Block 4 - Respiratory Flashcards
Describe the lungs.
There are 3 tubular systems – the airways, pulmonary blood supply and bronchial blood supply – all packed into the lungs, which is a low resistance, high surface area organ with a 6 litre volume.
Outline the 5 stages of lung development.
There are 5 stages of lung development that lead to the formation of the alveolar blood-gas barrier.
1) Embryonic -> establishes basic lung structure as a template for further growth.
2) Pseudoglandular -> establishes the branched network of gas conducting airways.
3) Canalicular -> formation of the blood-gas barrier.
4) Saccular -> formation of the respiratory acinus (the zone of gas exchange).
5) Alveolar -> formation of the alveolus and high surface area for gas exchange, 5x increase in surface area for 2x increase in lung volume.
Describe stage 1 of lung development.
Embryonic
Formation of left and right lung lobes -» from 26 days to 6 weeks after conception in humans.
The primordial lung (lung anlage) develop as buds which extends outwards from the fetal foregut (oesophagus).
Describe stage 2 of lung development.
Pseudoglandular
Formation of the gas conducting airway of the respiratory tree.
Gestation weeks 6-16 in humans.
Branching of the airway and vascular duct system for up to 21 further generations beyond embryonic stage.
Fluid secretion into the airway creates a distending pressure which gives mechanical support for the growth of the airway in 3 dimensions.
At the end of this stage, the airways and vasculature have developed to completely fill the space available in the chest cavity.
Developmental outcome of this stage is the formation of the conducting airways of the lung and accompanying blood vessels, together known as the respiratory tree.
Describe irregular dichotomous branching.
Airway growth follows a programme of Irregular Dichotomous branching, this allows the airway to fill spaces of varied dimensions.
Irregular Dichotomous Branching:
- Achieves even dispersal of gas among terminal airway branches, mechanical strain dispersed evenly among units.
- Regulated increase in the number of airways as each branch disperses air flow resistance which would otherwise increase with distance into the lung.
Describe the chloride gradient driving fluid movement.
A chloride gradient drives fluid movement into the airway lumen giving mechanical support for 3 dimensional growth.
Ion composition of blood plasma:
* Na+ 150 mM
* K+ 4.8 mM
* Cl- 107 mM
* HCO3- 2.8 mM
* Protein 4.09 g/L
Ion composition of airway fluid:
* Na+ 150 mM
* K+ 6.3 mM
* Cl- 157 mM
* HCO3- 2.8 mM
* Protein 0.027 g/L
Cl- is accumulated against its electrochemical gradient.
Describe stage 3 of lung development.
Canalicular
Airways and blood vessels meet to form the blood-gas barrier.
Gestation weeks 16-24.
The onset of this phase is marked by extensive angiogenesis within the mesenchyme that surrounds the more distal reaches of the embryonic respiratory system to form a dense capillary network.
The diameter of the airways increases with a consequent decrease in epithelial thickness to a more cuboidal structure, epithelial cell differentiation begins.
The terminal bronchioles branch to form the respiratory acini around which the alveoli will develop.
Differentiation of the mesenchyme progresses down the developing respiratory tree, giving rise to chondrocytes, fibroblasts and myoblasts.
Earliest stage of lung development at which infants born prematurely can survive.
Describe stage 4 of lung development.
Saccular
Formation of the first septal fold of the early alveolus.
Defines the respiratory acinus.
Gestation weeks 24-36.
Branching and growth of the terminal sacs or primitive alveolar ducts.
Continued thinning of the stoma brings the capillaries into apposition with the prospective alveoli.
Completion of pneumocyte differentiation, type I pneumonocytes differentiate from cells with a type II like phenotype. These cells then flatten, increasing the epithelial surface area by dilation of the saccules, giving rise to immature alveoli. Surface production is fully operational.
By 26 weeks, a rudimentary but functional, blood-gas barrier has formed. Maturation of the alveoli continues by further enlargement of the terminal sacs, deposition of elastin foci and development of the vascularised septae around these foci. The stroma continues until the capillaries protrude into the alveolar spaces.
Septa form, bifurcating airway terminus.
Septum contains two closely apposed capillary networks, one for each saccule.
Thin-walled airways are maintained patent by Cl- driven fluid secretion into the luminal space.
Describe stage 5 of lung development.
Alveolar
Increase in gas exchange surface area.
Gestation weeks 36 to ~6 years postnatal.
Maturation of the lung indicated by the appearance of fully mature alveoli begins at 36 weeks, though new alveoli will continue to form for up to 6 years.
A decrease in relative proportion of parenchyma to total lung volume still contributed significantly to growth for 1 to 2 years after birth, thereafter all components grow proportionately until adulthood.
