Cardio Respiratory - Week 2 Cardiac Excitation and Function Flashcards
What is Excitation-contraction coupling (ECC)? (1)
The physiological process of converting an electrical stimulus to a mechanical response
Describe the physiological process of Excitation-Contraction Coupling (3)
Action Potential (electrical stimulus) —> Increased Cytosolic Calcium (messenger release) —> Muscle Contraction (mechanical response)
Draw and describe the graph for the main events during a cardiac cycle (5)
Look at notes - week 2 cardiorespiratory
Changes in the cytoplasmic [Ca2+]i is determined by what? (1)
The electrical activation
What is a function of [Ca2+]i? (1)
Force and time course of contraction is a function of [Ca2+]i
What are transverse tubules? (2)
Extensions of the plasma membrane which invaginate into the centre of cardiac cells (typically around z-discs)
Extracellular fluid can flow freely down these tubules
Describe the structure of the sarcoplasmic reticulum (1)
Made up of longitudinal and terminal elements
Describe the function of the sarcoplasmic reticulum (1)
The internal store of Ca within the cell are contained within the Sarcoplasmic reticulum
Where is the terminal cisternae of the SR located? (1)
Located close to the t-tubules
Why is the terminal cisternae important? (1)
Where calcium is released
How can structure of the t-tubules vary between different species? (1)
Smaller animals which typically exhibit a higher heart rate have more intricate t-tubules compared to larger animals with a slower heart rate
How can T-tubules vary depending on the location of the cell within the heart? (1)
Atrial myocytes which are not required to produce as much force can lack t-tubules
Why can atrial myocytes lack t-tubules? (1)
Not required to produce much force
SR junctions contain Ca2+ release channels. What are they called? (1)
Ryanodine receptors (RYR)
Also known as foot proteins
Which Ca2+ channels are located in the walls of the t-tubule? (1)
L-type Ca2+ channels (DHPR)
What junction do the L-type Ca2+ channels and Ryanodine receptors (RYR) form? (1)
DYAD junction
Why is the DYAD junction important? (1)
Allow intracellular and extracellular coupling to facilitate event of calcium induced calcium release
Describe overview calcium induced calcium release occur and how does this link to excitation contraction coupling (4)
Action potential travels across the surface membrane of ventricular cell and down the T-tubules
This depolarises the T-tubular membrane and result in opening of the L-type Ca2+ channels
Calcium enters intracellular space between the t-tubues and SR, where the Ca2+ release units the (RYRs) are located
Calcium causes Ca to be released through the RYR out of the SR and contributes for the majority of the rise in intracellular calcium concentration
If calcium is released from just one of these units it causes a calcium spark
It is the spatio-temportal summation of these Ca sparks that give rise to the Ca transient activating a uniform and forceful contraction of the cell
Arrangement of RyR2 causes a wave of Ca2+ release from the SR which spreads along the musculature
Increased cytosolic Ca2+ binds to the contractile myofilaments, causing sarcomere shortening and cardiac contraction
What is Ca induced Ca release? (1)
Small amount of Calcium entering the cell causes a release of a larger amount of Ca from the intracellular stores
What is hierarchical structure of the cardiac muscle (4)
Muscle Fibre
Myofibrils
Sarcomeres
Myofilaments
Describe muscle fibres (2)
Individual myocyte (≈25 µm in diameter, ≈100 µm in length).
