Cardiac contraction Flashcards
Describe how the rise in intracellular [Ca2+] is central to contraction
0: Na+ channels are opened allowing Na+ to enter and depolarize the cell
1: Ca2+ channels are quite slow to open, here the cell slightly polarizes itself
2: Plateau phase whereby there is an influx of Ca2+ and Ca+ induced Ca+ release (CICR). The force of contraction is proportional to the [Ca2+]i. This is when the muscle contracts.
3: Ca2+ channels close and K+ channels open fully, allowing K+ to leave and repolarise the cell: here muscle relaxation occurs
4: Stable phase. The Na+/K+ pump: 3 x Na+ in and 2 x K+ out
Duration of action potential
200-500 ms
What is the amount of Calcium in the cell proportional to?
How hard the muscle contracts
Diastolic [Ca2+]
0.1 uM
Normal systole [Ca2+]i may rise
1 uM
Maximum systole [Ca2+] may rise
10 uM
What is the amount of Calcium in a cell proportional to
How hard the muscle contracts
How does electrical excitability contract cardiac myocytes
- Electrical excitability stimulated VGCCs to cause a Ca2+ influx (The VGCCs are opened when voltage reaches a certain level)
- Calcium rushes in, which increases intracellular [Ca2+]
- Ca+ binds to ryanodine receptors on the sarcoplasmic reticulum
- Calcium stores in the sarcoplasmic reticulum are released
- Therefore calcium stimulates its own release in the cell: Calcium Induced Calcium Release
Higher increases in Ca2+ leads to
Increased force of contraction
By how many uM do intracellular Ca2+ levels rise during contraction of cardiac myocytes?
from 0.1 uM to about 10uM
Describe how depolarisation can lead to contraction of the cardiac myocyte
- Action potential (Na+ ions) depolarizes T-tubules and activates VGCCs causing Ca2+ influx (when +30mV is reached)
- Ca2+ binds to ryanodine receptors located on the sarcoplasmic reticulum: close association with T-tubules
- Release of Ca2+ from the sarcoplasmic reticulum leads to Calcium Induced Calcium Release
- Ca2+ binds to troponin, displacement of he tropomyosin/troponin complex, which exposes active sites on the actin
- Myosin thick filament heads bind to active sites
- Myosin head ATPase activity releases energy (ATP to ADP) slides the filaments
What are T-tubules?
Invaginations of the muscle cell membrane (sarcolemma) that penetrate into the centre of cardiac muscle cells
What is the Sarcoplasmic reticulum?
Membrane bound structure within muscle cells similar to endoplasmic reticulum in other cells and stores Ca2+
What is the Ryanodine receptor?
Intracellular Ca2+ channel
Describe how rise in intracellular [Ca2+] causes actin-myosin interactions
- Binding of Ca2+ changes conformation of tropomyosin to expose binding site on actin
- The myosin head binds to the actin forming a cross bridge
- During the power stroke the myosin head bends as the ADP and phosphate are released
- A new molecule of ATP attaches to the myosin head, causing it to detach from the actin
- ATP hydrolyses to ADP and phosphate, which returns the myosin to the cocked position ready to bind the actin
What does a greater rise in Ca2+ lead to?
More sites exposed therefore more cross bridges and greater contractility
What is the role of troponin?
It regulates the conformation of tropomyosin
What is troponin composed of?
3 regulatory subunits
What is the role of Troponin T (TnT) subunit?
binds to tropomyosin
What is the role of Troponin I (TnI) subunit?
binds to actin filaments
What is the role of Troponin C (TnC) subunit?
Binds Ca2+
This binding of Ca2+ leads to conformation changes of tropomyosin and exposure of actin binding sites
How can troponin subunits be useful diagnostically if you have a heart attack?
Components of Troponin I and Troponin T can be released into the bloodstream. They are important blood plasma markers for cardiac cell death, e.g. following Myocardial Infarction
Describe how decrease in intracellular [Ca2+] leads to relaxation
- An action potential repolarisation occurs by the influx of K+ ions, which repolarises T-tubules, leading to the closure of VGCCs, and a decrease of Ca2+ influx.
- With no Ca2+ influx, there is no CICR.
- There is the extrusion of Ca2+ from the cell (30%) by Na+/Ca2+ exchanger (NCX)
- There is also Ca2+ uptake into sarcoplasmic reticulum via the Sarcoendoplasmic Reticulum Ca2+ ATPase (SERCA, 70%) on the SR membrane, this is responsible for retrieving Ca2+ in the SR for next contraction (this requires energy in the form of ATP).
- Lastly, there is also uptake of Ca2+ into the mitochondria.
What to Starling’s curves represent?
Ventricular function
What are the effects of keeping the pressure/volume the same?
- Increased contractility (inotropic effect)
- Extrinsic control due to rise in intraceullular [Ca2+]
What are the effects of increasing the pressure/volume?
Instrinsic stretch (Starling's law) When the muscle is stretched, force of the contraction is harder: more space for actin binding sites to be interacted with Calcium
Describe the multiple effects on the heart of sympathetic stimulation:
- There is an increased force of contraction, due to the Ca2+ influx (+ve inotropy)
- There is also an increased heart rate and conduction (+ve chronotropy, +ve dromotropy)
- The relaxation period stays relatively similar, which is important as we need the heart to relax so that the cardiac circulation can occur
- This means that we must not leave too much Ca2+ in the cell after contraction
Describe how B1-adrenoreceptors induce increased contractility
- B1-adrenoreceptors are GPCRs
- noradrenaline activates the G alpha
- This activates adenylate cyclase: removes the phosphates from ATP and makes cAMP
- cAMP activates protein kinase A: adds phosphate to the VGCC: increasing activity and making it easy to open
- Ca2+ influx
- Increase in Calcium Induced Calcium Release
- Ca2+ interacts with actin/myosin
- Therefore increased contractility
What does increasing pKA lead to?
- Increased Ca2+ channel so higher Ca2+ levels and - greater contraction
- Increased K+ channel opening so faster repolarisation and shorter action potential: leads to a faster heart rate
- Increased SR Ca2+ ATPase, so uptake of Ca2+ into storage by SR allowing faster relaxation
- Overall stronger faster contractions but same diastolic time to allow for filling with blood and coronary perfusion
Why are cardiac glyocosides called inotropes?
They have +ve inotropic effect on the hear
What is an example of a cardiac glycoside?
Digoxin
What are the uses of Digoxin?
- Increases the contractility of the heart
- Used for chronic heart failure
- However, it is not used as much now, due to its side effects that are difficult to manage
Mechanism of Digoxin action
- It inhibits Na+/K+ ATPase
- This leads to a build up of intracellular Na+
- This then leads to less Ca2+ extrusion via the Na+/Ca2+ exchanger
- This means that there is more Ca2+ uptake into the stores, and thus there is greater CICR
Use of the ionotropic agents Dobutamine and Dopamine
b1-adrenoreceptor stimulants, which may be used in acute heart failure
Use of the ionotropic agent Glucagon
acts as a GPCR, stimulates the Gs pathway, increases cAMP and PKA activity
* Used in patients with acute heart failure who are taking B-blockers
Use of the ionotropic agent Amrione
a phosphodiesterase inhibitor (so preventing the inactivation of cAMP)
