Lecture 2 Gas exchange O2 transport CO2 transport Control of VE Ventilatory response to CO2 Ventilatory response to O2 Ventilatory response to pH Ventilatory response to exercise

Gas Exchange It takes place at a respiratory surface. For unicellular organisms the RS is simply the cell membrane, but for a large organisms it is the respiratory system. In humans, respiratory GE or VE is carried out by mechanisms of the lungs.

Alv are designed for rapid GE Alv are designed for rapid GE. While no GE occur in the heart, arteries and arterioles. Alv are found at the end of the branching bronchioles and so they have a good air supply. The alv walls are very thin and have a moist surface. They are covered by a network of capillaries which transport the gases. Blood takes about 1 sec to pass through the lung capillaries. In this time the blood becomes nearly 100% saturated with O2 and loses its excess of CO2. In pulmonary capillaries, O2 diffuses into capillary blood, while CO2 diffuses into alveolar air. Blood returning to lungs is high in CO2 and is low in O2. Blood leaving lungs is enriched with O2, low in CO2. The amount of air reaching the alv with each breath is equal to VT – VD. The ratio of CO2 produced / O2 consumed is known as RQ.

O2 transport O2 is carried in the blood in 2 forms; 1) bound to Hb (approx 98.5 %) 2) dissolved in the plasma (approx 1.5 %). The amount of any gas that dissolves in blood is directly proportional to the partial pressure of the gas and the solubility of the gas. Therefore, CO2 = SO2 * PO2 (Henry's law). Each molecule of Hb can carry 4 mol of O2. Fully sat Hb can carry approx 1.36 ml O2 / g Hb, and normal human blood contains about 15 g Hb / 100 ml blood. Multiplying these two constants yields 20.4 ml O2 / 100 ml blood.

Hb is a protein in which a haem group is attached to each of 4 subunit polypeptide chain (2 alpha & 2 beta). Hb contains 4 iron atoms (4 haem group). Each one contain a Fe2+ within a haem group. If 100 ml of plasma is exposed to an atmos with a PO2 of 100 mmHg, only 0.3 ml of O2 would be absorbed. However, if 100 ml of blood is exposed to the same atmos, about 19 ml of O2 would be absorbed. WHY? The total quantity of O2 bound with Hb in normal systemic arterial blood is about 19.4 ml /100 ml of blood. On passing through the tissue capillaries, this amount is reduced to approx 14.4 ml. Therefore, 5 ml is the quantity of O2 that are transported from the lungs to the tissues by each 100 ml of BF. During heavy exercise, there might be upto 20 times ↑ in O2 transport to the tissues compared to normal,

Factors which affect the O2-Hb dissociation curve: These factors may shift the curve to the right, indicating lower affinity of Hb to O2, or shift the curve to the left, indicating an ↑ affinity of Hb to O2. These factors includes; 1) PCO2:↑ PCO2 → ↓ affinity of Hb to O2 → shift the curve to the right (this is called Bohr effect). 2) PH: ↓ PH (or ↑ [H+]) → ↓ affinity of Hb to O2 → shift the curve to the right. 3) Temp : ↑ Temp → shift the curve to the right. 4) 2,3- diphosphoglycerate (2,3-DPG): :↑ 2,3-DPG → ↓ affinity of Hb to O2 → shift the curve to the right. P50 is the pp of O2 required to achieve 50% Hb sat.

CO2 transport CO2 transported from the body cells back to the lungs in 3 forms; (1) Dissolved in the plasma (approx 7-10%). (2) Reacts with the amino group of plasma proteins to form carbamino proteins (carbaminohemoglobin) (approx 23-30%). (3) Reacts with H2O to form H2CO3 (approx 60-70%) CO2 + H2O ↔ H2CO3 ↔ HCO3- + H+

CO2 dissociation curve The relationship of CO2 content of blood to PCO2 is known as CO2 dissociation curve. The volume of CO2 carried in the blood is determined by PCO2. The dissolved form is directly proportionate to PCO2 (0.06 ml dissolved in 100 ml of blood/1 mmHg PCO2). The curve is affected by the saturation of Hb with O2 (Haldane effect). Oxyhemoglobin shifts the curve to the right, i.e. in the lungs CO2 is released from the blood. Reduced Hb shifts the curve to the left, i.e. more CO2 is taken up by the blood in the tissues.

Directional movement of CO2 All mov across membrane is by diffusion. Note: most of CO2 entering the blood in the tissues ultimately is converted to HCO3-. This occurs almost entirely in the erythrocytes because the CA enzyme is located there, but most of the HCO3- then moves out of the erythrocyte into the plasma in exchange for chloride ions “ the chloride shift”.