Describe myofibrils (2)
Densely bundled structures which contain sarcomeres repeated in series
Describe sarcomeres (2)
The functional contractile unit of muscle (Z disc ↔ Z disc)
Describe myofilaments (2)
Protein strands which slide over each other to shorten the sarcomere
How is the diffusion distance of Ca minimised in the contractile units? (3)
T-tubules are usually spaced along the z-lines
This places the Ca release sites intimately around the myofibrils
The maximum diffusion distance to activate myofilaments is ~ 500 nm
Despite the large size of a cell, how does a synchronised contraction of each contractile unit occur? (1)
Due to the diffusion distance of Ca minimised in the contractile units due to placement of T-tubules close to myofibrils
Describe the ultrastructure of sarcomeres (4)
The myofibrils are composed of two sets of interdigitating filaments
Contains A-bands and I-band which contain thick and thin filaments
The A-bands contain thick filaments
Thick filaments are composed mainly of the protein myosin
The I-bands contain thin filaments
The thin filaments are composed primarily of the protein actin
Titin is a filamentous protein spanning the half-sarcomere, with spring-like properties in the I-band region
Describe the roles of Titin (2)
Align the myosin filaments and contribute elasticity to the heart wall
Also thought to play a role in active and passive force regulation in the muscle
Describe the arrangement of filaments in the sarcomere in a cross-sectional view (3)
The thick and thin filaments overlap and interdigitate
Thin filaments attached to Z-disc and arranged in hexagonal array
Myosin filaments organised by M-line- also in a hexagonal arrangement.
Describe thin filament structure (5)
The actin filament has a double stranded rope-like structure
Associated with the actin filament is a long protein called tropomyosin
This protein lies in the groove made by the two strands of the actin filament
Each strand of the actin filament has a repeating structure composed of 7 actin monomers polymerised together and associated with that is one tropomyosin protein unit. This can be know as an actin tropomyosin filament
What is an actin tropomyosin filament (2)
Each strand of the actin filament has a repeating structure composed of 7 actin monomers polymerised together and associated with that is one tropomyosin protein unit
Describe the troponin complex (4)
Every 38.5 nm there is a troponin complex:
Every 38.5 nm there is a troponin complex:
Troponin-C (Tn-C)
Troponin-I (Tn-I)
Troponin T (Tn-T)
Describe Troponin-C (Tn-C) and its function? (2)
mol. wt, 18,000
Binds Ca2+ ions
Describe Troponin-I (Tn-I) and its function? (2)
mol. wt, 25,000
Binds to actin & inhibit the binding of myosin to actin
Describe Troponin-T (Tn-T) and its function? (2)
mol. wt. of 42,000
Binds Tropomyosin
Describe thick filament structure (5)
Mainly composed of Myosin
The head is made up of 2 identical sub-units
The heads of the molecules are known as cross bridges and are the site of ATP hydrolysis and consequent tension generation
Each thick filament is at the centre of a hexagonal array of thin filaments
Describe Actin-myosin interaction (2)
Activation of the heart muscle cells via the action potential is transduced into a rise of Ca2+ in the cytoplasm.
Then Ca2+ binds to troponin-C, which acts as a molecular switch to allow cross bridge cycling to occur.
Describe the Troponin complex in absence of Ca2+ (5)
Tropomyosin (Tm) is bound to the actin filament
Troponin-T (TnT) is bound to tropomyosin and Troponin-I (TnI)
TnI also binds strongly to actin in the absence of Ca2+
Troponin-C (TnC) is bound weakly to TnI
Tn-I binds to actin and covers up the actin-myosin binding site
As a result, the myosin head cannot bind to actin to form acto-myosin.
What can’t form without Ca2+ (1)
Cross bridges cannot form
Describe the Troponin complex in presence of Ca2+ (5)
When the levels Ca2+ rises in the cytoplasm, Calcium binds to the Troponin C and causes TnC to bind strongly to TnI
When there is a strong interaction between Troponin I and Troponin C then Troponin I can no longer bind to actin
This also then follows a cascade of changes in binding, causing a change in the binding of TnI to TnT and subsequent changes in the binding of TnT to tropomyosin and tropomyosin to actin
Explain the cross-bridge cycle (5)
Look at notes - week 2 cardiorespiratory
What needs to happen for relaxation? (1)
Ca2+ must be removed from the cytoplasm by one of three pathways
What are the three pathways by which Ca2+ must be removed from the cytoplasm? (3)
Pumped back into the SR (80%)
Via the Na+-Ca2+ exchanger (NCX) (18-19%)
Via the sarcolemmal Ca2+ ATPase (1-2%)
How is a steady state level of Ca2+ in cells maintained? (1)
The amount of Ca2+ that entered the cell during excitation is removed from the cell before the next beat
How does NCX remove Ca2+ from the cell? (3)
Uses the power of the inwardly directed electro-chemical gradient for Na+ to extrude Ca2+ from the cell against its concentration gradient
3 Na+ ions are required to remove one Ca2+ ion from the cell
Therefore, NCX is electrogenic.