Na+ driven fluid absorption from the lung lumen clears the lung of fluid and maintains a thin film of liquid o the surface of the airways throughout adult life.
Pulmonary circulation becomes fully established as the umbilical blood supply is cut off.
Describe the preparation for the first breath of life.
Preparing for the first breath of life; fluid absorption in the fetal lung is driven by the epithelial Na+ channel (EnaC).
EnaC – a Na+ selective ion channel found in all secretory epithelia (e.g. lung, kidneys, gut, salivary duct, sweat duct).
Maternal cortisol increases in the last trimester. This crosses into fetal circulation and induces ENaC subunit gene expression and membrane insertion in epithelial cells lining the fetal airways.
During labour, a rise in maternal adrenaline crosses into fetal circulation and activates this channel.
Fluid is rapidly cleared from the fetal lung in preparation for the first breath.
Describe the ENaC structure.
3 subunits – alpha, beta and gamma
Knockout of the alpha subunit is lethal at birth due to lung flooding.
Mutations in a subunit is associated with fluid balance problems in lungs in infants and adult life.
The _______ and _______ in the lungs are arranged in a ______ pattern.
Airways
Vasculature
Fractal
Describe gas movement.
Gas follows partial pressure not concentration gradients.
Partial pressures tell you the direction of the movement of gas.
Gas moves from high partial pressure to low partial pressure, both within phases and between phases.
Outline the consequences of airway branching.
Airway branching has two consequences for lung function:
1) Increases surface area for gas exchange.
2) Dissipates resistance to air flow as airway diameter narrows towards the respiratory zone. A doubling of total airway diameter at each branch generation reduces resistance 16 fold.
Describe when gas would move in/out of the alveoli.
The bulk flow of gas into the conductive zone is driven by differences in net pressure caused by the expansion and relaxation of the chest cavity.
Gas movement in the airways arises by convection not diffusion.
Gas moves into alveoli if:
Alveolar pressure is less than atmospheric pressure.
Airways are open.
Gas moves out of alveoli if:
Alveolar pressure is greater than atmospheric pressure.
Airways are open.
Alveolar pressure is the sum of elastic recoil pressure (always collapsing) and pleural pressure (variable by muscle effort).
Describe how oxygen is transported in the blood.
Oxygen is transported in two forms in blood.
1) Physical
2) Chemical
Physical
Plasma soluble O2 (2%)
- Less soluble than CO2
- Function of partial pressure of O2 in alveolus
- O.3 mL O2 / 100 mL blood at PO2 of 100 mmHg
Chemical
O2 bound to haemoglobin
Rapid ad reversible interaction
Reversible enables O2 off-loading to tissues
Describe oxygen content.
Content (CaO2 or CvO2) = determined by the amount of Hb an O2 in blood.
Oxygen content refers to the total amount of oxygen in the blood, encompassing both the oxygen bound to haemoglobin and the amount dissolved in the plasma, typically measured in millilitres of oxygen per 100 millilitres of blood.
Describe oxygen saturation.
Saturation (usually SaO2) = if the proportion
i.e. SaO2 (%) = oxyhaemoglobin / O2 carrying capacity of Hb
Oxygen saturation refers to the percentage of haemoglobin in your blood that is carrying oxygen, saturation can remain the same even if O2 content of blood differs.
Describe the oxyhaemoglobin dissociation curve.
P50 value gives PO2 required for half maximal Hb saturation.
Venous blood enters alveolus at 40mmHg, 75% saturation.
Equilibrates to alveolar PO2 of 100mmHg, 97% saturation.
Arterial plateau phase ensures maximal HbO2 saturation even if alveolar PO2 is below the normal (normoxic) oxygen tension.
Steep phase of the curve favours off-load of arterial oxygen to tissues. Greater HbO2, dissociation for small changes in tissue PO2.
Factors that alter Hb-O2 affinity shift the position of the oxyhaemoglobin dissociation curve.
- Normal P50 = 27mmHg at pH 7.4 and PCO2 of 40mmHg.
- Left shift P50 = increased Hb-O2 affinity and reduced O2 off-loading to tissues.
- Right shift P50 = decreased Hb-O2 affinity and raises O2 off-loading to tissues.
Right shift P50 may be induced by stressors such as acidosis, fever and hypoxia.
Draw a diagram f the oxyhaemoglobin dissociation curve.
[see notes for answer]
Describe the Bohr effect.
PCO2 and pH alter haemoglobin-O2 binding affinity.
Haemoglobin:
Heterotetramer composed of 2 alpha and 2 beta subunits (differs in fetus).