Chloride shift The rise in the HCO3- content of red cell is much greater than that in plasma as the blood passes through the capillaries. The excess of HCO3- leaves the red cell in exchange for cl-. This change is called the chloride shift. The chloride shift occurs rapidly and essentially complete in 1 second. The cl- content of the red cells in venous blood is therefore significantly greater than in arterial blood. In pulmonary capillaries; cl- leaves the red cell and move into the plasma in exchange for HCO3-; in systemic capillaries, the reverse occurs.

The Haldane effect It results from the simple fact that the combination of O2 with Hb in the lung causes the Hb to become a stronger acid. This displaces CO2 from the blood and into the alveoli in 2 ways; (1) The more highly acidic Hb has less tendency to combine with CO2 to form carbaminohemoglobin, thus displacing much of the CO2 that is present in the carbamino form from the blood. (2) The ↑ acidity of Hb also causes it to release an excess of H+, and these bind with HCO3- to form H2CO3; this then dissociate into H2O and CO2, and the CO2 is released from the blood into the alveoli and, finally, into the air.

Control of VE The 3 basic elements of the respiratory control system are: 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 VE.

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; (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.

(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 Botzinger complex (BC); which has widespread expiratory functions.

(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 pon. 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.

2) Effectors They are the muscles of respiration, including the diaphragm, intercostal 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).

3) Sensors The sensors that contribute to the control of breathing include lung stretch receptors in the smooth muscle of the airway, irritant receptors located between airway epithelial cells, 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.  The most important sensors are central chemoreceptors in the medulla as well as peripheral chemoreceptors in the carotid and aortic bodies.  

Central chemoreceptors (CC) They are most probably located on the ventrolateral surfaces of the medulla oblangato, which bathed CSF. The CCs in the medulla respond to changes in the pH of the CSF.  Decreases in CSF pH produce ↑ in breathing (hyperventilation) whereas ↑ in pH result in hypoventilation. They are highly sensitive to [H+] of the CSF evoked by PaCO2, since CO2 can freely cross the blood-brain barrier into the CSF while the barrier is relatively impermeable to H+ and H2CO3. Stimulation of these receptors ↑ both the rate of rise and the intensity of the inspiratory signals, thereby ↑ the frequency of the respiratory rhythm.

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 VE in response to decreases in PaO2, increases in arterial PCO2 and increases in arterial hydrogen concentrations (decrease 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 dapamine. 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 PaO2 and to a lesser extent to PaCO2 and pH. They are also sensitive to temp. of the blood and BF. The response of the PCs to PaCO2 is much less important than that of the CCs.

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

The Hering-Breuer reflexes thought to play a major role in VE 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 VT ↑ 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.

Ventilatory response to CO2 The most important factor in the control of VE is PaCO2. The VR to CO2 is normally measured by having the subject inhale CO2 mixture or rebreathe from a bag so that the inspired PCO2 gradually ↑. With a normal PO2 the VE ↑ by about 2-3 l/min for each 1 mmHg rise in PCO2. Lowering the PO2 produces 2 effects; 1) there is a higher VE for a given PCO2 2) the slope of the line becomes steeper. The VR to CO2 is reduced by sleep, ↑ age, and genetic, racial and personality factors. It can also be reduced by if the work of breathing is ↑.

Ventilatory response to O2 The way in which a reduction of PaO2 stimulates VE can be studied by having the subject breathe hypoxic gas mixture. When the PCO2 is ↑ a reduction in PO2 below 100 mmHg causes some stimulation of VE. Hypoxemia reflexly stimulates VE by its action on the carotid and aortic body chemoreceptors.

Ventilatory response to pH A reduction in arterial blood pH stimulates VE. 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 itself is affected by a change in blood pH if it is large enough.

Ventilatory response to exercise On ex, VE ↑ promptly and, during strenuous ex, it may reach very high levels. The ↑ in VE closely matches the ↑ in VO2 and VCO2. The PaCO2 does not ↑ during most form of ex, however, during sever ex it falls slightly. The PaO2 ↑ slightly, and it may fall at very high work levels. The arterial pH remains nearly constant for moderate ex, and falls during heavy ex. Factors which play a role in the ↑ in VE during ex includes; - ↑ body temperature - ↑plasma epinephrine conc - ↑plasma potassium conc - ↑ CO2 load to the lung - Passive movement of the limbs