How does sarcolemmal Ca ATPase remove Ca2+ from the cell? (3)
A high affinity pump but has a slow turnover rate compared to its distant cousin in the SR membrane
Relaxation of a single beat using this mechanism alone would take almost 60 seconds
As such, only ~1-2 % of calcium involved in contraction is extruded via this route
Compare cardiac and skeletal muscles (6)
Look at notes - week 2 cardiorespiratory
What is cardiac output? (1)
The amount of blood pumped by each ventricle of the heart in 1 minute.
How to calculate cardiac output? (1)
Heart rate (HR) x Stroke volume (SV)
How to calculate SV? (1)
EDV – ESV
(EDV: volume of blood in ventricle just before contraction)
(ESV: volume of blood left in ventricle after contraction)
What is ejection fraction? (1)
SV/EDV
Give typical resting values for HR, EDV, ESV (3)
HR, 70 bpm
EDV, 120 mL
ESV, 45 mL
What can CO exceed to during exercise? (1)
25 L/min
What are the factors affecting heart rate? (4)
Autonomic innervation
Hormones
Fitness levels
Age
What are the factors affecting SV? (7)
Heart size
Fitness levels
Gender
Contractility
Duration of contraction
Preload (EDV)
Afterload (resistance)
What are the intrinsic factors affecting regulation of cardiac output? (3)
Preload
Afterload
Inotropic state (contractility)
What are the extrinsic factors affecting regulation of cardiac output? (2)
Neurotransmitters/neural input
Hormones
What is preload how does it affect CO? (5)
Degree of filling of a ventricle
EDV determines the preload on the heart, i.e. the volume load on the ventricles before ventricular contraction begins.
Filling pressure (i.e. venous return)
Filling time (note: as heart rate increases, less time is spent in diastole and therefore filling time decreases)
Affects Cardiac Output because:
Preload increases which increases SV which increases CO
How is preload linked to cardiac muscle? (2)
An increase in preload (i.e. increasing the volume of blood in the ventricle) stretches the muscle cells before they contract
Increases the number of cross bridges formed between actin and myosin filaments and increases strength of contraction
What is the Frank-Starling law? (2)
Relationship between EDV and ESV
i.e. as the degree of stretch on the heart increases so does the force of contraction.
