Control of Respiration

Question 1

Starting at the periphery, how does that signal control breathing?

Answer 1

Peripheral receptors sense a change –> Vagus nerve (X) mechanoreceptor afferent and Glossopharyngeal nerve (IX) chemoreceptor afferent –> Dorsal respiratory group (DRG) in the NTS –> Efferents (Phrenic, Thoracic, Abdominal, Cranial) Motorneurons cross midline to control breathing behavior

Question 2

Ventral respiratory group (VRG)

Answer 2

Expiration

Anatomical location in medulla oblongata: retrofacial nucleus (RFN) = Botzinger complex (BotC), nucleus ambiguus (NA), nucleus retro-ambigualis (NRA)

Inspiratory and expiratory neurons from NRA provide rhythmical drive to phrenic and thoracic motorneurons (E, I, E)

Neurons from preBotC generate rhythm

Question 3

preBotzinger complex (preBotC)

Answer 3

Within VRG, below RFN and above NA in the VRG

Cluster of neurons generates rhythm

Question 4

Motor efferents coming out of brainstem

Answer 4

Phrenic motorneurons: for diaphragm

Thoracic motorneurons: for intercostal muscles

Abdominal motorneurons: for abdominal muscles

Cranial motorneurons: for larynx and pharynx

Question 5

Dorsal respiratory group (DRG)

Answer 5

Inspiration

Anatomical location in medulla oblongata: near 4th ventricle, ventro-lateral nucleus of the tractur solitarius (vl-NTS)

Afferent fibers from mechanoreceptors (vagus nerve X) and chemoreceptors (glossopharyngeal nerve IX): lung stretch receptors (SAR)

Efferent fibers cross midline and synapse with phrenic motorneurons

Question 6

Pontine respiratory group (PRG)

Answer 6

Shaping breathing pattern (switch from Insp to Exp)

Anatomic location in pons: nucleus parabrachialis medialis (NPBM), Kolliker-Fuse nucleus (KF)

Apneustic center is in lower pons: vigorous inspiration

Pneumotaxic center is in upper pons: signals termination of inspiration (and expiration, so you don’t injure lung?)

Question 7

Suprapontine (CNS) input

Answer 7

Influences on DRG, VRG, PRG that are higher up (deeper in brain, CNS)

These inputs will stimulate ventilation MORE than is needed for metabolic exchange of O2 and CO2, so will lead to alveolar hyperventilation, hypocapnia and respiratory alkalosis

Cerebral cortex (volitional), limbic system (distress?), hypothalamus (affective behaviour), descending reticular formation

Question 8

What happens if you ventilate MORE than is needed for metabolic exchange of O2 and CO2?

Answer 8

Alveolar hyperventilation

Hypocapnia (low PCO2)

Respiratory alkalosis

Question 9

Two spinal pathways that output signal to breathing muscles

Answer 9

Automatic: ventrolateral columns

Voluntary: dorsolateral cord (corticospinal tract)

Note: if autonomic pathway partially damaged, will get primary alveolar hypoventilation (PCO2 increased, “Ondine’s curse”)

Question 10

Reflexes of the upper airway

Answer 10

Nose: dive reflex, sneeze reflex

Pharynx: reflex swallowing

Larynx: cough, apnea

Question 11

Pulmonary vagal mechanoreceptors

Answer 11

These exert effects on breathing pattern:

SAR: slowly adapting (stretch) receptors

RAR: rapidly adapting (irritant) receptors

J: juxtapulmonary capillary receptors

Bronchial C fibers

Question 12

Slowly adapting (stretch) receptors (SAR)

Answer 12

Activated by lung inflation to cause inspiration to stop (Hering-Breuer reflex)

In parenchyma of lung and smaller airway smooth muscle

Myelinated afferent fibers signal to vagus nerve which goes to NTS

Hering-Breuer not that important in humans, but helps animals limit inspiration and helps them keep breathing (increase respiratory frequency)

Question 13

Rapidly adapting (irritant) receptors (RAR)

Answer 13

Stimulated by inhalation of irritant materials and by local mechanical distortion –> cause hyperpnea, cough, bronchoconstriction

Located in epithelium larger airway and larynx

Myelinated afferent fibers signal to vagus nerve which ends bilaterally at NTS

Note: inflate lungs faster, then get faster firing of these RARs

Question 14

Juxtapulmonary capillary (J) receptors

Answer 14

Stimulated by interstitial distortion, congestion, pulmonary emboli and cause tachypnea

Located in alveolar-capillary interstitial space

Non-myelinated free nerve endings signal to vagus nerve which terminates bilaterally in NTS and area postrema

Question 15

Bronchial C-fibers, RAR, and cough mechanism

Answer 15

Cough is due to activation of sensory receptors in larynx/lower respiratory tract that send impulses to brain stem

Cough reflex is interaction between C-fiber receptors and RAR

Tachykinins released from C-fibers and diffuse to RARs

Stimulation of C-fibers can cause inhibition of cough

Stimuli: dust, irritant gases, casaicin, PE, pulmonary congestion

Mediators: ACh, histamine, serotonin, prostaglandins, bradykinin, substance P

Question 16

ACE inhibitors and cough

Answer 16

ACE inhibitors cause accumulation of angiotensin I in the lung, and accumulation of bradykinin and other mediators activate cough mechanism

