Cardio Respiratory - Week 2 Cardiac Excitation and Function

Question 1

What is Excitation-contraction coupling (ECC)? (1)

Answer 1

The physiological process of converting an electrical stimulus to a mechanical response

Question 2

Describe the physiological process of Excitation-Contraction Coupling (3)

Answer 2

Action Potential (electrical stimulus) —> Increased Cytosolic Calcium (messenger release) —> Muscle Contraction (mechanical response)

Question 3

Draw and describe the graph for the main events during a cardiac cycle (5)

Answer 3

Look at notes - week 2 cardiorespiratory

Question 4

Changes in the cytoplasmic [Ca2+]i is determined by what? (1)

Answer 4

The electrical activation

Question 5

What is a function of [Ca2+]i? (1)

Answer 5

Force and time course of contraction is a function of [Ca2+]i

Question 6

What are transverse tubules? (2)

Answer 6

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

Question 7

Describe the structure of the sarcoplasmic reticulum (1)

Answer 7

Made up of longitudinal and terminal elements

Question 8

Describe the function of the sarcoplasmic reticulum (1)

Answer 8

The internal store of Ca within the cell are contained within the Sarcoplasmic reticulum

Question 9

Where is the terminal cisternae of the SR located? (1)

Answer 9

Located close to the t-tubules

Question 10

Why is the terminal cisternae important? (1)

Answer 10

Where calcium is released

Question 11

How can structure of the t-tubules vary between different species? (1)

Answer 11

Smaller animals which typically exhibit a higher heart rate have more intricate t-tubules compared to larger animals with a slower heart rate

Question 12

How can T-tubules vary depending on the location of the cell within the heart? (1)

Answer 12

Atrial myocytes which are not required to produce as much force can lack t-tubules

Question 13

Why can atrial myocytes lack t-tubules? (1)

Answer 13

Not required to produce much force

Question 14

SR junctions contain Ca2+ release channels. What are they called? (1)

Answer 14

Ryanodine receptors (RYR)
Also known as foot proteins

Question 15

Which Ca2+ channels are located in the walls of the t-tubule? (1)

Answer 15

L-type Ca2+ channels (DHPR)

Question 16

What junction do the L-type Ca2+ channels and Ryanodine receptors (RYR) form? (1)

Answer 16

DYAD junction

Question 17

Why is the DYAD junction important? (1)

Answer 17

Allow intracellular and extracellular coupling to facilitate event of calcium induced calcium release

Question 18

Describe overview calcium induced calcium release occur and how does this link to excitation contraction coupling (4)

Answer 18

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

Question 19

What is Ca induced Ca release? (1)

Answer 19

Small amount of Calcium entering the cell causes a release of a larger amount of Ca from the intracellular stores

Question 20

What is hierarchical structure of the cardiac muscle (4)

Answer 20

Muscle Fibre
Myofibrils
Sarcomeres
Myofilaments

Question 21

Describe muscle fibres (2)

Answer 21

Individual myocyte (≈25 µm in diameter, ≈100 µm in length).

Question 22

Describe myofibrils (2)

Answer 22

Densely bundled structures which contain sarcomeres repeated in series

Question 23

Describe sarcomeres (2)

Answer 23

The functional contractile unit of muscle (Z disc ↔ Z disc)

Question 24

Describe myofilaments (2)

Answer 24

Protein strands which slide over each other to shorten the sarcomere

Question 25

How is the diffusion distance of Ca minimised in the contractile units? (3)

Answer 25

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

Question 26

Despite the large size of a cell, how does a synchronised contraction of each contractile unit occur? (1)

Answer 26

Due to the diffusion distance of Ca minimised in the contractile units due to placement of T-tubules close to myofibrils

Question 27

Describe the ultrastructure of sarcomeres (4)

Answer 27

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

Question 28

Describe the roles of Titin (2)

Answer 28

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

Question 29

Describe the arrangement of filaments in the sarcomere in a cross-sectional view (3)

Answer 29

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.