Contains 4 iron-binding HAEM domains.
Oxygen reversible binds to Fe3+ ions in the centre of the haem ring.
CO2, pH and 2,3BPG alter this affinity by interacting with charged amino groups between the alpha and beta subunits.
Amino terminus of the haemoglobin alpha subunit binds to the carboxy-terminal histidine in beta subunit (this stabilises the Hb structure).
This interaction is pH and O2 sensitive, this requires 1H+ for each 2O2 released.
Describe acidosis.
In acidosis, decreased pH favours the alpha-beta subunit interaction and reduces the binding of O2 to haem.
[see notes for answer]
Describe the transport of carbon dioxide in blood.
Physical
1) Soluble CO2 gas (5%)
2) Bicarbonate ion (90%)
CO2 is 20 times more soluble in plasma than O2.
CO2 content of arterial blood (CaCO2) = 48 mL CO2 / 100 mL of blood.
CO2 content in venous blood (CvCO2) = 52 mL CO2 / 100 mL of blood.
Exhales CO2 = 4 mL CO2 / 100 mL of blood.
Chemical
Carbamino Haemoglobin
Carbamate reaction at N-terminus amino acid groups of Hb alpha subunit (5%).
Describe the carbon dioxide dissociation curve.
Blood carriage of CO2 in all 3 forms.
Relationship is nearly a straight line in physiological range.
Altered by tissue oxygenation (the Haldane effect).
Draw a diagram of the carbon dioxide dissociation curve.
[see notes for answer]
Describe Bohr and Haldane effects enabling reciprocal O2 and CO2 gas exchange.
o CO2 release from tissue / O2 release from Red cell:
1) CO2 dissolves into plasma & red cells along the partial pressure gradient.
2) Low tissue O2 favours CO2 carriage by blood (Haldane effect).
3) Carbamate reaction reduces HbO2 affinity (Bohr effect).
4) Carbonic anhydrase reaction generates carbonic acid which protonates. HCO3- leaves cells and maintains the inward CO2 gradient.
5) Increased red cell [H+] reduces HbO2 affinity by promoting Hb subunit interactions (Bohr effect).
o CO2 release from red cell / O2 uptake by alveolus
1) O2 dissolves into plasma and red cells along the partial pressure gradient.
2) High affinity Hb for O2 reverses Hb carbamation and protonation raising availability of high affinity Hb (Bohr effect).
3) CO2 diffuses into alveolus along pressure gradient. High PO2 decreases CO2 affinity for Hb (Haldane effect).
4) Movement of CO2 out of red cells increases HCO3- uptake, Cl- moves out.
5) Proton release from Hb and an increased HCO3- drive carbonic anhydrase reaction in reverse, maintaining outward CO2 gradient and lowering plasma bicarbonate.
Describe the ventilation-perfusion relationship.
O2 and CO2 define the ventilation-perfusion relationship in the lung (V/Q).
1) Oxygen equilibrates from alveolus to blood.
2) CO2 equilibrates from blood to alveolus.
So O2 and CO2 partial pressure in the alveolus and arterial blood can be used to understand how lung ventilation is matched with perfusion of the lung.
Why does this matter?
- Major effect on aerobic performance
- Major contribution to disease
- Its adaptable -> changes in breathing and lung perfusion allow fine-tuning of O2 uptake and CO2 clearance from one environment to another.
Describe ventilation-perfusion (V/Q) in disease.
Interplay between the local control of ventilation and perfusion within and between lung regions.
Poor ventilation and large blood flow = need to reduce perfusion, hypoxia constricts pulmonary arterioles.
Good ventilation and poor blood flow = need to reduce ventilation, low CO2 constricts bronchioles.
Ventilation (V) refers to the flow of air into and out of the alveoli, while perfusion (Q) refers to the flow of blood to alveolar capillaries.
Describe carbonic anhydrase.
Carbonic anhydrase is an enzyme that facilitates the conversion between carbon dioxide (CO2) and water (H2O) to form carbonic acid (H2CO3) and its dissociative ions (HCO3− and H+). It plays a key role in regulating pH and aiding in the transport of CO2 in biological systems.
State the equation to measure alveolar PO2.
[see notes for answer]
Define lung mechanics.
Lung mechanics -> physical forces that influence breathing.
Describe static mechanics.
Mechanical properties of the lung that influence gas flow but which are independent of volume change.
- Elasticity
- Compliance
- Surface tension
Describe static force 1; elasticity.
Elastance = change in pressure / change in volume
The pleural sac links elastic forces in the chest wall and lung. Elastic forces link pleural pressure to alveolar pressure.
