Lecture 4Lecture 4

Control of VControl of VEE

Ventilatory response to COVentilatory response to CO22

Ventilatory response to OVentilatory response to O22

Ventilatory response to pHVentilatory response to pH

Ventilatory response to exerciseVentilatory response to exercise

Control of VEControl of VE

The three basic elements of the The three basic elements of the respiratory control system are; SENSORS, respiratory control system are; SENSORS, CENTRAL CONTROLLER and EFFECTORS.CENTRAL CONTROLLER and EFFECTORS.

1- SENSOR; which gather information and 1- SENSOR; which gather information and feed it to the feed it to the

2- CENTRAL CONTROLLER (in the brain), 2- CENTRAL CONTROLLER (in the brain), which coordinates the information and, in which coordinates the information and, in turn, sends impulses to the turn, sends impulses to the

3- EFFECTORS (respiratory muscles), 3- EFFECTORS (respiratory muscles), which cause VE.which cause VE.

1)1) Central controllerCentral controller

Central control of breathing is achieved at the Central control of breathing is achieved at the brainstem, specially the pons and midbrain brainstem, specially the pons and midbrain (responsible for involuntary breathing) and the (responsible for involuntary breathing) and the cerebral cortex (responsible for voluntary cerebral cortex (responsible for voluntary breathing).breathing).

The respiratory centre is divided into 4 groups of The respiratory centre is divided into 4 groups of neurones spread throughout the entire length of neurones spread throughout the entire length of the medulla and pons;the medulla and pons;(1) DRG:(1) DRG:- It is located in the entire length of the dorsal - It is located in the entire length of the dorsal aspect of the medulla.aspect of the medulla.- It lies in close relation to the NTS where visceral - It lies in close relation to the NTS where visceral afferents from cranial nerves IX and X terminate.afferents from cranial nerves IX and X terminate.- It comprises inspiratory neurons. Thus, they are - It comprises inspiratory neurons. Thus, they are almost entirely responsible for inspiration.almost entirely responsible for inspiration.

(2) VRG:(2) VRG:It is located in each side of the medulla, about 5 It is located in each side of the medulla, about 5 milliliters anterior and lateral to the DRG.milliliters anterior and lateral to the DRG.They are inactive during quiet breathing, but become They are inactive during quiet breathing, but become activated during ↑ pulmonary VE, as in exercise.activated during ↑ pulmonary VE, as in exercise.They are mainly expiratory neurons with some They are mainly expiratory neurons with some inspiratory neurons, both of which are activated when inspiratory neurons, both of which are activated when expiration becomes an active process.expiration becomes an active process.They are comprises 4 nuclei;They are comprises 4 nuclei;a) the nucleus retroambigualis (NR); which is a) the nucleus retroambigualis (NR); which is predominantly expiratory with upper motor neurons predominantly expiratory with upper motor neurons passing to the expiratory muscles of the other side.passing to the expiratory muscles of the other side.b) the nucleus ambiguous (NA); which controls the b) the nucleus ambiguous (NA); which controls the dilator function of larynx, pharynx and tongue.dilator function of larynx, pharynx and tongue.c) the nucleus para-ambigualis (NP); which is mainly c) the nucleus para-ambigualis (NP); which is mainly inspiratory and control the force of contraction of the inspiratory and control the force of contraction of the inspiratory muscles of the opposite side.inspiratory muscles of the opposite side.d) the Botzinger complex (BC); within the nucleus d) the Botzinger complex (BC); within the nucleus rterofacialis) has widspread expiratory functions. rterofacialis) has widspread expiratory functions.

(3) AC ???:(3) AC ???:It is located in the lower pons.It is located in the lower pons.They sends excitatory impulses to the DRG of neurons They sends excitatory impulses to the DRG of neurons and potentiates the inspiratory drive.and potentiates the inspiratory drive.It receives inhibiting impulses from the sensory vagal It receives inhibiting impulses from the sensory vagal fibers of the Hering-Breuer inflation reflex and inhibiting fibers of the Hering-Breuer inflation reflex and inhibiting fibers from the pneumotaxic centre in the upper pons.fibers from the pneumotaxic centre in the upper pons.

