Ischaemia - Na+/Ca2+ in Cardiac Health Disease Flashcards
In which circumstances can ischaemia occur in?
- Open heart surgery
- Coronary artery occlusion (blockage)
- Cardiac transplantation
- Angina
What is the process in which cardiac myocytes contract?
- Na+ enters the cell via Na+ channels to depolarise the cell
- At -40mV, Ca2+ enters via L-type channels
- These Ca2+ ions bind to ryanodine receptors, which stimulates more Ca2+ release from the sarcoplasmic reticulum
- Ca2+ floods into cytosol & binds to contractile units
- The cardiac myocyte then contracts
- Ca2+ is then removed via Ca2+/ATPase & Na+/Ca2+ exchanger (NCX pump)
What is the ratio of Na+ & K+?
3Na+ OUT : 2K+ IN
Can Ca2+ also be stored in the mitochondrial reservoir?
Yes.
How are Ca2+ levels restored in the cell?
- By re-uptake into the SR
- Via the Ca2+ATPase pump
- NCX exchanger in the forward mode (decreasing Ca2+ entry & lowering contractility)
What is the Nernst equation used for?
It is used to predict the membrane potential using the conc. of K+ in and outside of the cell, as well as in different temperatures.
What is the resting membrane potential of a cardiac myocyte?
-90mV
What are the different sub-units of the Na+/K+ATPase pump?
3alpha and 2beta subunits
What is the beta subunit of the Na+/K+ATPase pump responsible for?
It modulates channel gatings, Na+ amplitude and pharmacological properties.
What is PLM & what does it do?
(Un)phosphorylated phospholemmon.
It inhibits the hydrolysis of ATP, so ions cannot move against their conc. gradient.
PLM is then phosphorylated by PKA/PKC, so this inhibition does not occur.
What causes Long QT syndrome?
Na+ channel mutations, which increases the duration of the action potential
What is the non-inactivating steady state window current?
It is responsible for the fast Na+ current during the start of an action potential, also called phase 0.
What happens in ischaemia, on a cellular level?
Cells metabolise fatty acids & generate acylcarnitine.
pH of cells during ischaemia become acidic, so NHE (Na+/H+ exchanger) is activated
Activation of the slow inactivating Na+ window current allows Na+ to increase inside the cell during ischaemia
NCX works in reverse mode, increasing the conc. of Ca2+ which can form insoluble Ca2+ phosphate & become very dangerous.
Activity of Na+/K+ATPase decreases due to less ATP
What is the function of the NHE1 (Na+/H+) pump?
It normally transports Na+ into the cell, and H+ out of the cell.
It uses the energy from the Na+ current/gradient as its driving force and is stimulated when the cytosol of the cell becomes acidic
It is also involved in osmolarity.
How many domains and pores are in the NCX (Na+/Ca2+) exchanger pump?
There are 9 transmembrane domains.
It also contains a long lipophilic group which is phosphorylated by PKA/PKC
The pores are S1-S6 which are responsible for voltage sensoring (S1-S4), and selectivity filters (S5-S6)
What are the 4 methods to measure Na+ inside the cell?
- Radioactive Na+
- Na+ selective micro-electrodes
- Na+ NMR
- Fluorescent dyes
What contributes to Na+ influx inside a cell?
- Na+ channels (Na+/K+ATPase)
- Na+/Ca2+ exchanger (NCX)
- Na+/H+ exchanger (NHE)
- Na+/HCO3- symport
- Na+/K+/2Cl- co transporter
- 2Na+/Mg2+ exchanger
Which pumps are responsible for the influx and efflux of Na+ ?
Influx: NCX (Na+/Ca2+)
Efflux: Na+/K+ ATPase pump
What happens during reperfusion of Na+?
This is the restoration of blood flow to the affected area.
No further Na+ increase inside cells.
Na+/K+ATPase pumps are restored and so are ATP levels.
pH also restored as NHE exchanger allows extracellular acidosis to be removed.
NCX pump works in forward mode to restore Na+ and Ca2+ levels.
Ca2+ levels increase during reperfusion.
What are the consequences of reperfusion?
Ca2+ overload, which can cause inflammation, activate proteases and myocardial infarction.
Mitochondrial Ca2+ also increases, which can disrupt ion regulation.