Elastin in alveoli acts as an inward ‘collapsing’ force, i.e. elastic recoil.
+
Opposing elastic recoil of ribs acts as an outward expanding force.
=
Balance of forces results in a sub-atmospheric intrapleural pressure.
Describe the changes in alveolar and intrapleural pressure in quiet breathing.
In quiet breathing, intrapleural pressure is always sub-atmospheric. Elastic retraction enables alveolar pressure to go above atmospheric pressure.
[see notes for answer]
List the forces contributing to elastic recoil.
The forces contributing to elastic recoil is the elastin fibres, matrix elements within the lung parenchyma, surface tension and the air-liquid interface of the alveoli.
Describe static force 2; compliance.
Is the measurement of the amount of work/effort you have to put in to breathe and expand the lung.
Compliance = change in volume / change in pressure
Lung with high compliance is easily distended.
Lung with low compliance is difficult to distend.
Static compliance is measured under conditions of no gas flow.
Compliance varies with lung diseases.
Idiopathic = diseases/conditions with unknown causes.
Pulmonary compliance/elastic recoil is produced by elastin connective fibres and alveolar surface tension.
Describe static force 3; surface tension.
Molecules at the surface experience fewer favourable interactions than those in the bulk of the solution because the surface molecules can only interact with other molecules in 2 dimensions where as those in the bulk interact in 3 dimensions. This gives an energy cost to forming more surface with a set amount of material.
Surface free energy (SFE) is the excess energy at the surface of a material compared to its bulk, arising from the imbalance of molecular forces at the surface.
The relationship between SFE and surface tension is essentially equivalent as surface tension is the force per unit of length and surface free energy is the energy per unit of area.
The high water/air tension explains why rain falls as drops and not sheets.
Outline spherical surface tension in an alveolus.
- Resists stretch (greater surface tension, less compliance thus higher elastance).
- Tends to become smaller.
- Tends to recoil after stretch -> contributes to elastic recoil pressure.
Outline the effect of air-liquid interface on lung compliance.
Lung requires greater trans-pulmonary pressure to inflate with air in order to overcome surface tension and elastic recoil effect.
Inflating with liquid overcomes recoil effect by dissipating surface tension.
Describe the law of LaPlace.
Small diameter bubbles have higher surface tension than large diameter ones.
↓
Variation in alveolar size/volume would cause small alveoli to collapse into larger ones.
Pressure in bubble = 2 x surface tension / radius of bubble
OR
P = 2T / r
Describe pulmonary surfactant stabilises alveolar structure.
Pulmonary surfactant stabilises alveolar structure by reducing surface tension.
Surfactant reduces surface tension by decreasing density of water molecules at the air-water interface. Because the hydrophobic tail pulls the surfactant molecule upward the resultant vector in minimal.
Composed of Dipalmitoyl phosphatidyl choline (DPPC) packaged around surfactant proteins.
Secreted by type II alveolar epithelial cells.
Reduces surface tension in alveoli.
As r falls, surfactant molecules crowded together surface tension reduces and smaller alveolus stabilised.
Alveoli also stabilised by mechanical interactions between neighbouring alveoli prevent alveoli collapse.
Loss of surfactant causes alveolar collapse.
Describe the relationship between elastance and compliance.
Elastance is the reciprocal of compliance, they are inversely related i.e. high compliance means low elastance and vice versa.
Describe dynamic mechanics.
Dynamic
Mechanical properties affecting flow of air into and out of lungs as volume changes with time.
- Resistance
- Flow
- Turbulence
Describe dynamic forces 1&2.
Resistance and Flow.
In a normal airway 90% of resistance to flow is in the upper airway.
The smallest tubes have the greatest airway resistance but there are loads of them so the cumulative resistance is actually lower.
To calculate airway resistance we rearrange Poiseuille’s Law for resistance:
i.e. Flow = change in pressure X [pi X radius^4 / 8 X the viscosity X tube length]
Becomes:
Flow = change in pressure /( 8 X the viscosity X tube length / pi X radius^4)
Outline the factors determining resistance.
- Lung volume and branching
- Bronchiolar smooth muscle tone
- Density and viscosity of gases
Affected by altitude
Consideration in artificial environments such as space and deep sea
Laminar flow is a function of gas viscosity but turbulent flow depends on gas density
Describe bronchiolar smooth muscle.
Lines the upper airway, alterations in tone alter the radius.
‘Tube’ radius decreases by muscular contraction.
‘Tube’ radius increased by muscular relaxation.
This plays a major role in ventilation-perfusion matching and lung diseases related to resistance such as asthma.
Draw a diagram of airway resistance and lung volume.
