1. Lecture 4 Control of VE Ventilatory response to CO 2 Ventilatory response to O 2 Ventilatory response to pH Ventilatory response to exercise

2. Control of ventilation 3 basic elements for the respiratory control system; SENSORS, CENTRAL CONTROLLER and EFFECTORS. 1- SENSOR; which gather information and feed it to the → 2- CENTRAL CONTROLLER; in the brain, which coordinates the information and, in turn, sends impulses to the → 3- EFFECTORS (respiratory muscles), which cause ventilation.

4. 1)Central controller Central control of breathing is achieved at the brainstem, specially the pons and midbrain (responsible for involuntary breathing) and the cerebral cortex (responsible for voluntary breathing). The respiratory centre is divided into 4 groups of neurones spread throughout the entire length of the medulla and pons; VRG, DRG, AC & PC. (1) DRG: - It is located in the entire length of the dorsal aspect of the medulla. - It lies in close relation to the NTS where visceral afferents from cranial nerves IX and X terminate. - It comprises inspiratory neurons. Thus, they are almost entirely responsible for inspiration.

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

6. (3) AC ???: It is located in the lower pons. They sends excitatory impulses to the DRG of neurons and potentiates the inspiratory drive. It receives inhibiting impulses from the sensory vagal fibers of the Hering-Breuer inflation reflex and inhibiting fibers from the pneumotaxic centre in the upper pons. (4) PC; It is located dorsally in the upper pons. It transmits inhibitory impulses to the AC and to the inspiratory areas to switch off inspiration. The function of this centre is primarily to limit inspiration. This has a secondary effect of increasing the rate of breathing. Some investigators believed that the role of this centre is “fine tuning” of respiratory rhythm because a normal rhythm can exist in the absence of this centre.

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

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

10. Central chemoreceptors (CC) They are most probably located on the ventrolateral surfaces of the medulla oblongata, which bathed CSF. The CCs in the medulla respond to changes in the pH of the CSF. A ↓ in CSF pH → ↑ in breathing (hyperventilation) whereas ↑ in pH → hypoventilation. They are highly sensitive to [H + ] of the CSF evoked by PaCO 2, since CO 2 can freely cross the blood-brain barrier into the CSF while the barrier is relatively impermeable to H + and H 2 CO 3. Stimulation of these receptors increases both the rate of rise and the intensity of the inspiratory signals, thereby increasing the frequency of the respiratory rhythm.

11. Peripheral chemoreceptors (PC) They are located in the carotid bodies at the bifurcation of the common carotid arteries and in the aortic bodies above and below the aortic arch. They cause an ↑ in V E in response to ↓ in PaO 2, ↑ in PaCO 2 and ↑ in arterial [H + ] ( ↓ in pH). The carotid bodies are most important in humans. They contain glomus cells of two or more types which show an intense fluorescence staining because of their large content of dopamine. The mechanism of chemoreception is not yet understood. A popular view has been that glomus cells themselves are chemoreceptors. They are highly sensitive to changes in PaO 2 and to a lesser extent to PaCO 2 and pH. They are also sensitive to temp of the blood and BF. (HOW)? The response of the PCs to PaCO 2 is much less important than that of the CCs.

14. Lung and airway receptors Receptors in the lung and airways are innervated by myelinated and unmyelinated vagal fibers. The unmyelinated fibers are C fibers. The myelinated fibers are commonly divided into SARs and RARs on the basis of whether sustained stimulation leads to prolonged or transient discharge in their afferent fibers. SARs are also known as pulmonary stretch receptors.They are thought to participate in ventilatory control by prolonged inspiration in conditions that reduce lung inflation. RARs are stimulated by chemicals such as histamine, dust, cigarette smoke. Therefore, they have been called irritant receptors. RARs are stimulated by chemicals such as histamine, dust, cigarette smoke. Therefore, they have been called irritant receptors. Activation of RARs in the lung may produce hyperpnea. Activation of RARs in the trachea causes coughing, bronchoconstriction & mucus secretion. J receptors are stimulated by hyperinflation of the lung. They respond to intravenous & intracardiac administration to chemicals such as capsaicin. They play a role in the dyspnea associated with left heart failure, interstitial lung disease, pneumonia and microembolism.

15. The Hering-Breuer reflexes thought to play a major role in V E by determining the rate and depth of breathing. This can be done by using the information from the SARs to modulate the “switching off” mechanism in the medulla. The Hering-Breuer inflation reflex is an ↑ in the duration of expiration produced by steady lung inflation, and the Hering-Breuer deflation reflex is a ↓ in the duration of expiration produced by marked deflation of the lung. In human beings, the Hering-Breuer reflex probably is not activated until V T ↑ to more than three times normal (i.e. < 1.5 l/breath). Therefore, this reflex appears to be mainly a protective mechanism for preventing excess lung inflation rather than an important ingredient in normal control of VE.

17. Ventilatory response to CO 2 The most important factor in the control of V E is PaCO 2. The VR to CO 2 is normally measured by having the subject inhale CO 2 mixture or rebreathe from a bag so that the inspired PCO 2 gradually ↑. With a normal PO 2 the V E ↑ by about 2-3 l/min for each 1 mmHg rise in PCO 2. Lowering the PO 2 produces 2 effects; (see the figure) 1) there is a higher V E for a given PCO 2 2) the slope of the line becomes steeper. The VR to CO 2 is reduced by sleep, ↑ age, and genetic, racial and personality factors. It can also be reduced if the work of breathing is ↑.

19. Ventilatory response to O 2 The way in which a reduction of PaO 2 stimulates VE can be studied by having the subject breathe hypoxic gas mixture. An ↑ in PCO 2 → ↑ V E at any PO 2. When the PCO 2 is ↑ a reduction in PO 2 below 100 mmHg causes some stimulation of V E. Hypoxemia reflexly stimulates V E by its action on the carotid and aortic body chemoreceptors.

21. Ventilatory response to pH A reduction in arterial blood pH stimulates V E. Patients with a partly compensated metabolic acidosis, such as diabetes mellitus, who have a low pH and Low PCO 2 shown an ↑ in V E. The chief site of action of a reduced arterial pH is the PCs, especially the carotid bodies in humans. It is also possible that the CCs or the respiratory center itself is affected by a change in blood pH if it is large enough.

22. Ventilatory response to exercise On exercise, V E ↑ promptly and, during strenuous exercise, it may reach very high levels. The ↑ in VE closely matches the ↑ in VO 2 and VCO 2. The PaCO 2 does not ↑ during most form of exercise, however, during sever exercise it falls slightly. The PaO 2 ↑ slightly, and it may fall at very high work levels. The arterial pH remains nearly constant for moderate exercise, and falls during heavy exercise. Factors which play a role in the ↑ in V E during exercise includes; - ↑ body temperature - ↑ plasma epinephrine conc - ↑ plasma potassium conc - ↑ CO 2 load to the lung - Passive movement of the limbs