventilation increases. Interestingly, asphyxia (hypercapnia plus hypoxia) stimulates the drive to breath much more than does hypoxia alone. Hypercapnia enhances the ventilatory response to hypoxia, and inversely, hypoxia enhances the ventilatory response to hypercapnia.

• both the rate and depth of breathing are regulated so that Pa_CO2 is maintained close to 40mmHg
• the Pa_CO2-sensitive mechanism is the main controller of breathing but can be overridden in systemic arterial hypoxemia by a PA_O2-sensitive controller (when PA_O2 < 60mmHg)
• Types of Control
• Metabolic (automatic) control pattern
• Concerned with O₂ delivery to mito and acid-base balance
• Metabolic controller lies in the brainstem
• Reticular activating system modulates the brainstem controller by affecting the state of alertness of the brain
• Intrinsic breathing controllers
• Medullary respiratory area
• Respiratory neurons in the medulla (effect muscles of rib cage, diaphragm, abdomen)
• Nucleus tractus solitarius (dorsal): discharge during inspiration
• Nucleus retroambiguus (ventral): excited during inspiration and expiration
• Pneumotaxic center (in the pons): influences the switching between inspiration and expiration
• Behavioral (voluntary) control pattern
• Higher brain center controllers in the thalamus and cerebral cortex are involved
• Coordinates breathing with other volitional motor activities that make use of the lungs and chest wall (ie swallowing)
• Rhythmic breathing depends on a continuous (tonic) inspiratory drive from the dorsal group, and on intermittent (phasic) expiratory inputs from the cerebrum, thalamus, cranial nerves, and ascending spinal cord sensory tracts
• Thoracic mechanoreceptors (stretch receptors in walls of the airways) set breathing freq.
• Stimulated by lung inflation and deflation; mainly influences inspiration
• Neurons in ventral motor group (nucleus retroambiguus) are excited by lung inflation
• Brainstem Mechanisms that generate respiratory rhythm
• Central and peripheral chemoreceptors Þ inspiratory neurons (dorsal motor group in nucleus tractus solitarius) Þ inspiratory muscle contraction
• Central inspiratory activity and/or pulmonary stretch receptors via vagus nerve and/or stretch receptors in chest wall Þ ventral motor group in nucleus tractus solitarius Þ activates inspiratory cutoff switch Þ inhibits dorsal motor group in nucleus tractus solitarius Þ inhibts inspiratory muscle contraction
• Thus have tonic inspiratory activity that is inhibited only when sufficient sensory signals are received
• Spinal Integration
• Stimuli to segments T1 to T8 inhibit phrenic motor neuron activity and terminate inspiration
• Stimuli to segments T9 to T12 excite intercostal and phrenic motor neurons and cause thoracic cavity to expand

• Medulla – four groups of respiratory neurons (two in each hemisphere); each group contains:
• inspiratory: synapse with inspiratory muscles (external intercostal/diaphragm)
• expiratory: synapse with expiratory muscles (internal intercostal/abdominal)
• usually not to threshold during passive breathing, so expiration is passive
• inspiration and expiration are mutually inhibitory (i.e., when one is active, the other is silent)
• Pons—pneumotaxic center (group of neurons bilaterally in upper pons); controls breathing rate
• not inherent pacemaker; receives impulses from other centers
• inactivation leads to reduced breathing frequency, or "apneustic breathing"

• modulate discharge intensity of medullary respiratory neurons to alter breathing
• measure chemical status of blood (peripheral) and brain tissue (central chemoreceptors)
• Peripheral Chemoreceptors – in carotid bodies (bifurcation of carotid) and aortic arch
• mostly sensitive to low arterial [O₂], but also respond to high [CO₂] or high [H⁺]
• responsible for most hypoxia-related stimulation of medullary respiratory centers
• Central Chemoreceptors – exact location not known, probably ventral midline medulla
• more active at rest than peripheral
• mostly measure [CO₂], also [HCO₃^-] and pH
• influenced by chemical composition of cerebrospinal fluid (CSF) and brain arterial blood
• CSF bathes ventral surface of medulla – CO₂ diffuses here from arteries, H⁺ and HCO₃^- do not

