BMS235 Physiology and Pharmacology Flashcards
What is the composition of cell membranes?
42% Lipid
55% Protein
3% Carbohydrate
Why is there a high intracellular concentration of PO42-?
Because ATP is present in cells
What are the types of transporters?
- Carriers (facilitated transport proteins) e.g. Na+Glucose transport protein
- Pumps eg. Na+K+ Pump
- Gated ion channels
What does active and passive transport require?
Active requires ATP
Passive requires a concentration gradient
What is the electrochemical driving force?
concentration gradient and potential gradient
How much can be transported in active transport?
Low turnover < 100/second
How does active transport use ATP?
ATP is hydrolysed to ADP and Pi
The phosphate binds to the protein which causes a conformational change releasing the ion
What are the characteristics of Na+/K+ ATPase?
- Ubiquitous
- Tetramere - (2alpha and 2beta subunits) - two separate gene sequences requires one for each subunit
- Electrogenic - produces negative charge as 3Na+ out and 2K+ in
Define electrogenic
Generates a charge
What is a secondary active transport protein and give an example?
Often in passive transport
- Doesn’t require ATP itself but may rely on another protein that does
Eg. Na+ Glucose go transporter requires concentration gradient created by Na+K+ pump
How much can be transported by passive transport?
High turnover 10^2 - 10^3 / second
Characteristics of passive transport
- Follows electrochemical gradient
- Highly Selective
- Maximum transport rate - becomes saturated
What are the three types of carriers?
- Uniporter - transports 1 substance
- Symporter (cotransporter) - transports 2 substances in the same direction
- Antiporter (exchanger) - transport 2 substances in opposite directions
Characteristics of ion channels
- Gated
- High turnover - 10^6 - 10^8 ions/second
- Conductive
How are ion channels conductive?
When channels are open ions flow producing a current when closed there is no current
What is the patch clamp technique?
A technique that measures the current in a cell membrane with respect to the bath where the current in 0mv and allows us to see ion channels opening and closing within cell membranes
What is the difference between open and closed patch clamp technique?
- Open measures the current flow through all of the ion channels in the cell membrane. The part of the membrane between the two glass electrodes is removed
- Closed only measures the current flow in the part of the cell membrane between the two glass electrodes
What are the uses if the patch clamp technique?
Allows identification of ion channels and allows their function and regulation to be investigated
What is the equation for the total current carried by channels?
I = N.Po.g.(Vm-Ei)
I = Total current carried by channels N= Number of channels Po= Probability that channels will be open g = Single channel conductance Vm= Membrane potential Ei = Equilibrium potential ion i
What is Vm - Ei ?
Membrane potential and equilibrium potential ion which add together to the driving force
Basic structure of K+ channel family
- 6 transmembrane domains
- 4 subunits come together to create a channel
- pore
Basic structure of Na+ channel family
- 24 transmembrane domains ( 4 groups of 6)
- Similar structure to K+ channels
What is the structure of K+ in bacteria?
- Crystal structure
- 4 subunits with a central pore
How would you measure the membrane potential (traditional intracellular method)l?
- Glass electrode filled with a KCl solution
- Silver electrode in centre measures the membrane potential with respect to the 0mV bath
What is the difference between the patch clamp method and the traditional intarcellular method?
The tip of the electrode in the patch clamp method is 1x10^-6 but in the traditional method the tip is much smaller
What is the contribution of Na+/k+ ATPase to the membrane potential?
- It directly contributes 20% of the membrane potential due to its electrogenic nature
- It also indirectly contributes to the intracellular Na+ K+
How is the Nernst potential reached by K+ ions across the membrane?
- K+ moves out of the cell due to the concentration gradient leaving a negative charge inside the cell
- This produces a potential gradient going the opposite way (Positively charged K+ ions will travel down gradient back to negatively charged inside of the cell)
- Eventually the concentration gradient and potential gradients are equal so K+ movement in both directions are equal => no net movement of K+ ions
What is the Nernst equation at body temperature?
Elon = 61/Z x log (5/150)
Why is the Nernst equation never completely accurate?
Because it is never just one type of ion channel open e.g. K+ and Na+ channels will be open so Nernst equation for just K+ won be accurate
How is the Nernst potential reached by Na+ ions across the membrane?
- Na+ moves into cell down its concentration gradient leaving a positive charge
- Na+ then repels the positive charge so creates a driving force going the opposite way
- Eventually movement of Na+ becomes equal in both directions so no net movement
What does the resting membrane potential suggest about Na+ and K+ channels?
Membrane potential for Na+ is +64mv but resting potential is -70mv suggesting Na+ channels are closed
Membrane potential for K+ is -90mv suggestion that K+ channels are open
What is the Goldmans equation at body temperature?
Vm = 61/7 log (PNa[Na+]o + Pk[K]o) / (PNa[Na]I + Pk[K+]I)
What drives the membrane potential?
Na+K+ ATPase
What causes depolarisation and hyper polarisation in the formation of an action potential?
- Massive opening of Na+ channels driving membrane potential towards nernst potential for Na+ (depolarisation)
- Na+ channels close driving Vm towards nernst potential for K+ (hyper polarisation)
What are the normal intracellular and extracellular concentrations of [Na+]?
Extracellular - 145mM
Intracelular - 15mM
Give examples of why intracellular and extracellular Na+ concentrations are important?
- Thick ascending limb - NaK2Cl cotransporter uses the Na+ gradient produced by the Na/K ATPase
- Excitable cells - Na+ ions move into the cell down the concentration gradient causing depolarisation
How does Na/K ATPase allow the exchange of Na+ and K+?
- Requires 1 ATP molecule
- ATP phosphorylates the pump leading to a conformational change, changing the binding site for Na+ releasing it
- K+ then binds causing dephosphorylation and a structural change causing the release of K+ inside the cell
Why is the rate of ion transport using Na/K described as a saturated function?
Because it has a maximum rate
Saturable function of [Na]I[k]o and ATP
What inhibits the Na/K pump?
Glycosides - ouabain and digoxin
What is the role of Na/K pump?
- Electrogenic transport of 3Na+ out and 2K+ in - make cell more negative
- Accumulation of K+ inside the cell creating a driving force for K+ to leave the cell through K channels
What are the normal intracellular and extracellular levels of Ca2+?
Extracellular - 1mM
Intracellular - 100nM
Why is calcium regulation important?
It acts as an important second messenger in many signalling pathways
e.g. Muscle contraction
What is the Nernst potential for Ca2+?
+120 mv
Why is it important to keep intracellular calcium low?
To provide a huge gradient for quick calcium entry
What are mechanisms are used to keep intracellular Ca2+ low?
Na/Ca exchanger
CaATPase
Under normal conditions what is the role of the Na/Ca exchanger?
Exchanges extracellular Na for intracellular Ca
It keeps intracellular so low by exchanging 1Ca for 3Na - electrogenic
What is the stoichiometry of the Na/Ca exchanger and why is it needed?
3Na+:1Ca2+
Because if the Na gradient was 10 fold but Ca 10000 then intracellular Ca would not be kept low if the exchanger was 1:1. Therefore 3Na means that the effect of the 10 fold gradient is cubed
What are the characteristics of the Na/C exchanger?