(4) PC;(4) PC;It is located dorsally in the upper pons.It is located dorsally in the upper pons.It transmits inhibitory impulses to the AC and to the It transmits inhibitory impulses to the AC and to the inspiratory areas to switch off inspiration.inspiratory areas to switch off inspiration.The function of this centre is primarily to limit The function of this centre is primarily to limit inspiration. This has a secondary effect of increasing inspiration. This has a secondary effect of increasing the rate of breathing.the rate of breathing.Some investigators believed that the role of this centre Some investigators believed that the role of this centre is “fine tuning” of respiratory rhythm because a normal is “fine tuning” of respiratory rhythm because a normal rhythm can exist in the absence of this centre. rhythm can exist in the absence of this centre.

2) Effectors2) Effectors

They are the muscles of respiration, including They are the muscles of respiration, including the diaphragm, intercostal muscles, abdominal the diaphragm, intercostal muscles, abdominal muscles and accessory muscles as muscles and accessory muscles as sternocleidomastoid.sternocleidomastoid.It is crucially important that these various It is crucially important that these various muscle groups work in a coordinated manner, muscle groups work in a coordinated manner, and this is the responsibility of the central and this is the responsibility of the central controller.controller.There is some evidence that some newborn There is some evidence that some newborn children, particularly those who are premature, children, particularly those who are premature, have uncoordinated respiratory muscle activity, have uncoordinated respiratory muscle activity, especially during sleep. For example, the especially during sleep. For example, the thoracic muscle may try to inspire while the thoracic muscle may try to inspire while the abdominal muscle expire. This may be a factor abdominal muscle expire. This may be a factor in the “sudden infant death syndrome” (SIDS).in the “sudden infant death syndrome” (SIDS).

3) Sensors3) Sensors

The sensors that contribute to the control of The sensors that contribute to the control of breathing include lung stretch receptors in the breathing include lung stretch receptors in the smooth muscle of the airway, irritant receptors smooth muscle of the airway, irritant receptors located between airway epithelial cells, joint located between airway epithelial cells, joint and muscle receptors that stimulate breathing and muscle receptors that stimulate breathing in response to limb movement, and in response to limb movement, and juxtacapillary (or J) receptors located in alveolar juxtacapillary (or J) receptors located in alveolar walls which sense engorgement of the walls which sense engorgement of the pulmonary capillaries and cause rapid shallow pulmonary capillaries and cause rapid shallow breathing.  breathing.  The most important sensors are central The most important sensors are central chemoreceptors in the medulla as well as chemoreceptors in the medulla as well as peripheral chemoreceptors in the carotid and peripheral chemoreceptors in the carotid and aortic bodies.  aortic bodies.  

Central chemoreceptors (CC)Central chemoreceptors (CC)They are most probably located on the They are most probably located on the ventrolateral surfaces of the medulla oblangato, ventrolateral surfaces of the medulla oblangato, which bathed CSF.which bathed CSF.The CCs in the medulla respond to changes in the The CCs in the medulla respond to changes in the pH of the CSF.  pH of the CSF.  ↓↓ in CSF pH produce in CSF pH produce ↑↑ in breathing in breathing (hyperVE) whereas (hyperVE) whereas ↑↑ in pH result in hypoVE. in pH result in hypoVE.They are highly sensitive to [HThey are highly sensitive to [H++] of the CSF evoked ] of the CSF evoked by PaCOby PaCO22, since CO, since CO22 can freely cross the blood- can freely cross the blood-brain barrier into the CSF while the barrier is brain barrier into the CSF while the barrier is relatively impermeable to Hrelatively impermeable to H++ and H and H22COCO33..Stimulation of these receptors Stimulation of these receptors ↑↑ both the rate of both the rate of rise and the intensity of the inspiratory signals, rise and the intensity of the inspiratory signals, thereby thereby ↑↑ the frequency of the respiratory rhythm. the frequency of the respiratory rhythm.

