Cardiac contraction Flashcards
What is central to contraction?
Rise in concentration of calcium is central to contraction
What is the duration of an action potential?
~200-500ms
Action potential in cardiac muscles?
Na + channels open allowing Na + to enter and depolarise o K + channels open allowing K + to leave Thereby restoring the resting potential
What is force of contraction proportional to and the concentrations of Ca2+?
Force of contraction proportional to [Ca 2+ ]
o Diastolic [Ca 2+ ] ~ 0.1 μM
o Normal systole [Ca 2+ ] may rise ~ 1 μM
o Maximum systole [Ca 2+ ] may rise ~ 10
μm
What is cell shortening usually less than?
Cell shortening usually less than maximum
When does the Ca2+ signal and cell shortening occur?
Ca 2+ signal and cell shortening occur
during depolarisation “plateau” phase
of the action potential
a. When intracellular calcium
is generated
When does cell relaxation occur?
Cell relaxation occurs during
repolarisation of the action potential
a. When the calcium signal is
reduced
What are the intracellular Ca2+ levels during electrical excitability?
Intracellular Ca 2+ levels increase from 0.1 μM to about 10 μM
Process of intracellular rise in Ca2+ concentration
1) Action potential (Na + ions) depolarises T-tubules and activates VDCCs causing a Ca 2+ influx
2) Ca 2+ binds to RyR located on SR – there is a close association with T-tubules
3) There is a release of Ca 2+ from the SR – CICR
4) Ca 2+ to troponin
a. The displacement of tropomyosin/troponin complex, exposing active sites on actin
5) Myosin thick filament heads bind to active sites
6) Myosin head ATPase activity release energy (ATP to ADP)
a. Filaments slide
What does a rise in Ca2+ concentration cause?
Rise in [Ca 2+ ] causes myosin-actin interactions
Actin myosin interaction during contraction
1) Myosin-actin binding sites blocked by troponin-tropomyosin complex (white star)
2) Ca 2+ displaces troponin-tropomyosin so actin-myosin binding
sites are exposed and an actin-myosin cross-bridge is
formed
3) Myosin head flexes to move actin and the Z line
towards the sarcomere centre
What does a greater rise in Ca2+ concentration do?
- Greater rise in [Ca 2+ ]
o More sites exposed
o More cross-bridges
o Greater contractility
How many regulatory sub units is troponin composed of?
Composed of 3 regulatory subunits
What are the three regulatory subunits?
o Troponin T (TnT) – binds to tropomyosin o Troponin I (TnI) – binds to actin filaments o Troponin C (TnC) – binds Ca 2+
What does the binding of Ca2+ to TnC lead to?
Binding of Ca 2+ to TnC leads to conformational changes of
tropomyosin and the exposure of
actin binding sites
Why are TnI and TnT important?
TnI and TnT are important blood plasma markers for cardiac cell death
Process of decrease in Ca2+ concentration and relaxation
1) Action potential repolarisation (K + ions) repolarises T-tubules – closure of VGCCs,
and a decrease of Ca 2+ influx
2) No Ca 2+ influx, no CICR
3) Extrusion of Ca 2+ from cell (30%) – by Na + /Ca 2+ exchanger (NCX)
4) Ca 2+ uptake into SR via SR Ca 2+ ATPase (SERCA, 70%) – Ca 2+ in SR for next
contraction
5) Uptake of Ca 2+ in mitochondria
6) Reduction in [Ca 2+ ], myosin head ATPase activity releases energy (ATP to ADP)
7) Prevention of contraction mechanism – chambers relaxed, and can fill with blood
Ways cardiac contractility is controlled?
In general, these drugs increase [Ca 2+ ]
1) Increasing VGCC activity (sympathetic mimetic)
2) Reducing Ca 2+ extrusion (cardiac glycosides)
- These are positive INOTROPES
o Increase energy/strength of contraction
- Sympathetic nervous system
o Noradrenaline (NA) acts on β 1 – adrenoreceptors to increase contractility
Activation of beta-1 adrenoreceptors and its pathway
Noradrenaline stimulates the GPCR(Beta 1 adrenoreceptor)
cAMP levels increase resulting in an increase in PKA levels
PKA phosphorylates VGCC, increasing its activity
This results in a Ca2+ influx which causes CICR.
Overall concentration of Ca2+ increases
Increase in sliding filament mechanism and ultimately an increase in contractility
What are positive inotropic effects?
Increased contractility of the heart
What are positive chronotropic effects?
Increased heart rate
What are positive dromotropic effects?
Increased conduction through AV node
What are lusitropic effect?
Increased rate of relaxation, K channels & SR Ca 2+ ATPase
What are cardiac glycosides?
Positive inotropic action of the heart and are therefore called inotropes
What is digoxin and what does it do and whats it used for?
Digoxin is a cardiac glycoside.
Digoxin increases contractility by reducing Ca 2+ extrusion
o Used for chronic heart failure
o Not used so much now – difficult side effects
o Useful to understand contractility mechanisms
Mechanism of action of cardiac glycosides
1) Digoxin inhibits Na + /K + ATPase
2) Build up of [Na + ]
3) Less Ca 2+ extrusion by Na/Ca exchanger
4) More Ca 2+ uptake into stores and greater CICR
Dobutamine and dopamine
Inotropic agent
o β 1 – adrenoreceptor stimulants
May be used in acute heart failure
Glucagon(Inotropic agent)
o Acts at GPCR
o Stimulates Gs pathway, increasing cAMP and PKA activity
Used in patients with acute heart failure who are taking β-blockers
Amrinone(Inotropic agent)
o A phosphodiesterase inhibitor
o Type III phosphodiesterase (PDE3) is heart specific
o PDE converts cAMP into AMP
Reducing cAMP and decreasing PKA activity
Reduces contractility
o PDE inhibition leads to a build up of cAMP that activates PKA to phosphorylate
VGCCs
An increase in calcium ions is only used in severe cases
E.g. those waiting for heart transplants