- They are members of the SLC8 gene family and the much larger CaCA superfamily
- Three forms exist in mammals names NCX1-3
Name the characteristics of Ca2+ ATPases
- Member of the P-type ATPase family which also includes Na/K pump
- Also pump protons in the opposite direction at the same time as transporting Ca2+
What are the three types of Ca pumps?
PMCA - plasma membrane calcium pumps
SERCA - Ca pumps found on the sarcoplasmic and endoplasmic reticulum membranes
SPCA - Ca pumps found o the Golgi apparatus
What is the role of PMCA pumps?
Act to pump Ca2+ across the plasma membrane out of the cell
What is the role of SERCA pumps?
Act to pump Ca2+ out of the cytoplasm into the organelles which act as calcium stores
What is the like of SPCA pumps?
Transport Mn2+ as well as Ca2+
What are the 4 types of Ca2+ channels?
- Voltage operated Ca Channels (VOCC)
- Receptor operated Ca channels (ROCC)
- Mechanically activated Ca Channels - found in many cells respond to deformation (e.g. stretch activated channels)
- Store operated Ca Channels (SOCC)
How are voltage operated Ca channels (VOCC) activated?
Found in excitable cells and activated by depolarisation
How are receptor operated Ca channels (ROCC) activated?
Found in secretory cells and nerve terminals and are activated by the binding of an agonist
e.g. NMDA receptor
How are mechanically activated Ca channels activated?
Found in many cells and respond to deformation eg. stretch activated channels
How are store operated Ca channels (SOCC) activated?
Activated following he depletion of calcium stores
What are the two classes of calcium channels in the store membranes?
- IP3 receptors
- Ryanodine receptors
What is an IP3 receptor?
A class of calcium channel in store membranes that is activated following the binding of IP3. This type of receptor is expressed in most cell types
What is a Ryanodine receptor?
A class of calcium channel found in store membranes that are activated by low concentrations of Ryanodine and inhibited by higher concentrations.
- Found in excitable cells
- Also stimulated by caffeine and cADP ribose
How is Ca released from stores?
- Phospholipase C (PLC) stimulates receptor in membrane forming DAG and IP3
- IP3 activates IP3 receptor channels in the stores releasing Calcium into the cytoplasm
- Signalling also from the ER to Ca channel in membrane (SOCC) which activates store refill.
How are the Ca stores refilled?
- When Ca2+ decreases in the store, the stim protein in the ER membrane senses this and undergoes a conformational change
- It stretches and binds to other stim proteins forming an 8 unit complex which binds to the cell membrane
- This interacts with ORAI1 causing Ca2+ to enter the cell
- When this happens the circa pump is stimulated favouring Ca2+ uptake into ER
What is the ORAI1?
A Ca channel in the membrane involved in refilling the Ca stores
- Tetramer like
What is the equation for pH?
pH = -log[H+]
What are the plasma and intracellular pH values?
plasma = 7.35-7.45 IC = 7-7.1
Why is regulation of pH important?
Can cause change in protein charge, conformation or function
e.g. Apical K+ channel ROMK is pH specific (activates when alkaline)
What are the two ways of measuring intracellular pH?
- Microelectrodes
- Fluorescent indicators
How is intracellular pH measured using micro electrodes?
- Uses two ion sensitive micro electrodes where one measures the voltage of all ions and the other measures everything except protons
- Take these voltages away to get the voltage of H+
- Calibrate electrodes with pH standards to work out what pH the voltage of H+ is proportional to
- Convert voltage into pH
When is it good to use microelectrodes to measure pH?
When the cells are big e.g. in the xenopus
What is a proton ionopore?
A small molecule that allows pH in a cell to equilibrate to pH outside
Outline the use of fluorescent indictors when measuring intracellular pH?
- Cells loaded with a lipid soluble form of indicator
- Inside the cell the indicator is lazed into an active form (Lipid insoluble)
- Indicator is excited with light of a specific wavelength and the amount of emitted fluorescent light at a second wavelength is measured
- Fluorescence is proportional to IC pH
How is the indicator used in measuring IC pH calibrated?
- Calibrated inside the cell
- membrane permeabilised with a proton ionopore
- pH of ionopore bath is changed
- In the presence of an ionopore bath the pH=IC pH
When is it good to use fluorescence indictors to measure IC pH?
When the cells are small eg. kidney or cardiac
What factors are involved in the control of intracellular pH?
- Buffering
- Acid extrusion
- Acid loading
What is the purpose of buffering?
To minimise pH changes and protect cells from damage
- Cant revers pH change or prevent pH changes
How does a buffer work?
moderates the effect of acid/alkali by reversibly consuming or releasing protons
Define buffering power
The amount of strong base that must be added to a solution in order to raise the pH by a given amount
How do proteins act as a buffer?
When pH increases, the COOH group from the amino acid donates a H+ becoming COO-
When pH decreases the amino acid gains a H+ on NH2 group becoming NH3+
When does acid extrusion occur?
When pH decreases
What does acid extrusion rely on?
- Na/H exchanger (NHE) pumps Na+ in and H+ out - set up Na+ gradient
- When pH is more than NHE set point then the exchanger is inactive
- Ca2+ binding to the c terminus of NHE stimulates acid extrusion
How does NHE have allosteric modification?
Protons other than the one being transported bind to the NHE protein leading to conformational change which increases the activity of the protein
What is meant by NHE1 having housekeeping functions?
Controls cell volume and regulates pH
What is NHE1 inhibited by?
low conc of amiloride and its analogue EIPA
What is acid loading?
- reduced pH as pH increases so does Cl/HCO3 exchanger activity
- moves HCO3- out of the cell and H+ in (acidification)
- has allosteric modification
Give the characteristics of AE family?
- 4 subunits
- all inhibited by stilbene derivative drug DIDS
- independant of Na+
Where is AE1 found?
- Predominantly in red blood cells, some in kidney - responsible for chloride/hamburger shift
What pressure gradients are required for inspiration and expiration to occur?
Inspiration = Patoms > Palv Expiration = Palv > Patmos
What inflation factors have to be overcome for respiration?
- Elastic recoil of tissues
- Surface tension in alveoli
- Airways resistance
Why when at rest are the elastic forces in the lungs balanced?
Elastic nature of the lungs would tend to cause them to collapse inwards
The chest wall would tend to expand
- At rest these two forces balance - as a result the pressure in the intrapleural space is less than atmospheric pressure
What is compliance?
The measure of elasticity
The ease with which the lungs and thorax expand during pressure changes
How is compliance measures?
C = ΔV/ΔP
Give an example of an illness causing low compliance?
Pulmonary fibrosis
- more work required to inspire
- Decrease in FRC
Give an example of an illness causing high compliance?
Emphysema
- difficulty when expiring
- Increase in FRC
What is function residual capacity (FRC)?
When the force of the lungs matches the expanding force of the chest wall
Palv=Patoms
What happens when the volume in the chest cavity is less than the FRC?
Forces favouring elastic collapse are low and forces on the chest favour expansion
Overall system wants to expand
What happens when the volume in the chest cavity is more than FRC?
Forces favouring elastic collapse are high and forces on the chest favouring expansion are high
Overall the system wants to collapse
What are the two components of elastic recoil in the lungs?