• Carbon Dioxide
• Central chemoreceptors located near ventrolateral surface of the medulla
• Account for 75% of CO₂ induced increases in ventilation
• Respond to changes in [H+] of surrounding brainstem interstitial fluid
• Peripheral chemoreceptors (carotid bodies) account for remaining 25%
• Ý [H+] stimulates periph chemo Þ Ý ventilation Þ PaCO2 ß Þ cerebral interstitial fluid has ß [H+] Þ central chemo activity ß
• Influence of Brain Blood Flow on Breathing
• As cerebral blood flow Ý Þ interstitial fluid P_CO2 ß
• Oxygen
• When arterial P_O2 ß sufficiently Þ O₂ sensors in carotid body stimulated Þ ventilation Ý
• Asphyxia (hypercapnia plus hypoxia) stimulates the drive to breathe much more than does hypoxia alone
• Factors that affect the Responses to CO2 and O2
• Hypoxia inhibits cerebral arterial vascular tone Þ increases brain blood flow Þ lowers brain P_CO2 Þ depresses breathing
• Sympathetic nervous activity Þ decrease carotid body blood flow Þ increase its sensitivity to hypoxia

• Sensory Receptors in the Lungs
• Sensory receptors in the lungs and airways are stimulated by irritation of the mucosa or by changes in distending pressure
• Afferent sensory info travels to brainstem via vagus nerve
• 3 types of pulmonary receptors
• (1) stretch receptors located within the smooth muscle layer of the extrapulmonary airways (regulatory function)
• excited by Ý in bronchial transmural press
• adapt slowly to a sustained stimulus
• as lung is inflated, these act to inhibit inspiration and promote expiration
• responsible for Hering-Breuer reflex: produces apnea in response to large lung inflations and augments expiratory muscle contraction
• (2) irritant receptors that ramify among airway epithelial cells and whose distribution is similar to that of the stretch receptors (protective receptor)
• rapidly adapt to sustained stimulus
• stimulated chemically (nitrogen dioxide, sulfur dioxide, ammonia, inhaled antigens (pollens)), by lung inflation, Ý in airflow, particles impinging on bronchial surfaces, changes in bronchial smooth muscle tone (asthma attack)
• stimulation causes: cough, bronchconstriction, mucus secretion, apnea, glottial closure followed by rapid shallow breathing
• (3) unmyelinated C fibers situated in the lung interstitium and alveolar walls (protective)
• rapidly adapt to sustained stimulus
• causes localized vasodilation and increased venular leakiness
• causes mucosa to swell owing to vascular congestion and edema
• Receptors in the Chest Wall
• Receptors in the chest wall modify motor nerve discharge to the breathing muscles through reflexes at the spinal cord level
• Receptors help minimize ventilation changes
• Receptor types:
• (1) Joint
• Vary with the extent and speed of rib movement
• (2) Tendon
• Monitor the force of muscle contraction and tend to inhibit inspiration
• (3) muscle spindle receptors
• abundant in intercostal and abdominal wall muscles but scarce in the diaphragm
• coordinate breathing during changes in posture and speech
• stabilize rib cage when breathing is impeded by increases in airway resistance or by decreases in lung compliance
• spindle afferent fibers project to the cerebral cortex and provide the info that allows conscious perception of the respiratory movements

Acute Ventilatory Responses to Hypoxemia/Hypercapnia – hypoxemia increases sensitivity to hypercapnia

• most knowledge from experiments on anesthetized animals – only inferential to humans
• modify pattern by:
• changing pattern of individual breaths (affect time spent in inspiration or expiration)
• changing intensity of medullary response motor neuron discharge
• may also contribute to sensation of dyspnea (complex cortical integrative response)
• Reflexes from Lung and Airways: three types of interpulmonary receptors – all send afferent neurons through vagus nerve:
• (1) pulmonary stretch receptors – trachea/larger airways – measure magnitude/change in lung vol.
• stimulation inhibits inspiration, promotes expiration (Hering-Breuer Reflex)
• (2) irritant fibers – bronchi/small airways; stimulated by smoke, dust, noxious gasses, histamine, anesthetic
• stimulation causes bronchoconstriction and rapid, shallow breathing
• (3) C-fibers – in alveolar epithelium near pulmonary capillaries; respond to increase in interstitial fluid
• stimulation causes rapid, shallow breathing
• Reflexes from Chest Wall – intercostal and abdominal muscles have muscle spindles/tendon organ receptors
• increase contraction intensity if mechanical load increased (more airway resistance/less lung compliance)
• maybe just for postural control/fine motor acts (speech)