[see notes for answer]
Describe asthma and resistance.
Allergic inflammation of the airways. → Bronchial smooth muscle thickening.
↘ ↗
Hyper-activity of airway smooth muscle contraction.
Connective gas flow in the lungs is much less efficient.
Gas flow slows to the molecular diffusion rate in the upper airway resulting in poor gas exchange in the respiratory acinus.
Gas fails to penetrate to distal regions of the respiratory zone causing alveolar pCO2 to rise.
Lung ceases to oxygenate Hb efficiently due to the reversal of proper alveolar Bohr and Haldane effects.
Measurement of airway resistance by whole body plethysmography.
R = (Pmouth – Palveolus) / flow
Describe airway resistance in inhalation and exhalation.
During inhalation airway resistance falls as gas flow and lung volume increase.
As lungs expand airways are also physically widened.
Dynamic lowering of resistance during lung expansion.
During exhalation, the resistance of the upper airway helps to keep airway pressure high to maximise gas movement out of alveoli.
Draw the exhalation/inhalation loop.
[see notes for answer]
Describe the work of breathing.
- To overcome elastic and non-elastic resistances
- Work = force x resistance, = pressure x volume
Describe neural inputs to ventilation.
- Breathing movements are not spontaneous (unlike the cardiomyocyte).
- Skeletal muscle which control breathing require neural input.
- Neural input can be involuntary (tidal breathing) and voluntary (IRV, ERV, breathing frequency).
- Chemo-receptive inputs monitor plasma and cerebral spinal fluid composition to maintain ventilating homeostasis (e.g. override voluntary breathing control).
Describe the respiratory centres in the brain.
Located in the brain stem; pons and medulla.
Respiratory control centres in the brain; 2 centres
1) Pons respiratory centres
- Pneumonic centre
- Apneustic centre
2) Medullary respiratory centre
- Pre-Botzinger complex
- Dorsal respiratory group (DRG)
- Ventral respiratory group (VRG)
Describe the dorsal respiratory group.
- Inspiratory control
- Located within the nucleus tractus solitaris and is dorsal to the VRG
- Site of sensory information input
- Site of central chemoreceptor input
- Has some promoter neurons
Describe ventral respiratory group.
- Spans 3 regions within the medulla
1) Rostral
2) Intermediate
3) Caudal
Rostral; expiration control (Botzinger complex).
Intermediate; inspiration control mediated through Pre-Botzinger complex – thought to be the site of Respiratory Pattern Generator.
Caudal; expiration control.
Describe the nerves involved in ventilation.
Hypoglossal nerve, laryngeal nerve and carotid sinus nerve = peripheral chemoreceptor feedback.
Vagus nerve = breathing frequency and volume.
Intercostal nerve = respiratory muscles.
Phrenic nerve = diaphragm inspiration control.
Describe the innervation of inspiratory muscles.
- Diaphragm
Phrenic nerves, C3-5
Flattens on contraction
Moves 1cm in quiet breathing can move up to 10cm
Major inspiration muscle - External intercostals
Intercostal nerves at ‘rib level’ - Accessory muscles
Sternocleidomastoid, scalenus and others
Chest expands, intrapleural pressure falls
Describe the innervation of expiratory muscles.
Mainly passive during quiet breathing (elastic recoil pressure is sufficient).
- Forced expiration
Abdominal wall; transverse abdominals and rectus abdominus – push up against diaphragm.
Internal intercostals
Cranial motoneurons are important for opening/closing glottis, affecting upper airway diameter, flaring nostrils etc. motoneurons controlling direct muscles of inspiration and expiration are therefore not the only ones active during breathing.
Define the respiratory rhythm generator (RRG).
A network of interneurons that produce a predictable and repetitive motor pattern. In the case of breathing, inspiratory neurons must be activated before expiratory neurons.
Outline the properties of a RRG.
- Always active even in the absence of conscious input (endogenous cyclical oscillation).
- Transmit in an orderly sequence to respiratory muscles.
- Respond to inputs from other parts of the brain (e.g. limbic system – emotions) as well as sensory afferents (e.g. pulmonary stretch receptors, peripheral chemoreceptors).
Outline the 3 phases of breathing.
1) Inspiration
2) Post-inspiration
3) Expiration
Outline the 6 types of neuronal discharge.