- Anatomical component: Elastic nature of cells and extracellular matrix
- Surface tension: generates elastic recoil at air fluid interfaces
What is surface tension?
Occurs at air water interfaces
- differences in forces on water molecules at this interface, surface tension develops
How is surface tension calculated?
Laplaces equation
- P=2T/r
Why is surfactant required in the lungs?
As explained in Laplaces equation - smaller alveoli are of a higher pressure than larger alveoli meaning air would move down the pressure gradient cause the small alveoli to collapse
- It reduces surface tension on the alveoli
How is surfactant produced?
By type II pneumocytes
What is surfactant composed of?
Lipids and proteins
- 30-40% DPPC
- 30-45% other phospholipids
- 5-10% protein (SP-A, B, C and D)
- Cholesterols
What is the role of the protein SP-A in formation of surfactant?
It is water soluble and has a role in innate immunity
What is the role of the protein SP-B in formation of surfactant?
Lipid soluble and speeds up formation of monolayer
What is the role of the protein SP-C in formation of surfactant?
Lipid soluble and speeds up formation of monolayer
What is the role of the protein SP-D in formation of surfactant?
Water soluble and has a role in innate immunity
What is the role of surfactant?
- Density of surfactant determines rate of alveolar inflation
- Decreases lung compliance
- Prevents oedema - reduces fluid entering alveoli
- Prevent over inflation
What factors determine air flow in the lungs?
Type of air flow
Resistance of the pathway
Pressure gradients generated across the airways
What is the relationship between airflow and the pressure gradient?
Proportional to each other
What is the relationship between airflow and the resistance?
Airflow is inversely proportional to the resistance
What are the three types of air flow?
Laminar flow
Turbulent flow
Transitional flow
What is laminar flow?
The steady flow sown a tube at uniform speed and direction
- Flow rate is maximal in the centre of the tube and reduces towards the edges
What is turbulent flow?
When the flow rate moves past a critical value and irregular currents (vortices) develop
- Greater pressure gradient is required to obtain the same flow as seen under laminar conditions
What is the relationship between gas movement and pressure difference under turbulent flow conditions?
Gas movement is proportional to the square root of the pressure difference
What is transitional flow?
In the airways there is a high number of bifurcations (branches) the flow is disrupted causing eddies
- Air flow changes between turbulent and laminar
How is air flow type determined?
Governed by Reynolds number
Re = (2radiusvelocity*density of gas)/viscosity
Re<1000 - Laminar flow
Re between 1000 and 1500 - Unstable flow
Re>1500 - Turbulent flow
Where in the airways is true laminar air flow shown and why?
Terminal part of the airways - by alveoli
- Because of velocity of air decreases and cross sectional area is high meaning Reynolds number will be as low as 10
Where in the airways is turbulent air flow shown and why?
Trachea
- Velocity of air very high
- Cross sectional area low
What is poiseuille’s law?
Determines the impact of resistance on airflow
Airway resistance is proportional to gas viscosity and the length of the tube but is inversely proportional to the fourth power of the radius
Does airway diameter have an impact on resistance?
yes big impact and hence flow rate
What is the airway resistance of a normal individual?
1.5cm H2O.s.litres-1
What contributes to airway resistance?
Pharynx - Larynx = 40%
Airways>2mm diameter = 40%
Airways <2mm diameter = 20%
What is the airway resistance of an individual with COPD?
5cm H20.s.litres-1
Wat contributes to airway resistance in a person with COPD?
Pharynx - Larynx = 12%
Airways>2mm diameter = 18%
Airways <2mm diameter = 70%
What factors impact airway resistance?
Mucas secretion - Reduce airway diameter
Oedema - Fluid retention - narrow airways
How does dynamic pressures allow for inspiration?
Interplural pressure becomes more negative (-5 to -15cm H2O)
Transmural pressure gradient decreases as it moves up from alveoli to trachea meaning that pressure increases to more than interplural pressure
Airways expand and airflow increases
How does dynamic pressures allow for expiration?
Interplural pressure increases to +10cm H2O
Transmural pressure +15 in alveoli and increases up the trachea
This makes positive pressure gradient from alveoli to atmosphere causing constriction and air to move out
Why do emphysema patients slow down their breathing?
Because the alveolar walls have broken down so have the risk of collapse
Slow breathing reduces the effect of dynamic pressures making airway collapsing less likely
- Also breath out through pursed lips to create a big resistance to slow airflow
How does lung volume affect airflow resistance?
- As lung volume decreases so does cross sectional area off airways causing increases resistance
- Dynamic pressure effect causes constriction of airways
- No matter how much effort required flow rate won’t increase
Why do patients with COPD struggle to exercise?
When there breathing rate increases they are not able to bring enough O2 before their next breath due to decreased lung volume
- Tidal volume decreases by as much as a half
- Not enough O2 to reach metabolic demands
How is the airway smooth muscle controlled?
Heavily dependant on GPCR cascades
- Gq pathway
- Gs pathway
- Gj pathway
Which GPCR cascade is responsible for the contraction of airway smooth muscle?
Gq pathway
How does the Gq pathway lead to contraction of airway smooth muscle?
- Activation if alpha q unit of membrane receptor
- Activates phospholipase C (PLC)
- Causes increased production of IP3
- IP3 activates receptors in calcium stores in the ER moving calcium into the cytoplasm
- Ca binds with calmodulin forming CaM complex
- This complex phosphorylates MLCK acting on myosin and causing contraction of smooth muscle
How does Gq pathway also stimulate cell growth?
When phospholipase C is activated it stimulates the breakdown of PIP2 and its conversion to diacylglycerol (DAG)
DAG stimulated protein kinase C
This stimulates cell growth
What receptors are involved in the Gq pathway?
- M3 muscarinic receptors
- H1 histamine receptors
- BK bradykinin receptors
How does the Gs pathway led to relaxation of the airway smooth muscle?
- Alpha s subunit is activated by GTP
- This stimulates adenylate cyclase producing CAMP
- Stimulates protein kinase A
- Protein kinase A phosphorylates IP3 receptor inhibiting it and therefore promoting relaxation
- Protein kinase A also phosphorylates MLCK reducing its action
- It also phosphorylates MLCP stimulating phosphatase promoting relaxation of muscle fibres
- Alpha s subunit interacts with K channels in membrane increasing the efflux of K+ causing hyperpolarisation
- This reduces Ca influx through voltage gated calcium channels promoting relaxation
What other effects does the Gs pathway have?
Reduction of gene activation an cell growth
How does protein kinase A promotes relaxation of airway smooth muscle in the Gs pathway?
- Phosphorylates IP3 receptor inhibiting its action
- Phosphorylates MLCK stopping it from phosphorylating myosin
- Phosphorylates MLCP promoting phosphatase, dephosphorylating myosin promoting relaxation
How does Alpha s subunit in the membrane promote relaxation of airway smooth muscle in the Gs pathway?
- Stimulates adenylate cyclase producing CAMP stimulating protein kinase A
- It also interacts with K channels in the membrane increasing the efflux of K+ causing hyperpolarisation reducing Ca influx through voltage gated calcium channels
What receptors are involved in the Gs pathway?
B2 adrenergic receptors
VIP receptors
What is the role of the Gi pathway in airway smooth muscle?
