Cardiac Output Flashcards
What is [Ca2+]i?
intracellular Calcium
What is Ca2+ signal?
• Ca2+ signal is when the cell is stimulated to release calcium ions from intracellular stores, and/or when calcium enters the cell through plasma membrane ion channels.
When does calcium signalling and cell relaxation occur in action potential?
- Ca2+ signal and cell shortening occurs during depolarisation ‘plateau’ phase of action potential – when ICa is generated.
- Cell relaxation occurs during repolarisation of action potential – when Ca2+ signal is reduced.
How does electrical excitability contract cardiac myocytes?
- Contraction is determined by increase in [Ca2+]i
- Higher increases in Ca2+ leads to increased force of contraction.
- Intracellular Ca2+ levels increase tenfolds
- And so, cell shortening is proportional to the amount of calcium ions.
How does the cell control the level of calcium very accurately?
1) By the plateau phase
- During plateau phase, the VGCC in the cell membrane, due to depolarisation.
- They don’t all open at once, they open slowly forming a plateau.
- Intracellular calcium levels rise, as calcium rushes in.
2) By the Ryanodine receptors (RyR) on the sarcoplasmic reticulum.
- The RyR bind to calcium, so when the intracellular levels of calcium rise, then they bind to these receptors.
- This causes more calcium to be released by Calcium Induced Calcium Release (CICR).
- The calcium causes muscle contraction.
In what ways does the intracellular levels of calcium rise?
- T-tubules (invaginations that get closer to the conrtactile fibres and SR) - Voltage gated calcium channels (VGCC) - Sarcoplasmic reticulum (stores Ca2+) - Ryanodine receptor (RyR) (intracellular Ca2+ channel)
• The T-tubules and everything else in the cell being close to each other means that the amount of calcium needed to raise the local concentration is really small.
- Action potential (Na+ ions) depolarises T-tubules and activates VGCCs causing Ca2+ influx
- Ca2+ binds to RyR on SR – close association with T-tubules
- Release of Ca2+ from SR – CICR
- Ca2+ to troponin, displacement of tropomyosin/troponin complex, exposing active sites on actin
Subunits of troponin and what they do?
• The three troponin regulatory subunits:
- Troponin T (TnT) – binds to tropomyosin
- Troponin I (TnI) – binds to actin filaments
- Troponin C (TnC) – binds Ca2+
- Binding of Ca2+to TnC leads to conformation changes of tropomyosin and exposure of actin binding site.
- TnI and TnT are released into the blood stream when the heart dies. – They are important blood plasma markers for cardiac cell death e.g. Following MI
How is there a decrease in [Ca2+]i and relaxation?
- Action potential repolarisation (K+ ions), repolarises T-tubules – closure of VGCCs, and decrease in Ca2+influx.
- No Ca2+influx, no CICR.
- Extrusion (ejection) of Ca2+from cell (30%) – by Na+/ Ca2+exchanger (NCX).
- Ca2+uptake into SR via SR membrane Ca2+ATPase (SERCA, 70%) - Ca2+in SR for next contraction, even relaxation requires energy (ATP).
- Uptake of Ca2+in mitochondria.
What is inotropy?
contractility
How do drugs increase contractility of the heart?
They increase [Ca2+]i by the following mechanisms:
1. Increasing VGCC activity (Sym. Mimetic)
2. Reducing Ca2+ extrusion (force out) (cardiac glycosides)
• These are positive inotropes
• Increase energy/strength of contraction
How does blood flow to the heart muscles?
• When the heart is contracting, the blood flow to the myocardium stops. Only when the heart is relaxed, there is blood flow to the heart muscles.
How does the sympathetic nervous system act to increase contractility?
- NA binds to the B1-adrenoceptors, on the contractile cells of the heart, the atrial and ventricular cells.
- The GS, subunit is coupled to adenylate cyclase, which converts ATP to cAMP.
- This activates PKA, which then goes to phosphorylate VGCC
- There’s an increase in Ca2+ influx, which increases [Ca2+]i
- There’s an increase in CICR, which also increases [Ca2+]i.
- Increases contractility.
What can increase in 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 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 (to allow oxygen to flow to the heart muscle).
What is Digoxin and what does it do?
- A poisonous compound found in foxglove that increases contractility by reducing Ca2+ extrusion.
- Sometimes used for heart failure - but has difficult side effects so not used so much.
- Mechanism:
1. Digoxin inhibits Na+/K+ ATPase
2. Build-up of [Na+]i
3. Less Ca2+ extrusion by Na/Ca exchanger (3Na in, 1Ca out)
4. More Ca2+ uptake into stores and greater CICR.
Other inotropic agents, besides Digoxin, and how do they work?
• Dobutamine and dopamine are 1-adrenoceptor stimulants – may be used in acute heart failure.
• Glucagon – acts at G protein coupled receptor, stimulates Gs pathways, increases cAMP and PKA activity. Used in patients with acute heart failure, who are taking β-blockers.
• Amrinone – a phosphodiesterase.
– Type III phosphodiesterase (PDE3) is a heart specific enzyme.
– PDE converts cAMP into AMP, reducing cAMP and decreasing PKA activity
– reduces contractility.
- PDE inhibition leads to a build up of cAMP, that activates PKA to phosphorylate VGCCs and increase Ca2+ influx. Only used in severe cases e.g. those waiting for heart transplants.
