Ionic currents Flashcards
How can we assess the rate of different parts of the heart?
Make a ligature between 2 sections
What part of the heart initiates the heart beat?
SA Node, in the right atrium
What are the 3 internodal tracts?
They are the paths by which AP propagates in right atrium from SA node to the AV node
- Anterior tract
- Middle tract
- Posterior tract
How does the contraction from SA node propagates to the left atrium?
Anterior tract gives rise to trapezoid shaped bundle of fibres, goes through interatrial sulcus from right to left atrium called Bachmann’s bundle
What is the order of propagation after the AV node?
- Bundle of His
- 2 bundle branches
- Purkinje fibers
What are the different parts of the SA node?
- Leading pacemaker site
- P cells (primary pacemaker cells)
- Crystal terminalis = muscle in myocardium of RA, extends between SVC and IVC
- Transitional cells = transmit electrical impulse from SA node → right atrium
*Conduction slower in the leading pacemake site and accelerates as we get farther
What are the types of connective cells in the SA node, in the atrium and in ventricles?
SA node → Cx40 and Cx45
Atrium and ventricles → Cx43
*higher # = better coupled, more conductive
What is the name of the connective tissue separating the right atrium and right ventricle?
Tendon of Todaro (not conducting)
What is the triangle of Koch?
Tendon of Todar + Tricuspid annulus + coronary sinus (CS)
Region wherethe AV node is
What is the approximated duration of an AP in the heart vs in muscle tissues?
heart ~ 100ms
muscles ~ 1ms
Which tissues have fast vs slow type action potentials?
Fast: Atrium muscle, Purkinje fibers, Ventricular muscle
Slow: SA node, AV node
What are the different phases of the cardiac action potential?
0 - Upstroke (Greater upstroke = greater conduction)
1 - Early repolarization
2 - Plateau
3 - Repolarization
4 - Resting potential
How is phase 4 of the heart action potential called and characterised in the SA node?
diastollic depolarization: potential goes from maxiaml diastollic potential → threhold potential
How long is approximately the Absolute Refreactory Period (ARP) and Aelative Refractory Period (RRP) for an atrial AP?
ARP ~ 200 ms
RRP ~ 70 ms
How are the cardiac muscle (CM) AP different from the skeletal muscle (SM) AP?
- Long APD in CM prevents them from being tetanized
- CM contraction controlled by APD vs SM force regulated by recruitment
- CM Ca influx → Ca release vs SM depolarization → contraction
What are the intracellular and extracellular concentrations of ions in the heart ?
Na+ extra = 140 mM, intra = 14 mM
K+ extra = 4 mM, intra = 140 mM
Ca++ extra = 2.5, intra = 0.0001
What is the Nernst equation?
E = -61.5 log ( [Conc. i]/[Conc o] )
How does extracellular K+ affect fast type ventricular AP?
- Depolarization of resting potential
- Decrease AP upstroke velocity, faster repolarization
What is the relationship between External [K+] and Vm?
At higher external [K+], it get closer to NERNST prediction of K+ equilibrium
What is the inward rectifier current? (I k1)
Channel: Kir2.1-2.3
Gene: KCNJ2
Contributes to the membrane potential (at rest) and late phase of repolarisation up to resting potential
What are the I k1 physiological blockers?
Polyamines: Spermine and Spermidine
What is the Kir channel structure?
N-terminus - TM1 - H5 - TM2 - C-terminus
How does channel conductance of different ions change during a fast type cardiac AP?
K+ conductance: ↓ upstroke, 2 small ↑ plateau, high at rest
Na+ conductance: low at rest, spikes at upstroke and goes back to low directly after (very quick and steep strike)
Ca+ conductance: ↑ slowly during upstroke and goes down gradually to low at rest
What is the channel responsible for Na current during fast type AP?
Channel: Nav1.5
Gene: SCN5A
3 states: opens during upstroke, inactivates very quickly, repolarization = removal from inactivation, at rest = closed
What is the effect of a mutation in the SCN5A gene?
Reduced I na inactivation → increase APD → Long QT Syndrome 3 (QT interval)
*Na current is sustained bc channels are not inactivated
What is the effect of an increase in extracellular K+ on the sodium channels?
↑ extracellular K+ → ↑ Vm → inactivation of Na channels → reduction of I Na → decrease in AP upstroke velocity
How long does it take for an Na channel to get removed from inactivation?
~ 100 ms, during repolarization
What are the names of the channels responsible for late and early Na current?
LATE → Plateau phase
Channel: Nav 1.5 (Burst mode and Late scattered mode)
reduced by low does of TTX (1-25 nM)
blocked by low does of ranolazine (6 uM)
EARLY → Upstroke
Nav 1.5 (Transient Mode)
blocked by high dose of TTX (1 - 10 uM)
blocked by high does fo ranolazine (300 uM)
Also is neural type Na v 1.x (1, 2, 3, 4, 6, 8)
What is the I na Window current?