Oppose the action of the Gs pathway
How does the Gi pathway oppose relaxation in airway smooth muscle?
Activation of the Gi receptors inhibit adenylate cyclase stopping the production of CAMP and stimulation of protein kinase A
- Has a knock on effect which counteracts the stimulators effect of Gs activation
- Opposes the relaxation of smooth muscle
- Also inhibits BK channel
What receptors are involved in the Gi pathway?
M2 muscarinic receptors
How is the bronchial smooth muscle controlled?
Autonomic nervous system
- Parasympathetic and sympathetic
Humoral factors
- Epinephrine and histamine
What is the role of the parasympathetic nervous system in bronchial smooth muscle?
Acetyl choline released from postganglionic vagus nerve stimulating M3 muscaranic receptors on airway smooth muscle causing contraction by the activation of Gq pathway
What is the role of M2 receptors in the control of bronchial smooth muscle by the parasympathetic nervous system?
M2 receptors are present on the outer side of postganglionic nerve and are involved in a negative feedback loop
- When M2 receptors detect Ach, it stops it release
- Prevents overstimulation of airway
How does epinephrine control bronchial smooth muscle?
It is an agonist - leads to dilation of muscle
How does histamine control the bronchial smooth muscle?
Its released during the inflammatory process and leads to constriction
What is the role of the sympathetic nervous system in bronchial smooth muscle?
Releases norepinephrine stimulation B2 adrenoreceptor on airway smooth muscle
- Stimulates Gs pathway leading to relaxation
- It changes the sensitivity of IP3 receptor so not as much calcium leaves the store
What are the triggers for an asthma attack?
Atopic - Allergies, contact with inhaled allergens Non-atropic - Respiratory infections - Cold air - Stress - Exercise - Drugs
What occurs during an asthma attack?
Movement of inflammatory cells into the airways, release of inflammatory mediators such as histamine and subsequent bronchoconstriction
how can you tell if a patient has an obstructive lung disease such as asthma from a spirometer?
If the FEV1 is lower then 80% of the forced vital capacity
Overall vital capacity shouldn’t change
What is through to be the cause of asthma?
Hypersensitivity of parasympathetic activity
- Decrease in neuronal M2 function - negative feedback loop not working - over stimulation of airway smooth muscle
What does the antigen - challenge model show about the link between M2 receptors and Asthma?
- Change in M2 function is linked to eosinophils
- They cluster around nerve fibres and release major basic protein (MBP)
- MBP inhibited M2 receptors
What does the virus model show about the link between M2 receptors and Asthma?
Interferon causes down regulation of M2 gene expression
- hyperactivity of airway smooth muscle
What are the treatments for asthma?
B2 Adrenergic agonists - Salbutamol - short acting - Salmeterol with corticosteroids - long acting Anticholinergics - Block effects of Ach - Acts on M1 and M3 receptors - e.g.. tiotropium bromide Glucocorticoids - Anti inflammatory actions - e.g.. beclometasone - steroids
What is the central control of respiration?
Basic respiratory rhythm is controlled by centres in the medulla
Is breathing involuntary or voluntary?
Essentially it is involuntary but can be altered consciously
- Hyperventilation
- Breath holding
However these are overidden if required
What group is the dorsal respiratory group responsible for?
Quiet inspiration
Not quiet expiration as that is just elastic recoil
What group is the ventral respiratory group responsible for?
Control of forced expiration (requires extra muscle groups) and forced inspiration
What is the pre botzinger complex?
- Contains pace maker cells that are linked to control of breathing
- Located near the ventral respiratory group
- 12th cranial nerve (hypoglossal) sends inputs to diaphragm and muscles in chest wall to control inspiration
How do we know that the hypoglossal nerve is used in the pre botzinger complex?
Because when brain slice were took, electrodes showed spontaneous bursts of action potentials which match activity shown in hypoglossal nerve
What are the three types of breathing patterns generated from the pre botzinger complex?
- Eupneic - Normal breathing rhythm
- Sigh - increased level of activity - inhale more for a longer period of time
- Gasp - often seen in hypoxic conditions - ‘gasping for air’
How does the pre botzinger generate three different patterns?
All three patterns are generated from the same region of the brain and the same neurones but their inputs and modulation differs
What are the two types of cell in the pre botzinger complex?
Pacemaker cells and non pacemaker cells
What is seen in the activity of pacemaker cells?
- Regular spikes
- Bursts which are linked to contraction of the muscles - depolarisation and therefore inspiration
- A gap where cells depolarise and quiet expiration occurs (elastic recoil)
What is the NALCN?
Sodium leak channel
What is the importance of NALCN in the pre-botzinger complex?
- Contributes to the depolarisation phase
What occurs in a mutant NALCN knockout mouse compared to a wild type?
Breathing is irregular - mouse will stop breathing and then pant
The nerve recording show very little burst in mutant but normal spikes and burst in wild type
- Mimics what occurs in humans with CNS damage
What is the role of potassium in the pre-botzinger complex?
[K+] has an important effect on resting potential
- increase in extracellular [K+] increases bursting pattern
What are the two types of inward current responsible for bursting activity?
- The persistent sodium current ( INaP)
- CAN cation current (ICAN)
How are pacemaker cells classified?
- Neurones relying on ICAN for bursting are cadmium sensitive as cadmium blocks ICAN current
- Neurones relying on INaP for bursting are cadmium insensitive
What is the effect of hypoxia on the pre-botzinger complex?
- Decreased O2 available
- Cadmium sensitive bursting cells become inactive so rely on cadmium insensitive
- Leads to basic gasping pattern of breathing
What is the role of pneumotaxic centre?
Increases the rate by shortening inspirations - inhibitory effect on inspiratry centre
What is the role of apneustic centre?
Increases the depth and reduces the rate by prolonging inspiration - stimulates inspiratory centre
What is the Hering-Breuer reflex?
- Stops overinflation of the lungs
- Negative feedback loop
- Phrenic nerve causes contraction of diaphragm and lung inflation
- Stretch receptors in lung cause vagus nerve to inhibit inspiratory centre
What are the two types of chemoreceptors?
Central chemoreceptors
Peripheral chemoreceptors
What is the role of central chemoreceptors?
Monitors conditions in the cerebrospinal fluid sensing CO2 and pH
- Response to rise in CO2 so stimulation leads to ventilation
What is the role of peripheral chemoreceptors?
Located in the carotid body and aortic arch
- Respond to an increase in CO2 and decrease in pH and O2
- Stimulation leads to ventilation
What is the primary driving force for respiration?
CO2
What do drugs usually target?
- Receptors
- Enzymes
- Transporters/carriers
- Ion channels
What are receptors classified based on?
Structure, pharmacology and signalling
What does specify mean to do with drugs?
Receptors show specificity in the classes of drugs that they recognise - no drug is completely specific
Comment on the structure of receptors with a similar function
Structures are very similar but structure of the communication part (binding site) is slightly different - making finding specific drugs difficult
What are the four families of receptors?
- Ligand gated
- G protein coupled receptors
- Kinase linked receptors
- Nuclear receptors
What is required for a drug to produce a response?