Question 30

Describe thin filament structure (5)

Answer 30

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

Question 31

What is an actin tropomyosin filament (2)

Answer 31

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

Question 32

Describe the troponin complex (4)

Answer 32

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)

Question 33

Describe Troponin-C (Tn-C) and its function? (2)

Answer 33

mol. wt, 18,000 Binds Ca2+ ions

Question 34

Describe Troponin-I (Tn-I) and its function? (2)

Answer 34

mol. wt, 25,000 Binds to actin & inhibit the binding of myosin to actin

Question 35

Describe Troponin-T (Tn-T) and its function? (2)

Answer 35

mol. wt. of 42,000 Binds Tropomyosin

Question 36

Describe thick filament structure (5)

Answer 36

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

Question 37

Describe Actin-myosin interaction (2)

Answer 37

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.

Question 38

Describe the Troponin complex in absence of Ca2+ (5)

Answer 38

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.

Question 39

What can't form without Ca2+ (1)

Answer 39

Cross bridges cannot form

Question 40

Describe the Troponin complex in presence of Ca2+ (5)

Answer 40

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

Question 41

Explain the cross-bridge cycle (5)

Answer 41

Look at notes - week 2 cardiorespiratory

Question 42

What needs to happen for relaxation? (1)

Answer 42

Ca2+ must be removed from the cytoplasm by one of three pathways

Question 43

What are the three pathways by which Ca2+ must be removed from the cytoplasm? (3)

Answer 43

Pumped back into the SR (80%) Via the Na+-Ca2+ exchanger (NCX) (18-19%) Via the sarcolemmal Ca2+ ATPase (1-2%)

Question 44

How is a steady state level of Ca2+ in cells maintained? (1)

Answer 44

The amount of Ca2+ that entered the cell during excitation is removed from the cell before the next beat

Question 45

How does NCX remove Ca2+ from the cell? (3)

Answer 45

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.

Question 46

How does sarcolemmal Ca ATPase remove Ca2+ from the cell? (3)

Answer 46

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

Question 47

Compare cardiac and skeletal muscles (6)

Answer 47

Look at notes - week 2 cardiorespiratory

Question 48

What is cardiac output? (1)

Answer 48

The amount of blood pumped by each ventricle of the heart in 1 minute.

Question 49

How to calculate cardiac output? (1)

Answer 49

Heart rate (HR) x Stroke volume (SV)

Question 50

How to calculate SV? (1)

Answer 50

EDV – ESV (EDV: volume of blood in ventricle just before contraction) (ESV: volume of blood left in ventricle after contraction)

Question 51

What is ejection fraction? (1)

Answer 51

SV/EDV

Question 52

Give typical resting values for HR, EDV, ESV (3)

Answer 52

HR, 70 bpm EDV, 120 mL ESV, 45 mL

Question 53

What can CO exceed to during exercise? (1)

Answer 53

25 L/min

Question 54

What are the factors affecting heart rate? (4)

Answer 54

Autonomic innervation Hormones Fitness levels Age

Question 55

What are the factors affecting SV? (7)

Answer 55

Heart size Fitness levels Gender Contractility Duration of contraction Preload (EDV) Afterload (resistance)

Question 56

What are the intrinsic factors affecting regulation of cardiac output? (3)

Answer 56

Preload Afterload Inotropic state (contractility)

Question 57

What are the extrinsic factors affecting regulation of cardiac output? (2)

Answer 57

Neurotransmitters/neural input Hormones

Question 58

What is preload how does it affect CO? (5)

Answer 58

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

Question 59

How is preload linked to cardiac muscle? (2)

Answer 59

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

Question 60

What is the Frank-Starling law? (2)

Answer 60

Relationship between EDV and ESV i.e. as the degree of stretch on the heart increases so does the force of contraction.

