PBL 4 - control of cardiac contractility Flashcards
what are the contractile/working cells of the heart?
cardiomyocytes
what is the role of cardiomyocytes?
to contract in unison in order to provide effective pump action to ensure adequate blood perfusion of the organs and tissues
what is the approx size of cardiomyocytes?
approx 100um x 20um — make up the bulk of the volume of the heart but constitute to only 30-40% of the total cell number
how to cardiomyocytes attach to each other?
attach end-to-end via intercalated discs
label this diagram of gap junctions
what do gap junctions do?
transmit ionic currents from one cell to the next
what is each gap junction made up of?
6 connexin subunits which form a hollow tube known as the connexon
the connexon tube spans the 2-4nm intercellular gap, enabling the myocardium to what?
to act as an electrically continuous sheet and all the myocytes to be activated simultaneously
what are desmosomes?
- ‘glue’ cells together
- specialized adhesive protein complexes that localize to intercellular junctions and are responsible for maintaining the mechanical integrity of tissues
describe the structure of desmosomes
- glycoproteins called cadherins span the 25nm gap between the cell membranes
- desmin forms the intermediate filaments
label this diagram
what is the sarcolemma?
membrane surrounding the cardiomyocyte
what structures does the sarcolemma also dip into?
T-tubules
what provides a ready supply of ATP to sustain contraction?
mitochondria
name 2 contractile proteins
- actin
- myosin
what is the name of the essential contractile unit of a cardiomyocyte?
sarcomere
what are sarcomeres made up of?
actin and myosin
how many sarcomeres roughly are there end-to-end in a cardiomyocyte?
around 50
what are Z lines attached to?
the thin filaments = actin
what do the thin filaments form a sandwich with?
myosin thick filaments
label this sarcomere
what is the A band generated by?
myosin thick filaments
what is the I band mainly composed of?
actin thin filaments
what are T-tubules?
= transverse tubules
- invaginations of the cell membrane which run into the interior of the cell
what do t-tubules do and promote?
- transmit the electrical stimulus rapidly into the interior of the cell
- promote the synchronous activation of the whole depth of the cell, despite the fact the signal to contract is relayed across the external membrane
in what stage of a contraction do calcium levels peak?
peak in systole, then come back down to baseline in diastole
what is the trigger for contraction?
a rise in intracellular (cytosolic) Ca++ in the cardiomyocyte
what is meant by the term excitation-contraction coupling?
the Ca++ dependent pathway via which electrical activation of the myocyte induces contraction
Ca++ intracellular levels at rest (diastole) vs in contraction (systole)
at rest: 100nM
in contraction: 1uM = MUCH HIGHER
what is an action potential (AP)?
the transient depolarisation of a cell as a result of ion channel activity
the relationship between AP and contraction — explain this diagram (1-5)
- voltage-gated Na+ channels open
- Na+ inflow depolarises the membrane and triggers the opening of more Na+ channels — creates a +ve feedback cycle and a rapidly rising membrane voltage
- Na+ channels close when the cell depolarises, and the voltage peaks at nearly +30mV
- Ca++ entering through slow calcium channels (L-type) prolongs depolarisation of membrane, creating a plateau — plateau falls slightly because of some K+ leakage, but most K+ channels remain closed until end of plateau
- Ca++ channels close and Ca++ is transported out of cell. K+ channels open and rapid K+ outflow returns membrane to its resting potential
when the AP is triggered and Ca++ enters the cell, what then happens to induce a contraction?
- Ryanodine receptors open = calcium induced calcium release — calcium can flood out of the sarcoplasmic reticulum, causing this rise in intracellular calcium levels (that we can measure with the calcium transient)
- calcium then binds to the contractile machinery and we get contraction of the heart
where are RyRs located?
on the sarcoplasmic reticulum membrane
what needs to occur between filaments in order for a contraction to happen?
cross bridges need to form between filaments
what 3 things is the thin filament composed of?
- actin
- tropomyosin
- troponin complex — made up of 3 cardiac specific proteins = cTnT, cTnC, cTnI (cardiac troponin)
what is the thick filament composed of?
- myosin
- hinged stalk
- globular head
what happens when calcium binds to cTnC?
it induces a rearrangement in the troponin-tropomyosin complex
what is the effect of the rearranged of the troponin-tropomysoin complex, leading to contraction?
movement of tropomysoin exposes a myosin binding site on actin, allowing the globular head of the myosin to bind to it, resulting in cross-bridge formation and shortening of the sarcomere —> CONTRACTION
what does the binding of calcium to cardiac troponin c regulate?
the contractile state of the cardiomyocyte
for relaxation to occur what do we need to happen?
calcium levels to come back down to baseline
where does the majority if the Ca++ need to re-enter?
the sarcoplasmic reticulum
what does Ca++ enter the SR through?
a protein called the sarcoplasmic ATPase (SERCA)
what regulates the action of sarcoplasmic ATPase (SERCA)?
an additional protein called phospholamban
where else does Ca++ get transported into and why?
into mitochondria as Ca++ is very important for mitochondrial function
what 2 ways is the equivalent of the Ca++ that entered the cell through the LTCC removed?
- either via the sodium calcium exchange (swaps calcium for sodium)
- or it goes out throguh the plasma membrane calcium ATPase (PMCA)
what would the relationship between Ca++, contraction and AP look like on a graph?
DIASTOLE: explain phase 1 and phases 5-7
phase 1:
- atrial depolarisation — P wave
- both atria contract — ventricles full
phases 5-7:
- ventricles are relaxed
- mitral and tricuspid valves open
- blood flows passively from atria into ventricles
what is LVEDV roughly in an adult heart?
120ml
in what stage of the cardiac cycle do the ventricles contain the full amount of blood?
end of diastole
SYSTOLE: explain phase 2 and phases 3-4
phase 2:
- AV valves close
- ventricles contract, pressure increases, volume unchanged = isovolumetric contraction
- ventricular depolarisation = QRS complex
phases 3-4:
- outflow valves open
- blood ejected into aorta and pulmonary artery
- volume decreases = LVESV
what is LVESV in an adult heart?
50ml
what is it called when there is no change in volume of blood as all of the valves are shut?
isovolumetric contraction
what ion channel is responsible for the plateau phase of the ventricular AP? why is the plateau relatively stable?
= L-type Ca++ channel
- the LTCC is an inward current, so depolarises the membrane in competition with the repolarising K+ channels (outward currents), therefore creating a plateau where the MP is relatively stable
describe what is happening with the cardiac valves at points A, B, C, D
A = mitral valve closes — LVEDV B = aortic valve opens C = aortic valve closes — LVESV D = mitral valve opens