Agonist + receptor —> Drug receptor complex —-> active drug receptor complex —-> Response
Its not enough for the drug and receptor to bind (affinity) it must also produce a conformational change (efficacy) causing a response
What is the difference between affinity and efficacy?
Efficacy induces a change that causes a response in the cell but affinity is just the likely hood that the drug and receptor will bind
How does affinity for a drug effect the dissociation rate?
High affinity for a drug means slow disassociation - dependant on structure of drug and receptor
What is the relationship between drug types and affinities?
No relationship between agonists and antagonists and affinity
Antagonists may have a higher affinity than agonists and other way round
What is occupancy?
Proportion of receptors occupied will vary with drug concentrations
How is occupancy calculated?
Number of receptors occupied/ total number of receptors
Varies between 0 and 1
How can occupancy be measured?
Radio ligand binding assays
- Response and occupancy is not directly proportional so cannot rely on response to measure it
How is radio ligand binding assays carried out?
- Prepare cells or membranes that contain protein of interest
- Aliquot out membranes onto filters
- Add radio label at different concentrations and equilibrate
- When equilibrated remove unbound drug by filtration
- Rinse
- Count radioactivity of filter
How is non specific binding in radio ligand binding assays dealt with?
- Most ligands bind non specifically to tissue, filter paper, glass ect
- Rinsing will not get rid of it all
- use two test tubes where one measures specific and nonspecific binding of radioactive drug and other just non specific binding
- Take them away from each other
What can cause non specific binding in radio ligand binding assays?
- Starting material not 100% pure - drugs may bind to unwanted proteins
- Drugs may enter fat (lipids) in plasma membrane
What characteristics must a radio ligand have?
- Must be biologically active
- Purity - e.g. no enantiomers
- Radioactive - labelling- very high specific activity to allow low concentrations
What are the two main choices of radio ligands?
- Tritium (3H)
- Iodine 125
What are the advantages of using tritium as a radio ligand?
- Labelled product indistinguishable from native compound
- High specific activities can be obtained
- Good stability
- Long half-life (12.5 years)
What are the disadvantages of using tritium as a radio ligand?
- Specialised labs required
- Labelling is expensive and difficult
What are the advantages of using iodine 125 as a radio ligand?
- If it has aromatic hydroxyl group can be incorporated at high specific activities
- Iodination east in most labs and cheap
What are the disadvantages of using iodine 125 as a radio ligand?
- More readily degraded
- Biological activity of ligand can be reduced
- Short half life (67 days)
What is the role of incubation in radio ligand binding assays?
To maintain the integrity of both ligands and binding sites
What should the protein concentrations be in a radio ligand binding assay?
Range of 0.1-1mg membrane potential/ml with assay volumes of 0.25-1ml
What is the role of additives in radio ligand binding assays?
Used to protect the tissue
Why must the temperature be controlled in a radio ligand binding assay?
Stop denaturation of receptor
Stop enzymes from breaking down proteins as they are usually contained in lysosomes but they will have been disrupted during the process
How are tissue+bound ligand and free ligands separated in radio ligand binding assays?
- Filtration or centrifugation
- In solubized receptors - dialysis, column chromatography and precipitation is used
What are the problems when separating tissue+bound ligand and free ligands in radio ligand binding assays?
The rate of dissociation of ligand receptor complex
- Lower affinity (higher KD) requires faster more efficient separation
What analysis is used on radio ligand binding assays?
Scatchard plot - shows:
- total bound
- Specific binding
- non specific binding
What scale is a scatchard plot plotted on?
Semi logarithmic scale - because if drug had a low affinity it could not be represented on a linear scale axis
Non specific binding only becomes a problem at a high concentration of ligand
What type of binding is saturable in radio ligand binding assays?
Specific - total number of receptors in the tissue is limited
Non specific is not saturable
What is The Langmuir Equation?
It describes the relationship between receptor occupancy, affinity and drug concentration
LR = RX/ X+KD
What is KD?
The dissociation constant - When 50% receptors are occupied by drugs the drug concentration is KD
What is the relationship between KD and affinity?
Low KD - High affinity
High KD - low affinity
What is EC50?
Effective concentration giving 50% of maximal response
- not 100% of receptors need to be occupied to give a maximum response (receptor reserve)
What is the ‘receptor reserve’?
Not 100% of the receptors are occupied to give a max response
Allows amplification of the signal
What is KD a measure of?
Affinity
What is the relationship between KD and EC50?
EC50 may be less than KD if we have less receptors
Why do binding and response curves differ?
- Because efficacy of agonist may influence size of response
- May activate multiple second messengers which would amplify the response
What is a limiting factor of response curves?
The machinery of response - e.g. used all the enzymes/2nd messengers
How is response calculated using a drug response graph?
Response = (Maximum response[X]^slope factor) / ([X]^slope factor + [EC50]^slope factor)
What does EC50 measure?
Agonist potency
- If a drug requires a small concentration to receive a high response it would have a high potency
On a drug response curve, where would the sigmoidal line be for a drug with a high potency be in relationship to others?
The sigmoidal line most left has the highest potency as a drug requires a small concentration to receive a high response
What does potency depend on?
Affinity efficacy and spare receptors
What is a partial agonist?
Partial agonists are not capable of achieving the full response
- Drugs may have the same EC50 but different maximal responses
What is the relationship between potency and partial agonists?
A partal agonist could be more potent even though it is a partial agonist - no effect
How do you know if a drug is a partial agonist?
Only by comparing the response to that of a full agonist
Why are partial agonists useful?
Because it doesn’t evoke a full response
- Less chance of overdose
- Much less desensitisation of receptors e.g.. B2 inhaler
- Easing of addiction
How can a partial agonist act as an antagonist?
The previously bound to receptors and the a full agonist is added
What is efficacy?
The measure of a single agonist-recepor complex’s ability to generate a full response
What properties determine the effect of a drug in a living system?
- Specificity
- Affinity
- Efficacy
What is specificity in relation to drugs?
The interaction with a structurally defined site/receptor
What is affinity in relationship to agonists and antagonists?
Ability to bind to a receptor
What is efficacy in relationship to agonists?
Ability to activate receptor
What is an inverse agonist?
Evokes a response opposite to that of a normal agonist
- Not an antagonist
- Has an efficacy below 0
- Cannot consume an active configuration
What can alter the efficacy?
GPRC’s may have allosteric sites which make it easier for the agonist to evoke a response
What type are most drugs used clinically?
Antagonists
Define antagonist
A drug that prevents the response of an agonist
What are the 5 different classes of antagonism?
- Chemical antagonism
- Pharmacokinetic agonist
- Physiological antagonism
- Non - competitive antagonism
- Competitive antagonism by receptor block
What is a chemical antagonism?
The substance combines in a solution so that the effects of the active drug is lost - agonist is chemically altered by the antagonist
Give an example of chemical antagonism
Adding a chelating agent (antagonist) to a heavy metal will inactivate toxicity
What are the two types of pharmacokinetic antagonism?
- Reduction in amount of drug absorbed
- Change in drug metabolism
Give an example of pharmacokinetic antagonism (reducing drug absorbed)
Opiate will reduce absorption in the GI tract
Give an example of pharmacokinetic antagonism (change in drug metabolism)
Antibiotics may lead to metabolism of warfarin for those patients taking it - problem
What is physiological antagonism?