1) Pre-inspiration
2) Early-inspiration
3) Inspiration
4) Late-inspiration
5) Early-expiration
6) Expiration
Describe in detail the neuronal discharge in breathing.
o Pre-inspiration neurons inhibit expiratory neural circuit. Effect; expiratory muscles relax.
o Early-inspiration neurons inhibit the output from the entire RRG. Effect; refractory period, no breathing movements.
o Inspiratory neurons ramp fire, as frequency increases more inspiratory neurons are contributing. Activates motoneuron circuit to inspiratory muscles and inhibit expiration and pre-inspiration neural circuits. Effect; inspiratory muscles contract as intensity of inspiratory firing increases, expiratory muscles ae relaxed.
o Late-inspiratory neurons feedback to suppress inspiratory neuronal firing when at peak intensity. May involve stretch receptor input (from the vagus nerve). Effect; inspiratory muscles relax and lung begins to deflate due to elastic recoil.
o Early-expiration neurons repress all inspiratory and expiratory neuronal firing. Creates refractory period at peak inhalation. Effect; inspiratory muscles relax and lung begins to deflate by elastic recoil.
o Expiratory neurons ramp fire, activate motoneuron circuit to expiratory muscles. Major point of conscious input into breathing (e.g. during exercise). Effect; expiratory muscles contract as expiratory firing intensity increases, inspiratory muscles are relaxed.
Describe how breathing patterns change.
- Normal -> burst firing of phrenic nerve causes diaphragm contraction and inhalation.
- Increased tidal volume (VT) -> increased action potentials per burst gives stronger diaphragm contraction and deeper breathing.
- Increased ventilation volume (VE) -> increased burst per minute gives increased breathing frequency. When combined with increased action potentials per burst (increased VT) then VE increases.
Describe the basic mechanism of chemoreceptors.
1) Central chemoreceptors – monitor pCO2 in cerebral spinal fluid (CSF).
2) Peripheral chemoreceptors – monitor pO2 and pCO2 and pH in blood and mixed lung gases.
- Carotid body (blood)
- Neuroepithelial bodies (airway)
3) Other receptor inputs
Stretch receptors
Hering-Breuer reflex.
Inhibition of lung over-inflation (>50% resting tidal).
Increased breathing frequency following rapid lung deflation.
Allergens and Irritant receptors
Located along the airway – feed into vagus.
Cough, sneeze and bronchoconstriction reflex.
Outline features of central chemoreceptors.
- Surface of the medulla
- 80% contribution to normal control of breathing
- Primarily detects pH changes caused by increase pACO2 in the CSF
- Slow response time (minutes)
- Linear response mode
- Can be altered by training, is adaptive
Outline features in peripheral chemoreceptors.
- Found in arterial vasculature and airway
- 20% contribution to normal control of breathing
- Primarily detects decreased pAO2 in blood and airway, less responsive to increased pACO2 and decreased pH
- Fast response time (seconds)
- Non-linear response mode
- Cannot be altered by training, is not adaptive
Describe central chemoreceptors.
o Control system for normal breathing.
o Directly responsive to CO2 driven pH changes in cerebral spinal fluid.
o Response to changing alveolar pCO2 (pACO2)
- Very sensitive to small changes in pACO2
- Hypoxia makes the response steeper (bigger change in VE per pACO2)
- Hypoxia may bring central chemoreceptor cells closer to firing threshold
o Adapt to sustained changes in pACO2 over several days, relevant to disease, high altitude, free diving, drug action.
o Shallow water blackout;
1) Hyper ventilation drives pACO2 down.
2) O2 consumed during breath-hold dive.
3) Low central chemoreceptor sensitivity (caused by breath-hold training) fails to trigger breathing response in time to prevent severe hypoxaemia.
4) Loss of consciousness and drowning.
Describe peripheral chemoreceptors.
o Carotid body – carotid sinus. Aortic body – aortic arch.
o Primary response to hypoxia, also respond to hypercapnia (increased pACO2) and acidosis (decreased pH).
1) Response to hypoxia is not linear, increases dramatically below pAO2 = 60 mmHg.
2) Response is driven by low partial pressure of O2 and not O2 concentration or HbO2 saturation. Does not occur with anaemia.
3) Hypercapnia or acidosis raises the sensitivity of chemoreceptor to pAO2.
Describe the cellular mechanism of pO2, pCO2 and pH sensing.
1) Hypoxia
The cell might sense pO2 by three mechanisms.
a) O2 dissociates from haem- containing protein near K+ channel.
b) Low pO2, somehow elevates [cAMP]i.
c) Low pO2 inhibits NADPH-oxidase in mitochondria, raising the ratio of reduced to oxidised glutathione.
Hypercapnia
Elevated pCO2 leads to an influx of CO2 into the cell and production of H+.
Acidosis
Low extracellular pH inhibits acid-extruding transporters (e.g. Na-H exchangers) and also promoted intracellular acids loading, leading to a buildup of H+ inside the cell.