Question 61

What is afterload? (6)

Answer 61

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

Question 62

What is inotropic state and contractility? (3)

Answer 62

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+

Question 63

What is positive inotropic influence (or increased contractility)? (1)

Answer 63

Cardiac muscle can generate more tension from an unchanged resting length

Question 64

How does action potential impact inotropic state? (3)

Answer 64

Increase AP plateau length causes increased Ca2+ influx which increases inotropic state

Question 65

How does external ion concentration impact inotropic state? (7)

Answer 65

Increasing external Ca2+ Increases influx Increases inotropic state Lower external Na+ Slows Na+/Ca2+ exchange Ca2+ accumulates inside Increases inotropic state

Question 66

How does force-frequency relationship impact inotropic state? (3)

Answer 66

Increase stimulation frequency of piece of papillary muscle More Ca2+ entry (more APs) Ca2+ accumulation

Question 67

What is an extrinsic mechanism for increasing CO? (1)

Answer 67

Sympathetic Stimulation through sympathetic fibres

Question 68

How do sympathetic fibres increase CO and why is this considered an extrinsic mechanism? (4)

Answer 68

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

Question 69

How does Sympathetic Stimulation Increase the Force of Contraction? (6)

Answer 69

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

Question 70

How does PKA target the L-type calcium channel? (3)

Answer 70

PKA phosphorylates L-type calcium channel Increases L-type calcium channel flux Increased calcium release from SR and therefore increases contraction force

Question 71

How does PKA target the Ryanodine Receptor? (3)

Answer 71

PKA phosphorylates RyR receptors Increases RyR sensitivity to Ca2+ (trigger for release) Increased calcium release from SR and therefore increases contraction force

Question 72

How does PKA target Phospholamban? (6)

Answer 72

PKA phosphorylates phospholamban Removal of inhibition of SERCA Increases calcium uptake in SR Increases Calcium content in SR Increases calcium release Increases contraction force

Question 73

How does PKA target Troponin? (2)

Answer 73

PKA phosphorylates troponin Decreases sensitivity to Ca2+ Quicker relaxation

Question 74

Describe Parasympathetic Stimulation (3)

Answer 74

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

Question 75

How is the heart innervated? (2)

Answer 75

By the two branches of the autonomic nervous system

Question 76

How does the parasympathetic arm (the vagus nerve) innervate the heart? (2)

Answer 76

Innervates atrial muscle and the SA and AV nodes (+ Ventricles)

Question 77

How does the sympathetic arm innervate the heart? (1)

Answer 77

Innervates all parts of the heart.

Question 78

What is tachycardia? (1)

Answer 78

Increased activity in sympathetic NS leads to a faster heart rate - tachycardia

Question 79

What is bradycardia? (1)

Answer 79

Increased activity in parasympathetic NS leads to a slower heart rate – bradycardia

Question 80

Severing autonomic nerves leads to what? (2)

Answer 80

Severing autonomic nerves leads to an increase in heart rate to ~110 bpm (intrinsic rate of SA node)

Question 81

How does exercise affect activity in the Sympathetic NS (3)

Answer 81

When you begin exercising, the sympathetic arm of the ANS is stimulated and norepinephrine is released into the vicinity of the heart cells

Question 82

What happens when norepinephrine is released into the vicinity of the heart cells? (2)

Answer 82

Increases the strength of cardiac contractions The SA node generates action potentials at a higher frequency and so heart rate increases

Question 83

What does a rise in cAMP do? (2)

Answer 83

Rise in cAMP increases If so pacemaker potential rate accelerated

Question 84

What does Reduction in K+ permeability do? (1)

Answer 84

Reduction in K+ permeability so MDP more positive

Question 85

What does increased L-type Ca2+ current do? (3)

Answer 85

Increased L-type Ca2+ current, so upstroke faster - more action potentials per unit time - tachycardia

Question 86

Describe the relationship between the strength of contraction and the action potential (4)

Answer 86

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

Question 87

Describe what happens when there is increased activity in the Parasympathetic NS (4)

Answer 87

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).