The interaction of drug with opposing actions in the body
Give an example of physical antagonism?
Noradrenaline raises arterial blood pressure by acting on the heart and peripheral blood vessels - while histamine lowers arterial pressure by causing vasodilation
What is non competitive antagonism?
Blocks some step in the process between receptor activation and response - does not compete with agonist for the receptor site
Give an example of non competitive antagonism?
Smooth muscle interfering with gated Ca2+ channel which is required to bind to MLCK to contract - doesn’t directly block channel non competitive
What is competitive antagonism?
Competing with agonist for for binding site on a receptor
- Similar structure
- Does not create a response
Give an example of reversal competitive antagonism?
Effects of atropine on response to acetylcholine for guinea pig ileum
What happens to a dose response curve when a reversible competitive antagonist?
Sigmoidal shape moves to right- more conc required for max response
- EC50 increases
What is the dose ratio?
How many more times agonist is needed in the presence of an antagonist
How do you calculate dose ratio?
[Concentration of agonist in presence of antagonist] / [Conecentration of agonist in absence of antagonist]
What is schild analysis?
Measure antagonist affinity
How can you calculate dose ration from a schild plot?
Dose ratio = (conc of antagonist (Xd) / antagonist affinity constant (KD)) +1
What does PA2 value imply?
Higher the number higher the affinity
What are irreversible competitive antagonists?
Cannot be reversed by washing of the tissue
- Irreversible antagonism is time dependant
Give an example of the irreversible competitive antagonists?
The effects of the alkylating drug dibenamine on histamine responses in the guinea pig ileum
How does the drug become present in every cell?
- Absorption
- Distribution
- Metabolism
- Excretion
What is the role of diffusion in distribution of drugs through the body?
Drug crosses the plasma membrane to travel between cells
What factors effect whether a drug can diffuse through a lipid?
The physiological properties of the drug and if it is non polar
How do physiochemical properties of a drug effect whether it can diffuse through lipid?
Lipid solubility partition coefficient
- Measure of how easily the drug will dissolve into the lipid/aqueous phase
How does the polarity of a drug effect whether it can diffuse through lipid?
Non polar molecules dissolve through lipids freely
- Increasing rate of absorption from gut, penetration into brain and renal elimination
What are the characteristics of the intravenous route of drug administration?
- Straight into plasma (fastest way)
- Avoids metabolism
- Quick in emergency situation
- Not convenient
What are the characteristics of the intramuscular route of drug administration?
- e.g.insulin
- Speed of effect depends on muscle
- Short delay getting into plasma
What are the characteristics of the intrathecal route of drug administration?
- Inject into spinal cord - effects CNS
- eg. epidural
What are the characteristics of the inhalation route of drug administration?
- Gas
- Potential route if the target is in the lungs e.g. inhaler (salbutamol)
What are the characteristics of the oral route of drug administration?
- Most widely used route
- Pass through the gut into plasma through diffusion within the intestines
- Rate depends on gut contents
- Drug capsules used to alter rate of absorption
What is bioavailability?
Fraction of injected drug/fraction in plasma
What are the characteristics of the rectal route of drug administration?
- Through the gut
- Used in paediatric medicine
- also when local target
What are the characteristics of the percutaneous route of drug administration?
- Though the skin e.g. patches
- Can be used for when condition is in the skin
What factors effect drug absorption?
- Method of administration
- Molecular weight
- Lipid solubility
- pH and ionisation
How does pH and ionisation effect drug absorption?
Most drugs are weak acids
- be a salt so easily made into a tablet
- Will be in its undissociated from in stomach acid so can easily pass though membranes as its not charged
How does the pKa of a weak acid drug show how easily it will pass through the membranes using aspirin as an example?
pKa = pH +log(HA/A-)
When the dissociation of he drug is HA H+ + A-
- In stomach acid (pH 3), aspirin (pKa=3.5):
3. 2 = (HA/A-) meaning three times more of the drug is in its uncharged form so can pass through the membrane - In plasma (pH 7.4) - more drug in dissociated from so will stay in blood circulating the body
- In kidney (pH 8) favours dissociated form so will be trapped and excreted
Why would a weak base be used as a drug?
In poisoning situations
- Increases pH of plasma by sodium bicarbonate causing weak acid to be trapped an excreted
When does pKa=pH?
When 50% molecule is in its dissociated form
What regulated drug access to CNS?
Blood brain barrier
How does the blood brain barrow regulate drug access to the CNS?
Endothelial cells lining blood vessels in CNS form tight junctions impermeable to water soluble molecules
Lipid soluble molecules e.g. ethanol cross it easily
Tight junctions become laky during inflammation
What part of the CNS has a sparse blood brain barrier?
The chemoreceptor trigger zone
Give an example how the chemoreceptor trigger zone causes problems in drug effectiveness?
The chemoreceptor trigger zone is rich in dopamine receptors so when drugs fro Parkinson’s disease are added nausea is caused
- to stop this you have to co administrate a drug that inhibits the dopamine receptors in the chemoreceptor trigger zone
- It only inhibits those dopamine receptors as the drug has a large structure so cannot surpass the blood brain barrier in most if the CNS but can in the trigger zone as the blood brain barrier is sparse
What characteristic does a drug that needs to pass the CNS need to have and what is the disadvantage of this?
High solubility
- However means it can easily enter body fat
- Making dosage more difficult to calculate
What are the two reactions required for drug metabolism in the liver?
Phase 1 - catabolic reactions
Phase 2 - synthetic reactions
What occurs in the phase 1 creation of drug metabolism?
Catabolic reactions
- made more active to increase its size using microsomal enzymes such as cytochrome p450, alcohol dehydrogenase, MAO
- to allow it to pass the plasma membrane
What occurs in the phase 2 creation of drug metabolism?
Synthetic reaction
- Involve conjugation to produce an inactive product
What are pro drugs?
The active form of the drug isn’t released until after metabolism
- Slows doen rate of response
- Can be useful in avoiding symptoms like tiredness
How is aspirin eliminated from the body?
- Enters liver cells
- Encounters cytochrome enzyme which swaps the acetyl group for a hydroxyl group
- Conjugate into a larger molecule decreasing its access to tissues
- Cant interact with its target
- Excretion is promoted
How can drug metabolism be increased?
By adding inducers of P450 (an enzyme involved in drug metabolism)
Why do expectant mothers have to be careful what drugs they take?
Because spree rugs are distributed and trapped in the milk meaning it could be passed on to the baby
What is the time course of clearance for a single dosage of drug?
Follows a memo-exponential decay
- t-half value is the amount go time for the concentration to decrease by half
- Rate of elimination may very even if the drugs are of the same concentration targeting the same receptors
- t - half is not directly proportional to the concentration
What parts of the heart are involved in the spread of electrical activity?
Nodal cells
Conducting cells
Muscle cells
Connections – intercalated discs
Give overview of excitation in the heart
- Initiated at sino-atrial node
- Conduction to atria and atrioventricular node and then atrioventricular ring
- Passage through bundle of his
- Purkinjie system distribution to ventricular muscle cells
What is the size of the Sino atrial node?
15mm x 5mm x 2mm
Where is the sinoatrial node located?