2) These mechanisms reduce the open-probability of K+ channels.
3) Inhibition of K+ channels depolarises the cells.
4) Depolarisation open voltage-gated Ca2+ channels, causing increased Ca2+ entry and increased [Ca2+]i.
5) Elevated [Ca2+]I triggers the release of neurotransmitters.
6) Neurotransmitters (probably dopamine) bind to postsynaptic membrane of afferent nerve fibres, generating action potentials that are conducted along the axon of the glossopharyngeal nerve (CN 9) which leads to the medulla.
Describe the changes in metabolism in fever and exercise.
A person with an extremely high fever (approaching lethality), body metabolism increases 100% above normal. In comparison, metabolism of the body during a marathon may increase to 2000% above normal.
Exercise;
- Initially disrupts homeostasis.
- Often requires prolonged coordination among most body systems such as the muscular, skeletal, nervous, circulatory, respiratory, urinary, skin and endocrine.
Describe the changes in cardiovascular parameters in exercise.
- Heart = rest – 70 bpm, maximal exercise – 200 bpm.
- Stroke volume = rest - ~70 ml, maximal exercise - ~130 ml.
- Cardiac output = rest – 5 litres/min, maximal exercise – 25 litres/min.
- Systolic pressure = rest – 120 mmHg, maximal exercise – 180 mmHg.
- Diastolic pressure = rest – 80 mmHg, maximal exercise – 70 mmHg.
Describe cardiac output in exercise.
During exercise, cardiac output can increase to 20-25 l/min (~40 l/min in trained athletes during heavy endurance type exercise). Cardiac output increases in proportion to work load.
Describe the change in heart rate in exercise.
Control of heart rate is coordinated by the cardiovascular control centre in the brain stem. The immediate response to exercise; heart rate increases to deliver more oxygenated blood to the exercising muscles. Heart rate increases in proportion to work load, long-term adaptation to a regular exercise programme = increasing strength and efficiency. Max heart rate = 220 – age.
Describe intrinsic and extrinsic control of stroke volume, including a supporting diagram.
- Intrinsic; muscular contractions compress veins + venoconstriction.
- Extrinsic ; sympathetic stimulation + adrenaline.
[see notes for answer]
Outline ventricular filling during normal and rapid heart rates.
At rest (75 bpm); systole = 300 msec, diastole = 500 msec.
At 180 bpm; diastole = ~125 msec.
Describe blood flow to active skeletal muscles.
Working muscles change the local chemical environment:
Local pO2 falls
Local pCO2 increases
Local [H+] rises (pH falls)
Muscle temperature rises
All of the above lead to metabolic hyperaemia (localised vasodilation). Local controls override generalised sympathetic vasoconstriction e.g. blood flow to skeletal muscles in legs cf. arms during cycling.
Effects are reinforced by the vasodilatory effects of adrenaline.
Describe the alpha1 adrenoreceptor.
They are located in all arteriolar smooth muscle except in the brain.
Chemical mediator
Norepinephrine from sympathetic fibres and the adrenal medulla.
Epinephrine from the adrenal medulla (but has less affinity for this receptor).
Effect: Vasoconstriction.
Describe the beta2 adrenoreceptor.
Located in arteriolar smooth muscle in the heart and skeletal muscles.
Chemical mediator
Epinephrine from the adrenal medulla (has a greater affinity for this receptor than alpha1).
Effect: Vasodilation
Describe metabolic hyperaemia.
Cardiac muscle
Increased metabolic activity of cardiac muscle cells (increased oxygen need)
↓
Increased adenosine.
↓
Vasodilation of coronary vessels.
↓
Increased blood flow to cardiac muscle cells.
↓
Increased oxygen available to meet increased oxygen need.
Describe why diastolic pressure drop upon exertion.
Arterioles are the major resistance vessels.
Resistance inversely proportional to r^4.
Blood pressure is proportional to total peripheral resistance.
To meet the metabolic demands of the skeletal muscle there is a large drop in total peripheral resistance brought about by the vasodilation of the arterioles supplying the working muscles (40-50% of total body weight).
Diastolic blood pressure drops due to decreased total peripheral resistance.
Systolic blood pressure is increased due to the increased cardiac output.
The overall effect is a marginal increase in mean arterial blood pressure.
Draw a diagram summarising the full pathways that lead to mean arterial blood pressure.