(ACE inactivates bradykinin, so ACE inhibitors lead to accumulation of bradykinin)

ACE inhibitors: lisinopril and captopril

Question 17

Chest wall mechanoreceptors

Answer 17

Coordinate breathing during changes of posture and speech

Muscle spindles

Golgi tendon organs

Question 18

Muscle spindles

Answer 18

Respond to muscle stretching and cause stimulation of respiratory motorneurons

Located on intrafusal muscle fibers of intercostal muscles (and a little on diaphragm)

Question 19

Golgi tendon organs

Answer 19

Respond to muscle tension (pressure) and cause inhibition of respiratory motor neurons

Located on diaphragm

Question 20

Peripheral sensory afferents that ALL stimulate ventilation

Answer 20

Muscle spindles (in limb muscles)

Articular proprioceptors (in limb joints)

Pain afferents

Question 21

Autonomic regulation of airways

Answer 21

NE and EPI at beta receptors cause bronchodilation

ACh at muscarinic receptors causes bronchoconstriction

Vasoactive intestinal peptide and NO act through non-adrenergic non-cholinergic (NANC) system and cause bronchodilation

Question 22

Peripheral chemoreceptors

Answer 22

Located in carotid bodies in carotid bifurcation (aortic arch not that important)

Sense low PaO2, high PaCO2, high [H+] and increase ventilation

Only respond when PaO2 is BELOW 60 mmHg

Hypoxia (lack of O2) potentiates response to PaCO2, and high PaCO2 potentiates response to low O2

Question 23

Central chemoreceptors

Answer 23

Located as regions of chemosensitivity bilaterally on ventrolateral surface of medulla (RTN, d-NTS, near vagus and glossopharyngeal) in ECF and exposed to CSF

Sense high PaCO2 (strictly speaking), and high [H+] of CSF and increase ventilation

Even though BBB impermeable to ions, CO2 diffuses easily and turns into H+ and HCO3- so central chemoreceptors can indirectly respond to [H+]

Question 24

How does carotid body communicate with the brain?

Answer 24

Carotid body –> carotid sinus nerve –> glossopharyngeal nerve –> DRG

Question 25

Do the peripheral or central chemoreceptors respond to hypoxia (PaO2)?

Answer 25

Peripheral chemoreceptors (carotid bodies)

Only respond to hypoxia when PaCO2 less than 60 mmHg (makes sense bcause this is when hemoglobin actually gets less saturated!)

Question 26

Do the peripheral or central chemoreceptors respond to hypercapnia (PaCO2)?

Answer 26

Central responsible or 70-80% of response

Peripheral responsible for 20-30% of response

Note: in low O2 situations, carotid bodies help increase ventilation more; in high O2 situations, carotid bodies don’t do anything

Question 27

Do the peripheral or central chemoreceptors respond to metabolic acidosis (increased [H+])?

Answer 27

Carotid bodies only (peripheral), UNLESS cerebral anaerobiosis happens in the brain and that can trigger central chemoreceptors

Acidosis –> left shift –> any given PaCO2 gives higher ventilation

Alkalosis –> right shift –> any given PaCO2 gives lower ventilation

Question 28

Dejor’s Test

Answer 28

Breathing 100% O2 decreases ventilation (carotid bodies turned off!) and increases end tidal CO2

Question 29

Primary and secondary (2-3 days later) ventilatory response to altitude

Answer 29

Primary: Hypoxia –> increased ventilation via carotid bodies –> increased PAO2 and decreased PACO2 –> as PaCO2 decreased (pH is increased–respiratory alkalosis), less stimulation via central chemoreceptor response to low PaCO2 –> decrease breathing (bad!)

Secondary: After 2-3 days, kidneys excrete HCO3- to compensate so that pH decreases again –> increased [H+] in CSF increases ventilation via central chemoreceptors, and still have carotid body stimulation

Summary: peripheral stimulation to increase ventilation blunted by central stimulation, then kidneys correct pH back to more acidic and central chemoreceptors increase ventilation again

Note: can give acetazolamide (carbonic anhydrase inhibitor) before going to altitude to help acclimatization (you’ll still hyperventlate, but won’t get as much of an increase in CSF pH because you’re operating at minor metabolic acidosis already)

Question 30

Adaptations to chronic hypoxia

Answer 30

Polycythemia: kidneys secrete erythropoietin –> increase RBCs –> increased O2 content for given PaO2

Increased 2,3-DPG: shifts Hb-O2 curve right –> more O2 unloaded at tissues (but can impair O2 loading in lung)

Pulmonary hypertension: hypoxic pulmonary vasoconstriction –> increased vascular resistance –> increased pulmonary artery pressure –> can cause right side heart failure (BAD!)

Question 31

Why is ventilation decreased during sleep?

Answer 31

Reduced metabolic rate

Diminished cortical and reticular activating system activity

Respiratory muscle relaxation during REM sleep