The posterior aspect of the heart
- Junction between superior vena cava and right atrium
What is the speed of conduction of the sinoatrial node?
0.05m/s
What is the speed of conduction of the sinoatrial node via the atrial myocardium?
1m/s
this is the pathway that allows spread of electrical activity from right atria to left
Where does the electrical activity of the sinoatrial node spread?
To atrioventricular node and left atrium
What is the size of the atrioventricular node?
22mm x 10mm x 3mm
Where is the AV node located?
Posterior aspect
- Right side interatrial septum
What are the three sub zones of the AV node?
AN, N, NV
What is the speed of conduction through the AV node?
Slow concussion through AN-N= 0.05m/s
What is the role of the delay caused by the AV node?
Allow atrial contraction to finish
What is AV refractoriness?
Prevents excess ventricular contraction
It increases at higher heart rate to allow the hart to move maximum amount of blood and therefore CO2
What is the speed of conduction at the bundle of his?
1m/s
What is the speed of conduction at purkinje fibres?
4m/s
What is the speed of conduction at the ventricular muscle?
1m/s
Why do the ventricles contract in a spiral pattern?
Squeeze maximum amount of blood out
Describe the action potential for the Sinoatrial and atrioventricular node?
Gradual and slow depolarisation of the membrane
Which of the hearts nodes are dominant?
Sinoatrial node
- The atrioventricular node had the ability to take over for the sinoatrial node if it fails
What is the absolute resting potential for the atrial and ventricular muscle?
-80mv
How do cardiac muscle and nodal action potentials differ?
The muscle have a plateau phase in order to sustain contraction of the atria and ventricles
Why would summation of action potentials in cardiac cells cause problems?
Would never allow the ventricles to actually contract so cardiac muscle cannot fire another action potential until first is completely done
What parts of the heart can also act as pacemaker cells?
AV node and purkinje fibres
Describe the action potential of a pacemaker cell in the heart?
Slow depolarisation, fast depolarisation and fast repolarisation
What is the If current (funny current)?
- A cation channel with a Nernst of 0
- K+ channels are closed from the last action potential
- Hyperpolarition induced - so inactive when vm is positive
What causes the fast depolarisation of pacemaker cells in the heart?
When vm goes over -40mv
- Ca2+ channels open
- Peaks at 0mv
What causes the fast repolarisation of pacemaker cells in the heart?
- Ca2+ channels close and K+ open
- Shifts the membrane potential towards that of Nernst for K+
How is heart pacemaker action potentials regulated?
Innervation, temperature and by other pacemakers
How are the hearts pacemaker cells controlled?
Parasympathetic - ACh released from vagus nerve causes hyper polarisation and decreased pre potential slope Sympathetic - Noradrenaline released - Increase the prepotential slope - Increase the firing rate
Describe the cardiac muscle action potential
Fast depolarisation - Na+ channels open (shifts membrane potential towards Nernst for Na+) - Na+ close and Ca2+ open Spike - Leakage of some K+ channels Plateau - Ca2+ channels balance with K+ as Ca2+ tries to drive it positive and K+ negative Repolarisation - Ca2+ channels close - Ca2+ is transported out - K+ open and moves in
What is the purpose of the effective refractory period in the heart?
Due to the Na+ channels
Before they can become activating again, they have to go from open to inactive to closed
- Stops summation
What is the purpose of the relative refractory period in the heart?
- Stimulus to get action potential must be higher as membrane is still slightly hyper polarised
- Stops summation
On an ECG what happens between Q and T?
Start of ventricular depolarisation to repolarisation
Name sone inherited cardiac ion channel syndromes?
Short and long QT syndromes
How would the ECG of someone with long and short QT syndrome compare to a normal one?
Short QT - distance between Q and T is smaller - Repolarisation is accelerated Long QT - distance between Q and T is larger - Repolarisation is slower
How can ventricular action potentials be used to diagnose long and short QT syndrome?
Normal - 0.36 s
Long - >0.45 s
Short - <0.34 s
Some pathologies only show variety QT interval when exercising
What are the implications of long and short term QTs?
- Triggered activity
- Re entrant excitation
How do cardiac channelopathies cause triggered activity and what does that lead to?
Long QT
- Na+ channels may be closed and ready to be active and therefore open to early
- Generates another action potential causing a ectopic beat
- Ventricular tachycardia
- Ventricular fibrillation
What is ventricular fibrillation?
Lack of control of the heart
How do cardiac channelopathies cause re-entrant excitation and what does that lead to?
- Different layers of cells are impacted
- Trigger of electrical activity but not in all of the ventricular muscle
- Spatial and temporal dispersion of refractory period - extra electrical activity at certain parts of the muscle and at certain times
- Leads to ventricular tachycardia
- Ventricular fibrillation
What are the symptoms of long QT syndrome?
- Fainting
- Palpitations
- Sudden death
- Torsades de points on ECG
When does long QT syndrome onset?
Teen years
When are effects of long QT syndrome more likely?
When exercising or jumping into cold water
What are torsades de points?
Seen on an ECG - loss of coordination
How common is long QT syndrome?
1:10000 to 1:150000
What is the most common types of long QT syndrome?
LQT1 -Loss of function in Iks channel - 30-35% of cases LQT@ - loss of function in Ikr channel - 25-30%
What type o f long QT syndrome is similar to LQT1?
LQT5
- Loss of function in MinK
- 1%
What is LQT1?
Most common type of long QT syndrome
- K+ channel channelopathy
- Caused by a mutation in KV7.1
- Lots of mutations in transmembrane domains
- Loss of function
What is also associated with LQT1 and LQT5 long QT syndromes and why?
Deafness
- Due to Q1 k+ channel and its regulators E1 role in the ear
- In a E1 knockout mouse (MinK protein which is what is mutated in LQT5), there is no resigners membrane and no K+ rich endolymph meaning can’t hear
- Same in humans with these cardiac channelopathies
How does a gain of function in Na+ channels cause long QT syndrome?
- Na+ channels stay open
- Balance between anions and cations is lost
- Depolarisation lasts longer and repolarisation is delayed
- Long QT syndrome
How does a gain of function in Ca2+ channels cause long QT syndrome?
- Ca2+ channels dont close
- K+ channels can’t repolarise
- Repolarisation takes longer -
- Long Qt
How does a loss of function in K+ channels cause long QT syndrome?
- Not as much K+ leaves as quickly
- Repolarisation takes longer
- Long QT
What are the treatments for long QT syndromes?
B blockers
- Atenolol - B1 selective antagonist - slows down heart as has chronotrophic and ionotrophic actions but can’t be used if asthmatic as causes bronchoconstriction
What are the symptoms of short QT syndrome?
Arrhythmias, palpitations, fainting, sudden death
How many forms of short QT syndrome is there?
5
How many forms of long QT syndrome is there?
12
Who is short QT syndrome more prominent in?
75% males
- Onsets at late adolescence
What would an ECG of someone with short QT syndrome be like?
- Short/absent ST segment
- Tall T wave
- QT doesn’t vary when exercising - normal people it gets shorter
What are the 5 types of short QT syndromes?