It is a little bump current at the end of repolarization (phase 3)
Caused by the overlap between inactivation of Na channels and the Na activation curve (Channels are activating and inactivating at the same time)
What will be responsible for upstroke of AP if TTX blocks Na currents?
Calcium current → slow upstroke
What drug blocks calcium channels?
nifepidine
What is L-type current responsible for in fast type AP? (Channel, Gene)
Channel: Cav1.2
Gene: CACNA1C
*Same closed/activation/inactivation as Na channels
Responsible for Plateau and repolarizing phase
↑ I CaL → ↑ APD → Long QT Syndrome 8, Timothy Syndrome
What is the link between conductance curves and AP section for which the specific ion current is responsible?
Responsible for the phase of AP that corresponds to when the conductance is higher
When do Calcium channels inactivate?
They inactivate at more depolarized/later than Na channels
What are the 2 delayed rectifiers K+ potassium Currents/Channels/Genes present in AP repolarization?
Current: I Ks (earlier)
Channel: Kv7.1 → KvLQT1 when mutation
Gene: KCNQ1/KCNE1
Current: I Kr (later phase of repolarization)
Channel: Kv11.1
Gene: KCNH2 → (hERG)
What would be the effect on a fast type AP of a decrease in I Kr and I Ks ?
↓ Ikr → ↑ APD = LQTS2 (affects plateau phase)
↓ Iks → ↑ APD = LQTS1 (affects later phase of repolarization)
How do the channels responsible for the slow delayed rectifier K+ current (I ks) work?
2 state model: C ↔ O
Stay open as long as the membrane is depolarized → creates an outward current that helps with repolarization → deactivated when goes back to more negative potentials
*outwardly rectifier current, the more depolarized the membrane is, then bigger the current is
Reponsible for 1st increase inconductance of K+ during plateau phase
How do the channels responsible for the rapid delayed rectifier K+ current (I kr) work?
3 state model: C ↔ O ↔ I
C ↔ O : activation and deactivation (SLOW)
O ↔ I: inactivation and removale of inactivation (RAPID, C-type inactivation)
*Has to go through Open all the time, different parts of the channel responsible for both switches
Responsible for final repolarization to membrane potential, last increase of K+ conductance to resting high level
What is the effect of hERG PAS (domain) mutant defect?
- Increased internalization rate
- Decreased recycling
- Increased lysosomal localization (degradation)
*Less ion channels for I kr current to pass?
What is the K+ transient outward current (I to)?
Has much more effect on rats as they have faster HR, not much on human
Review L2-p45
What are the 2 main ion exchange mechanisms in the cells that ensure stable ion concentrations?
*What drug affects them?
Na-K pump (3:3) → Brings Na outside, K+ inside
Ca 2+ / Na+ exchange (2:3) → Brings Na outside, Ca2+ outside
Digitalis → block Na/K pump → more intracellular Na+ →competes with Ca2+ for CaNa exchange → more intacellular Ca++ → increase in force of contraction
Which current are responsible for slow type action potential in the SA node?
Ik = delayed rectifier K+ currents
I caL = L-type calcium currents
I f = pacemaker current (~ -20mV equilibrium)
I background (~ -40 mV equilibrium)
How do Na blocking drugs affect early Ina?
Blocked by high does of TTX (1-10 uM)
Blocked by high dose of ranolazine (300 uM)
How does Na blocking drug affect late Ina?
Reduced by low does of TTX (1-25 nM)
Blocked by low does ranolazine (6 uM)
What are the differences between ion channels Kir, Kv, Nav1.5?
Kir = N-term-TM1-H5-TM2-C-term
Kv = N-term-TM1-TM5-H5-TM6-C-term (4 Kv together)
Nav1.5 = N-term-TM1-TM5-H5-TM6-TM1…..4x…TM6-C-term (1 protein with 4 domains)
What happens to the SA node AP if you block Ca current?
If you block Ikr?
If you block If?
Ica → Stops beating completely
I kr → stops beating at more depolarized potential (can’t repolarizes)
If → slow down the beat rate (takes more time to depolarize back to threshold)
What is Ivabradine?
I f specific blocking drug → slows beating rate
Explain the calcium clock and the membrane clock.
Calcium clock → Spontenous local Ca release from SR → larg Ca release from SR → Ca refill
Membrane Clock → slow type AP
Link between them: Spontaneous local Ca release → Diastolic I ncx activation → T-type calcium → L-Type calcium → depolarization → Calcium influx calcium release (large release of Ca from the SR in the Ca clock)
How can we change the beating rate / frequency of the slow type AP?
- Change the slope of the pacemaker potential (I f intensity to bring current back up to threshold)
- Change the maximum diastolic potential (equilibriums/how much If activates at more negative potentials)
- Change AP threshold
*All make slower cycles