Peripheral chemoreceptors (PC)Peripheral chemoreceptors (PC)

They are located in the carotid bodies at the bifurcation They are located in the carotid bodies at the bifurcation of the common carotid arteries and in the aortic bodies of the common carotid arteries and in the aortic bodies above and below the aortic arch.above and below the aortic arch.They cause an ↑ in VE in response to They cause an ↑ in VE in response to ↓↓ in PaO in PaO22, ↑ in , ↑ in PaCOPaCO22 and ↑ in arterial hydrogen concentrations ( and ↑ in arterial hydrogen concentrations (↓↓ in in pH).pH).The carotid bodies are most important in humans. They The carotid bodies are most important in humans. They contain glomus cells of two or more types which show contain glomus cells of two or more types which show an intense fluorescence staining because of their large an intense fluorescence staining because of their large content of dopamine.content of dopamine.The mechanism of chemoreception is not yet The mechanism of chemoreception is not yet understood. A popular view has been that glomus cells understood. A popular view has been that glomus cells themselves are chemoreceptors.themselves are chemoreceptors.They are highly sensitive to changes in PaOThey are highly sensitive to changes in PaO22 and to a and to a lesser extent to PaCOlesser extent to PaCO22 and pH. They are also sensitive to and pH. They are also sensitive to temperature of the blood and blood flow.temperature of the blood and blood flow.The response of the PCs to PaCOThe response of the PCs to PaCO22 is much less important is much less important than that of the CCs.than that of the CCs.

Lung and airway receptorsLung and airway receptorsReceptors in the lung and airways are innervated by Receptors in the lung and airways are innervated by myelinated and unmyelinated vagal fibers. myelinated and unmyelinated vagal fibers. The unmyelinated fibers are C fibers.The unmyelinated fibers are C fibers.The myelinated fibers are commonly divided into SARs The myelinated fibers are commonly divided into SARs and RARs on the basis of whether sustained stimulation and RARs on the basis of whether sustained stimulation leads to prolonged or transient discharge in their afferent leads to prolonged or transient discharge in their afferent fibers.fibers.SARs are also known as pulmonary stretch receptors.They SARs are also known as pulmonary stretch receptors.They are thought to participate in ventilatory control by are thought to participate in ventilatory control by prolonged inspiration in conditions that reduce lung prolonged inspiration in conditions that reduce lung inflation.inflation. RARs are stimulated by chemicals such as histamine, RARs are stimulated by chemicals such as histamine, dust, cigarette smoke. Therefore, they have been called dust, cigarette smoke. Therefore, they have been called irritant receptors.irritant receptors.Activation of RARs in the lung may produce hyperpnea.Activation of RARs in the lung may produce hyperpnea.

J receptors are stimulated by hyperinflation of the lung. J receptors are stimulated by hyperinflation of the lung. They play a role in the dyspnea associated with left heart They play a role in the dyspnea associated with left heart failure, interstitial lung disease, pneumonia and failure, interstitial lung disease, pneumonia and microembolism. microembolism.

The Hering-Breuer reflexes thought to play a major role The Hering-Breuer reflexes thought to play a major role in VE by determining the rate and depth of breathing. in VE by determining the rate and depth of breathing. This can be done by using the information from the This can be done by using the information from the SARs to modulate the “switching off” mechanism in the SARs to modulate the “switching off” mechanism in the medulla. medulla.

The Hering-Breuer inflation reflex is an ↑ in the The Hering-Breuer inflation reflex is an ↑ in the duration of expiration produced by steady lung duration of expiration produced by steady lung inflation, and the Hering-Breuer deflation reflex is a ↓in inflation, and the Hering-Breuer deflation reflex is a ↓in the duration of expiration produced by marked the duration of expiration produced by marked deflation of the lung.deflation of the lung.