- SQT1 - gain of function - K+ channel
- SQT2 - gain - K+
- SQT3 - gain - K+
- SQT4 - loss - Ca2+
- SQT5 - loss - Ca2+
How does a loss of function in Ca2+ cause short QT syndrome?
Loss of function in Ca2+
- Repolarise too quickly as Ca2+ cant enter to balance K+
How does a gain of function in K+ cause short QT syndrome?
Gain of function in K+
- K+ moves in to quickly
- Repolarisation to quick
What are the treatments for short QT syndromes?
Implant defibrillator
Define cardiac cycle
Mechanical and electrical events that repeat with every heartbeat
What are the four stages in the cardiac cycle?
- Inflow phase
- Isovolumetric contraction
- Outflow phase
- Isovolumetric relaxation
What is the middle of phase 1 of the cardiac cycle?
- AV valves open but little blood flows between atria and ventricles so ventricular pressure rises very slowly an approaches a plateau
- Pressure in atria also rise very slowly
Why is the end diastolic pressure less in the right ventricle then the left in the cardiac cycle?
Because the capillaries in the lungs are one cell thick and have lots of gap junctions so would rupture if the pressure was high
- would cause the lungs to fill with tissue fluid
What is the end of phase 1 of the cardiac cycle?
Atrial contraction
- After excitation contraction coupling, contraction of atria occurs and pushes the remaining blood into the ventricles
- <20% of the blood from atria is moved to atria in this phase
- Small rise in both chambers pressure
Why do the atrioventricular valves close in the cardiac cycle?
When the intraventricular pressure exceeds the atrial pressure
How is it ensured that the atrioventricular valves remain closed?
Ventricular contraction triggers contraction of the papillary muscles with their cordae tendinae that are attached to valve leaflets
- this tension prevents them from bulging back too far into the atria
What is the first heart sound?
Closure of the AV valves
- Split sound (0.04 secs) as mitral valve is slightly before tricuspid
What is phase 2 of the cardiac cycle?
Isovolumetric contraction
- Systole commences
- As ventricles contract, pressure in the ventricles exceeds the pressure in the atria causing the AV valves to shut
- Means ventricles are contracting with all the valves shut so that the pressure is increasing but the volume is staying the same causing a rapid increase in ventricular pressure
- Pressure rises above the pressure in the aorta/pulmonary valve causing aortic/pulmonary valves to open
What is phase 3 of the cardiac cycle?
As aortic valves open, the pressure in the ventricles and aorta rise and this is followed by a fall in ventricular volume
- Decrease in ventricular pressure becomes less rapid
- 50ml blood remains in the ventricles
When is maximal outflow velocity reached in the cardiac cycle?
Early in Phase 3 (ejection)
Maximal aortic and pulmonary artery pressures are also achieved
Are their any sounds in phase 3 of the cardiac cycle?
No because during ejection the opening of healthy valves are silent
When do the AV valves open in the cardiac cycle?
First part of phase 1
What causes the second heart sound?
Intraventricular pressures fall causing the aortic and pulmonic valves close abruptly
What causes the dichotic notch in the aortic and pulmonary artery pressure tracings?
When the aortic and pulmonary valves close it cases small back flow of blood into the ventricles
What occurs in phase 4 of the cardiac cycle?
Isovolumetric relaxation
- Blood flow across aortic/pulmonary valve becomes very slow so blood starts to flow backwards causing the aortic/pulmonary valve to close and blood continues o move forwards (dicrotic notch)
- Both valves are closed so pressure falls and the volume stays the same
What is lusitropy?
The rate of relaxation of the muscle fibres - rate of pressure decline in ventricles is determined by this
What is responsible for regulating lusitropy?
The sarcoplasmic reticulum
- responsible for re sequestering calcium following contraction
Why do the volumes of blood in the ventricles not change in isovolumetric relaxation of the heart?
Because all the valves close
- Volume doesn’t change but pressure decreases
What is the end systolic volume?
The volume of blood left in the ventricles after systole
- usually around 50ml
What volumes in the cardiac cycle represents the stroke volume?
The difference between the end diastolic volume and the end systolic volume
- Usually around 70ml
Why is there blood left in the ventricles?
So when start exercising, the cardiac output can increase immediately
Why does the left atrial pressure continue to rise after systole?
Because of venous return from the lungs
- The peak at the end of the left atrial pressure line is termed v-wave (just before mitral valve open)
What occurs in the start of phase 1 of the cardiac cycle?
- When ventricular pressure falls below that in the atrium the AV valves opens causing rapid ventricular filling
- Ventricular pressure continues to fall in this phase as its still undergoing relaxation
What is the ‘third heart sound’ and when is it audible?
During rapid filling and it may represent the tensing of the chordate tendinae
- low pitched so is best heard using the bell of a stethoscope
Why does the rate of filling fall during late diastole?
As the ventricles fill, they become less complaint and the intraventricular pressures rise
- reduces pressure gradient across AV valves so slows filling
How much of ventricle filing occurs passively?
90%
- 90% of the filling occurs before atrial contraction
Give some examples of asynchrony in the heart?
- Right atria contracts before left
- Left ventricle before right
- Right ventricular ejection before left
What should the heart rate of newborn babies be?
70-190 bpm
What should the heart rate of children be?
70-130bpm
What should the heart rate of adults be?
60-100bpm
What should the heart rate of athletes be?
40-60bpm
How are action potentials transmitted in the myocardium?
T -tubules and intercalated discs rapidly transmit action potentials in the myocardium
Electrical excitation - muscle contraction
What is the sarcolemma?
Myocyte plasma membrane
How are transverse tubules formed?
Formed by thousands of invaginations and inward foldings of sarcolemma forming transverse tubules
What is the role of the transverse tubules in the sarcolemma?
Allows the action potential to stimulate all parts, deep into myocyte simultaneously
- Faster rate of contraction
What is the sarcoplasmic reticulum?
Fluid filled membranous sac surrounding each myofibril
- Ca2+ store
In a relaxed muscle (myocardium) what are the concentrations of Ca2+ in the sarcoplasmic reticulum?
Sarcoplasmic [Ca2+] is low = 0.1 micro molar
Ca2+ pumps moved Ca2+ from sarcoplasm to sarcoplasmic reticulum = [10 micro molar]
What is the role of calsequestrin in the relaxed muscle?
Present in sarcoplasmic reticulum
- Binds ro Ca2+ to lower the [Ca2+] in sarcoplasmic reticulum so their is greater gradient and the pumps can work more efficiently
What is the role of the tropomyosin in a relaxed muscle?
It obscures the myosin/actin binding site preventing the myosin head from sticking to the actin molecule
Outline myocardium contraction
- Action potential propagates along transverse tubules
- Activate Ca2+ channels - Ca2+ diffuses out of SR into sarcoplasm
- Binds to troponin
- Conformational change in troponin/tropomysoin complex exposed myosin/actin binding site
- Myosin sticks to binding site
- ATP causes crossbruge cycling
- Muscle shortens
What is the relationship between muscle tension, number of crossbridges and sarcomere length?
Muscle tension should be proportional to no of crossbridges
Number of cross bridges proportional to sarcomere length
Why does short and long sarcomeres generate less muscle tension?
Short
- Overlapping thin filaments
Long
- Reduced areas for crossbridge formation
So there is an optimum sarcomere length