[see notes for answer]
Describe heart rate, venous return, stroke volume and cardiac output during exercise.
o Heart rate = increases
Occurs as a result of increased sympathetic and decreased parasympathetic activity to the SA node.
o Venous return = increases
Occurs as result of sympathetically induced venous vasoconstriction and increased activity of the skeletal muscle pump and respiratory pump.
o Stroke volume = increases
Occurs both as a result of increased venous return by means of the Frank-Starling mechanism (unless diastolic filling time is significantly reduced by high heart rate) and as a result of a sympathetically induced increase in myocardial contractility.
o Cardiac output = increases
Occurs as result of increases in both heart rate and stroke volume.
Describe the changes to blood flow to active skeletal muscles and heart muscles, blood flow to the brain and blood flow to the skin.
o Blood flow to active skeletal muscles and heart muscle = increases
Occurs as a result of locally controlled arteriolar vasodilation, which is reinforced by the vasodilatory effects of epinephrine and overpowers the weaker sympathetic vasoconstrictor effect
o Blood flow to the brain = unchanged
Occurs because sympathetic stimulation has no effect on brain arterioles; local control mechanisms maintain constant cerebral blood flow whatever the circumstances.
o Blood flow to the skin = increases
Occurs because the hypothalamic temperature control centre induces vasodilation of skin arterioles; increased skin blood flow brings heat produced by exercising muscles to the body surface where the heat can be lost to external environment.
Describe the changes in blood flow to the digestive system, total peripheral resistance and mean arterial blood pressure.
o Blood flow to the digestive system, kidneys, and other organs = decreases
Occurs as result of generalised sympathetically induced arteriolar vasoconstriction.
o Total peripheral resistance = decreases
Occurs because resistance in the skeletal muscles, heart, and skin decreases to a greater extent than resistance in the other organs increases.
o Mean arterial blood pressure = increases moderately
Occurs because cardiac output increases more than total peripheral resistance decreases.
Draw a diagram depicting oxygen deficit and oxygen ‘debt’.
[see notes for answer]
Draw a diagram of the increasing rate of external work graph.
[see notes for answer]
Describe what brings about the disproportionate rise in VE during heavy exercise.
In severe exercise, lactic acid production.
H+ stimulates peripheral chemoreceptors.
Ventilation excessively stimulated.
CO2 excessively blown off – VCO2 exceeds VO2.
Respiratory exchange ratio exceeds 1 (in severe exercise, RER does not reflect the predominant metabolic substrate.
Describe alveolar ventilation increasing during exercise.
Exercise profoundly increases ventilation but the mechanisms involved remain unclear.
Alveolar ventilation can increase up to 20 fold during heavy exercise. Mechanisms remain speculative as:
- Arterial pO2 does not decrease (may actually increase)
- Arterial pCO2 des not increase (may actually decrease)
- During mid-moderate exercise [H+] plasma does not increase (H+ - generating CO2 is held constant)
- During heavy exercise elevation of H+ from lactate (lactic acid) is not enough to account for the large increase in ventilation
Slight decline in arterial pCO2 during heavy exercise + ventilation increases abruptly at the onset of exercise (within seconds), long before changes in arterial blood gases can influence the respiratory centre.
Describe the potential factors that may increase ventilation during exercise.
1) Reflexes originating from body movements.
2) Increase in body temperature.
3) Adrenaline release.
4) Impulses from the cerebral cortex.
None of these factors (or combinations) are fully satisfactory in explaining the abrupt and profound effect has on ventilation.
Describe VO2 max.
Predictor of a person’s work capacity is determination of maximal O2 consumption (VO2 max).
Bicycle ergometer or treadmill
Workload is progressively increased until exhaustion
Expired air is collected during the last minutes (when O2 consumption is at a maximum)
%O2 and %CO2 + volume of air measured
Regular exercise can improve VO2 max; heart and respiratory system become more efficient, exercised muscles become better equipped to use O2 once it is delivered.
VO2 max is measured in l/min, then converted to ml O2/kg body weight/min to allow comparison between individuals.
Individuals can be classified as being low, fair, average, good or excellent in aerobic capacity for their age group.
Exercise physiologists use VO2 max measurements to prescribe or adjust training programmes to help individuals achieve their optimal level or aerobic conditioning.
Describe the work of breathing.
The work of breathing requires ~3% of total energy expenditure. During strenuous exercise this may increase 25 fold. However, total energy expenditure increases 15 to 20 fold during heavy exercise, the energy used for increased ventilation still represents ~5% of total energy expended.
During exercise the surface area for exchange can be increased to enhance the rate of gas transfer. Increased cardiac output -> increased pulmonary blood pressure open previously closed capillaries.
Alveolar membranes are stretched due to larger tidal volume (deeper breathing).
VE = TV x Rf
Describe the oxygen and carbon dioxide related variables during exercise.
[see notes for answer]