In human beings, the Hering-Breuer reflex probably is In human beings, the Hering-Breuer reflex probably is not activated until VT increases to more than three not activated until VT increases to more than three times normal (i.e. < 1.5 l/breath). Therefore, this reflex times normal (i.e. < 1.5 l/breath). Therefore, this reflex appears to be mainly a protective mechanism for appears to be mainly a protective mechanism for preventing excess lung inflation rather than an preventing excess lung inflation rather than an important ingredient in normal control of VE. important ingredient in normal control of VE.

Ventilatory response to COVentilatory response to CO22

The most important factor in the control of VE is The most important factor in the control of VE is PaCOPaCO22..

The ventilatory response to COThe ventilatory response to CO22 is normally is normally measured by having the subject inhale COmeasured by having the subject inhale CO22 mixture mixture or rebreathe from a bag so that the inspired PCOor rebreathe from a bag so that the inspired PCO22 gradually ↑.gradually ↑.

With a normal POWith a normal PO22 the VE ↑ by about 2-3 l/min for the VE ↑ by about 2-3 l/min for each 1 mmHg rise in PCOeach 1 mmHg rise in PCO22. Lowering the PO. Lowering the PO22 produces 2 effects;produces 2 effects;

1) there is a higher VE for a given PCO1) there is a higher VE for a given PCO22

2) the slope of the line becomes steeper.2) the slope of the line becomes steeper.

The ventilatory response to COThe ventilatory response to CO22 is reduced by sleep, is reduced by sleep, increasing age, and genetic, racial and personality increasing age, and genetic, racial and personality factors. It can also be reduced by if the work of factors. It can also be reduced by if the work of breathing is ↑. breathing is ↑.

Ventilatory response to OVentilatory response to O22

The way in which a reduction of PaOThe way in which a reduction of PaO22 stimulates stimulates VE can be studied by having the subject VE can be studied by having the subject breathe hypoxic gas mixture.breathe hypoxic gas mixture.

When the PCOWhen the PCO22 is ↑ a reduction in PO is ↑ a reduction in PO22 below below 100 mmHg causes some stimulation of VE.100 mmHg causes some stimulation of VE.

Hypoxemia reflexly stimulates VE by its action Hypoxemia reflexly stimulates VE by its action on the carotid and aortic body chemoreceptors.on the carotid and aortic body chemoreceptors.

Ventilatory response to pHVentilatory response to pH

A reduction in arterial blood pH stimulates A reduction in arterial blood pH stimulates VE.VE.

The chief site of action of a reduced The chief site of action of a reduced arterial pH is the PCs, especially the arterial pH is the PCs, especially the carotid bodies in humans. It is also carotid bodies in humans. It is also possible that the CCs itself is affected by a possible that the CCs itself is affected by a change in blood pH if it is large enough.change in blood pH if it is large enough.

Ventilatory response to exerciseVentilatory response to exerciseOn exercise, VE ↑ promptly and, during strenuous exercise, it may On exercise, VE ↑ promptly and, during strenuous exercise, it may reach very high levels.reach very high levels.

The ↑ in VE closely matches the ↑ in VOThe ↑ in VE closely matches the ↑ in VO22 and VCO and VCO22..

The PaCOThe PaCO22 does not ↑ during most form of exercise, however, does not ↑ during most form of exercise, however, during sever exercise it falls slightly.during sever exercise it falls slightly.The PaOThe PaO22 ↑ slightly, and it may fall at very high work levels. ↑ slightly, and it may fall at very high work levels.The arterial pH remains nearly constant for moderate exercise, The arterial pH remains nearly constant for moderate exercise, and falls during heavy exercise.and falls during heavy exercise.

Factors which play a role in the ↑ in VE during exercise includes;Factors which play a role in the ↑ in VE during exercise includes;- ↑ body temperature- ↑ body temperature- ↑ plasma epinephrine conc- ↑ plasma epinephrine conc- ↑ plasma potassium conc- ↑ plasma potassium conc- ↑ CO2 load to the lung- ↑ CO2 load to the lung- Passive movement of the limbs - Passive movement of the limbs