Cardiac Contraction Flashcards
What are the effects of positive inotropic agents?
Increase myocardial contractility by increasing intracellular [Ca2+]
What are dopamine and dobutamine usually used for?
Acute heart failure
Outline a possible mechanism of action for dopamine
- stimulate β-adrenoreceptors on the heart
- weak stimulation of other adrenoreceptors found in body - so main target is heart
- similar action to noradrenaline
When is glucagon used clinically?
- Treat acute heart failure
- Glucagon is used if patient uses beta blockers
Outline a mechanism of action for glucagon
- acts on the heart
- stimulates Gαs-linked GPCRs ∴increased conversion of ATP to cAMP ∴ increased activation of PKA
What is the purpose of PDE3?
TYPE 3 PHOSPHODIESTERASE
- Converts cAMP to ATP ∴ reduced concentration of cAMP ∴ reduced activation of PKA ∴ reduced contractility
Outline the mechanism of action of Amrinone
- Inhibits PDE3
- Prevents reduction in cAMP concentration ∴ increased activation of PKA ∴ greater phosphorylation of calcium ion channels ∴ greater contractility
What are cardiac glycosides - give an example.
- Increase output force of contraction of heart whilst decreasing rate of contraction through inhibition of the sodium-potassium ATPase exchanger
- Example - digoxin
Outline the importance of the sodium-potassium ATPase exchanger.
- Draws on energy from ATP hydrolysis
- For every ATP molecule consumed, 3 sodium ions are exported and 2 potassium ions are imported (maintains sodium ion gradient)
How does the sodium-calcium ion exchanger use the sodium ion gradient?
- Gradient is used to remove calcium ions from inside the cell
Given that digoxin inhibits the sodium-potassium ATPase exchanger, suggest how the sodium-calcium exchanger is affected by digoxin.
Increased intracellular [Na+] ∴ reduced gradient and therefore reduced entry of sodium ions through sodium-calcium ion exchanger
How are the calcium ion concentrations affected by digoxin?
- Reduced influx of sodium ions through sodium-calcium ion exchanger
- Increased intracellular [Ca2+] ∴ increased cardiac contraction
- Increased [Ca2+] within SR stores ∴ greater CICR ∴ greater force of contraction
Where are the β-adrenergic receptors found?
- Contractile cells of the heart
Briefly outline the structure of the β-adrenergic receptors.
- Made up of a single protein
- 7 transmembrane domains
- Linked to a Gαs subunit
Outline the mechanism of action of a beta adrenergic receptor
- Gαs subunit binds to and stimulates adenylate cyclase
- Increased conversion of ATP to cAMP
- Increased activation of PKA ∴ calcium ion channels are phosphorylated
- Increased intracellular [Ca2+] ∴ greater CICR ∴ greater binding to troponin C
- Greater actin-myosin interactions ∴ greater pacemaker potentials - increased ionotropy and contractility
How does sympathetic stimulation influence the activity of voltage-gated calcium ion channels?
- Increased activity ∴ increased calcium ion influx ∴ increased intracellular [Ca2+]
- Greater amplitude in plateau phase
- Greater depolarisation ∴ greater contraction
How does sympathetic stimulation influence sarcoplasmic reticulum Ca2+-ATPase activity?
- Increased activity
- Increased uptake of calcium ions into SR stores ∴ faster decrease in calcium ion concentration ∴ faster relaxation
How does sympathetic stimulation influence potassium ion channel activity?
- PKA causes these channels to open
- Faster repolarisation ∴ shorter but faster action potentials but with greater amplitudes in given time∴ greater heart rate
How does sympathetic stimulation influence diastolic time?
- Time stays constant
- Still needed for filling of chambers with heart and coronary perfusion
Name two ways in which pharmaceuticals can influence cardiac output
- Increase in activity of voltage-gated calcium ion channels ∴ increase intracellular [Ca2+] e.g noradrenaline
- Reduced expulsion of calcium from cytoplasm ∴ high intracellular [Ca2+] is maintained for longer e.g cardiac glycosides
What is the typical result of increasing [Ca2+]?
- Harder/faster contraction
- Greater cardiac output
What are the typical effects of calcium blockers and beta blockers?
- Reduced intracellular [Ca2+]
- Slower contraction
- Reduced cardiac output
RELAXATION OF CARDIAC MUSCLE - What occurs to the voltage-gated sodium and potassium ion channels?
- Voltage-gated sodium ion channels close
- Voltage-gated potassium ion channels open
- Repolarisation occurs
RELAXATION OF CARDIAC MUSCLE - What occurs after repolarisation of the action potential?
- Repolarisation of the T-tubules
- Closure of the voltage-gated calcium ion channels ∴ reduced influx of calcium ions
- No CICR from the SR
RELAXATION OF CARDIAC MUSCLE - How does the muscle cells respond to the high calcium ion concentration in the cell?
- Sodium-calcium exchanger removes calcium ions from the cell in exchange for sodium ions
- Most calcium ions are taken back up into the SR using the sarcoplasmic Ca2+ ATPase (requiring energy)
- Some calcium ions are taken up by the mitochondria
Define myocardium
The muscles found within the central layer of the walls of the heart
What specialised cells is the myocardium made up of?
Cardiomyocytes
Outline the difference between inotropy and Starling’s Law.
Starling’s Law is intrinsic - inotropy is extrinsic
- Starling’s Law is linked to an increase in volume due to stretch ∴ not linked to a rise in [Ca2+]
What does a typical Starling curve tell about filling pressure.