What is afterload? (6)
Pressure that needs to be overcome (in arteries) in order to eject blood from the ventricles
Afterload (on the left ventricle) is the diastolic aortic pressure
Left ventricular pressure has to exceed the afterload before any blood can be ejected from the ventricle
If afterload increases, e.g. in patients with high blood pressure, less blood will be ejected from the ventricle, increasing ESV
As a consequence SV and CO will fall at a constant heart rate
As a consequence, the heart muscle hypertrophies and the left ventricular wall of the heart becomes thicker
What is inotropic state and contractility? (3)
Inotropic state - The ionic basis of contraction
Contractility - How well ventricles can contract (i.e. speed, force, duration)
Is related to the degree of activation of the contractile proteins by Ca2+
What is positive inotropic influence (or increased contractility)? (1)
Cardiac muscle can generate more tension from an unchanged resting length
How does action potential impact inotropic state? (3)
Increase AP plateau length causes increased Ca2+ influx which increases inotropic state
How does external ion concentration impact inotropic state? (7)
Increasing external Ca2+
Increases influx
Increases inotropic state
Lower external Na+
Slows Na+/Ca2+ exchange
Ca2+ accumulates inside
Increases inotropic state
How does force-frequency relationship impact inotropic state? (3)
Increase stimulation frequency of piece of papillary muscle
More Ca2+ entry (more APs)
Ca2+ accumulation
What is an extrinsic mechanism for increasing CO? (1)
Sympathetic Stimulation through sympathetic fibres
How do sympathetic fibres increase CO and why is this considered an extrinsic mechanism? (4)
Sympathetic fibres release noradrenaline, increases sympathetic activity of heart, increases force of contraction which increases cardiac output
Considered to be an extrinsic mechanism for increasing CO as it originates outside the heart muscle itself
How does Sympathetic Stimulation Increase the Force of Contraction? (6)
Norepinephrine binds to β1 receptors in membrane causing a conformational change within the receptor
Releases G alpha s protein
The α-subunit of Gs activates Adenylate Cyclase
This increases cAMP production from ATP
This in turn activates protein kinase A (PKA)
PKA phosphorylates protein targets to affect function
How does PKA target the L-type calcium channel? (3)
PKA phosphorylates L-type calcium channel
Increases L-type calcium channel flux
Increased calcium release from SR and therefore increases contraction force
How does PKA target the Ryanodine Receptor? (3)
PKA phosphorylates RyR receptors
Increases RyR sensitivity to Ca2+ (trigger for release)
Increased calcium release from SR and therefore increases contraction force
How does PKA target Phospholamban? (6)
PKA phosphorylates phospholamban
Removal of inhibition of SERCA
Increases calcium uptake in SR
Increases Calcium content in SR
Increases calcium release
Increases contraction force
How does PKA target Troponin? (2)
PKA phosphorylates troponin
Decreases sensitivity to Ca2+
Quicker relaxation
Describe Parasympathetic Stimulation (3)
Ach binds to muscarinic M2 receptors
Activates another G-protein Gi- this has an inhibitory effect on adenylate cyclase
Opposes effects of sympathetic stimulation via this mechanism
How is the heart innervated? (2)
By the two branches of the autonomic nervous system
How does the parasympathetic arm (the vagus nerve) innervate the heart? (2)
Innervates atrial muscle and the SA and AV nodes (+ Ventricles)
How does the sympathetic arm innervate the heart? (1)
Innervates all parts of the heart.
What is tachycardia? (1)
Increased activity in sympathetic NS leads to a faster heart rate - tachycardia
What is bradycardia? (1)
Increased activity in parasympathetic NS leads to a slower heart rate – bradycardia
Severing autonomic nerves leads to what? (2)
Severing autonomic nerves leads to an increase in heart rate to ~110 bpm (intrinsic rate of SA node)
How does exercise affect activity in the Sympathetic NS (3)
When you begin exercising, the sympathetic arm of the ANS is stimulated and norepinephrine is released into the vicinity of the heart cells
What happens when norepinephrine is released into the vicinity of the heart cells? (2)
Increases the strength of cardiac contractions
The SA node generates action potentials at a higher frequency and so heart rate increases
What does a rise in cAMP do? (2)
Rise in cAMP increases If so pacemaker potential rate accelerated
What does Reduction in K+ permeability do? (1)
Reduction in K+ permeability so MDP more positive
What does increased L-type Ca2+ current do? (3)
Increased L-type Ca2+ current, so upstroke faster - more action potentials per unit time - tachycardia
Describe the relationship between the strength of contraction and the action potential (4)
Action potentials are generated more frequently and propagated through the heart more rapidly
Action potentials are shorter in duration
The strength of contraction associated with each action potential is greater
The duration of each contraction is reduced
Describe what happens when there is increased activity in the Parasympathetic NS (4)
Parasympathetic stimulation:
Acetylcholine (ACh)
ACh decreases If (inhibits adenylate cyclase and reduces cAMP)
ACh increases the K+ permeability of the SA node cells (via IK-ACh) which hyperpolarises the MDP
Fewer action potentials per unit time (bradycardia).