Filling pressure on x-axis
- As pressure increases so does the cardiac output
- Greater initial stretch ∴ greater force of contraction up to a certain point - beyond this point, plateaus
How does the use of a positive inotropic agent influence a Starling curve?
- Curve shifted upwards so Starling’s law still applies
- Force of contraction increases
Outline the first step of cardiac contraction.
- Action potential initiated at SAN and passed through adjacent cardiomyocytes through gap junctions
- Activates VGCCs in the T-tubules causing Ca2+ influx into the cardiomyocyte
- Calcium ions bind to troponin-C in the sarcomere
- Binding causes conformation of the tropomyosin complex ∴ actin binding sites are exposed
Outline the second and third steps of cardiac contraction
- Myosin in high energy form has ADP+phosphate
- Binds to exposed actin binding site, causing cross bridge to be formed ∴ phosphate released
- Myosin changes conformation and releases ADP ∴ actin filaments pulled towards centre of sarcomere (i.e powerstroke) . Myosin left in low energy configuration
Outline the fourth and fifth steps of cardiac contraction
- Myosin remains bound to actin until binding of ATP causes release from actin
- ATP hydrolysed to ADP and inorganic phosphate - myosin brought back to high energy form. Head is ‘cocked’ - prepared for another power stroke
- Cycle repeats along as calcium ions are present and actin binding sites remain exposed
Outline the final step of cardiac contraction
- Intracellular Ca2+ removed from SR actively ∴ decrease in [Ca2+]
- Troponin complex brought back into inhibiting position ∴ myosin can no longer bind
- Actin filaments return to original position ∴ muscle relaxes
What does troponin regulate?
Conformation of tropomyosin
What are the three subunits that troponin is made up of?
Troponin T
Troponin I
Troponin C
What does Troponin T bind to?
Tropomyosin
What does Troponin I bind to?
Actin filaments
What does Troponin C bind to?
Calcium ions
Describe the original conformation of tropomyosin (i.e when no calcium ions bound to troponin C)?
- Troponin I brought to active site and binds to actin filaments
- Prevents binding of myosin to actin
What is the clinical significance of the isoforms of Troponin I and Troponin T?
- Released into blood following damage to myocardium e.g following myocardial infarction
- Used to diagnose MI/ differentiate it from angina
What is cardiac contraction dependent on?
Increase in intracellular [Ca2+]
What are the striations in cardiac muscle a result of?
Z-lines
What do Z-lines mark?
Junction of actin filaments in adjacent sarcomeres
What does the relative movement of actin and myosin filaments cause?
- Z-lines brought closer together
- Muscle fibres shortened during contraction
What does calcium ions activate in smooth muscle?
Myosin light chain kinase (NOT TROPONIN)
What is the sarcoplasmic reticulum?
Membrane bound structure in muscle cells that stores calcium ions
What is the T-tubule system?
Invaginations in the sarcolemma - pass deep into the cardiac muscle cells
How do action potentials cause local rising in intracellular [Ca2+] through VGCCs?
- Wave of depolarisation - during action potentials - depolarises T-tubules ∴ activates VGCCs causing calcium influx
How do action potentials cause local rising in intracellular [Ca2+] through ryanodine receptors?
- Some calcium ions activate ryanodine receptors found in close proximity to ion channels
- Causes intracellular calcium release from SR.
- Local [Ca2+] rises ∴ CICR occurs
Why are the T-tubules and RyRs found near the sarcomeres?
Allows coordinated link between electrical activity and contraction
Outline how cardiac action potentials spread from cell to cell
Passes through gap junction-rich intercalated discs
What does the passage through intercalated discs allow the action potential to do?
Induce depolarisation in adjacent cells
- Allows spread of wave of depolarisation across the heart
What ion type facilitate the spreading of cardiac action potentials?
Na+
Outline a potential diagram fora cardiac action potential
SEE SLIDES
Outline what occurs during Phase 0 of the cardiac action potential
- Initial depolarisation triggers opening of sodium ion channels ∴ influx of sodium ions
- Membrane potential becomes more positive
Outline what occurs during Phase 1 of the cardiac action potential
- VGCCs open ∴ influx of calcium ions
- Initial dépolarisation due to action of sodium-potassium exchanger
Outline what occurs during Phase 2 of the cardiac action potential
- Plateau phase - calcium influx and CICR from intracellular stores ∴ increase in intracellular [Ca2+]
- Force of contraction will be proportional to intracellular [Ca2+]
Outline what occurs during Phase 3 of the cardiac action potential
- Repolarisation - voltage gated potassium ion channels open and VGCCs close ∴ muscle relaxation
- Membrane potential becomes less positive ∴ reaches stable resting potential
TRUE or FALSE - Calcium rise is part of an all or nothing response during contraction
WRONG
- Contraction is concentration-dependent
- Depending on how high [Ca2+] is, there can be greater forces of contraction
What is the normal cytosolic calcium concentration during resting phase?
0.1 μM
During normal contraction, what is the usual calcium concentration?
1 μM
During strong exercise/fight or flight responses, what is the usual calcium concentration?
10 μM
What do the intercalated discs contain?
Gap junctions
What is the purpose of gap junctions during contraction?
Allows wave of depolarisation to spread from one cell to next
What are the myofibrils made up of?
Sarcomeres
How do the myofibrils cause contraction?
They shorten
How do sarcomeres cause contraction?
Relative movement of actin and myosin filaments towards each other
