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Transcript of CS 2015 The Cardiac Action Potential Christian Stricker Associate Professor for Systems Physiology...
CS 2015
The Cardiac Action PotentialChristian Stricker
Associate Professor for Systems PhysiologyANUMS/JCSMR - ANU
[email protected] http://stricker.jcsmr.anu.edu.au/Cardiac_Action_Potential.pptx
THE AUSTRALIAN NATIONAL UNIVERSITY
CS 2015
CS 2015
Cardiovascular Part in Block 2• Week 1
1. Cardiac Action Potential
2. Modulation of the Action Potential
3. Basis of the ECG• Week 2
4. Pressures, Flows and Volumes during the Cardiac Cycle- Practical: ECG
5. CO as HR·SV and Introduction to Starling's Law
6. Cardiac Work and Coupling of Venous Return and CO• Week 3
7. Regulation of Blood Pressure.• Week 4
8. Neural and Humoral Regulation of Blood Pressure
9. PV Loops and Principles of Left and Right Heart Failure
10. Vessels of the Systemic Circulation• Week 5
11. Special Circulations (coronary, etc.)– Practical: Cardiovascular Simulations
CS 2015
AimsAt the end of this lecture students should be able to
• identify the cellular specialisations supporting AP spread;
• distinguish the AP phases in cardiac myocytes and ICS;
• describe important in- and outward currents, how they
contribute to cardiac AP and what their properties are;
• outline determinants of the refractory period;
• recognise determinants of AP propagation in the tissue;
• argue why there is a hierarchy of pacemakers;
• explain different AP shapes and repolarisations; and
• point out drugs that target ion channels involved in AP.
CS 2015
Contents• Two types of cells in heart
– Relevant anatomy incl. histological specialisations• Myocytes – coupled via gap junctions forming a functional syncytium
• Cardiac impulse conduction system (ICS)
• Cardiac myocyte– RMP, AP and currents involved
5 phases and determinants, relationship to contraction,
refractory periods, determinants of action potential propagation
• Cardiac ICS– RMP, AP and currents involved in ICS
3 phases and determinants, pacemaker currents incl. If and ICaT
determinants of action potential propagation
• AP and drug targets
CS 2015
Cardiac Specialisations• Cardiac myocytes
– Intercalated discs• Desmosomes
– complexes of cell adhesion proteins
and linking proteins
• Gap junctions: connexins– “electrical syncytium”
• Impulse conduction system (ICS)– Specialised cells expressing
different ion channels and amounts
of contractile protein.• Sinoatrial node (SA)
– Round cells: pacemakers
– Elongated cells: conductors
• Atrioventricular node (AV)
• Purkinje fibres
CS 2015
I. AP in the Cardiac Myocyte
CS 2015
RMP and AP of Cardiac Myocyte• Ventricular myocyte (~80 BPM)
– RMP: ~ -90 mV, ± constant!– AP peak: 20 – 30 mV; amplit.: ~120 mV.– Duration: 300 – 450 ms → 200 x longer than
neuronal AP!– Shape depends on location in heart.
• Net inward currents depolarise.– On: Na, Ca channels (voltage-gated).– Off: Some K channels
• Net outward currents hyperpolarise.– On: various different K channels (voltage-dep., G
protein coupled and ATP gated).– Off: Na, Ca channels
• 5 Phases of AP (0 – 3 ± fixed dur.)0. Fast depolarisation: Na+ “overshoot” – NaV 1.5- Not a “neuronal” Na channel – different properties.
1. Early (partial) repolarisation (fast)
2. Plateau (Ca2+ shoulder)
3. Final repolarisation (slow)
4. RMP restoration: “diastole”, duration variable
Draper & Weidmann (1951), J Physiol 115:74-94
CS 2015
Currents in Different Phases• Phase 0
– Threshold @ -60 – 70 mV (negative!)
– Activation of fast INa; deactivation of IK1
– Overshoot determined by [Na+]
• Phase 1– Inactivation of fast INa (NaV 1.5)
– Activation of K channels: Ito,f&s
– INCX (Na-Ca exchange – early hyperpolarising)
• Phase 2– ICaL (L-type, blocked by nifedipine)
– INCX (Na-Ca exchange – late depolarising)
• Phase 3– Deactivation of ICaL
– Activation of IK (del. rectifier (DR), IKs, IKr)
– Re-activation of INa and ICaL
• Phase 4– Activation of IK1 (inward rectifier, IR)
– Re-establishes “constant” RMP
Mod
ified
from
Rho
ades
& B
ell (
2009
), 3
rd E
d.
CS 2015
Relationship to Contraction
• AP peaks before Ca2+ rise.
• Peak of Ca2+ signal during phase 2.– ICaL.
– INCX (adds to early Ca2+ influx – “reversed”
as Na+↑; later causes Ca2+ efflux).
• Twitch peaks when Ca2+ is already
decaying.– Highly efficient Ca2+ extrusion
mechanisms.
– Excitation-contraction coupling (see next
lecture).
Spurgeon et al. (1990), Am J Physiol 258:H574
CS 2015
Refractory Periods in Myocyte• Absolute refractory period (ARP): Very
few Na+ channels can be reactivated
above Vm > -50 mV (technical term).
• Effective refractory period (ERP): before,
myocytes nearby cannot be physiologi-
cally activated as early current spread is
too small for activation.
• Relative refractory period (RRP): follows
ARP; during this time, no full AP can be
generated (smaller amplitude and slower
rise).
• Full AP generated again after Vm
hyperpolarised to ~ <-70 mV.
Ber
ne &
Lev
y, 2
008
CS 2015
Action Potential Propagation
• Passive spread of AP: “slow” – about 1 m/s
• Depolarisation spreads passively, accelerated by gap
junctions between cells (intercellular current ahead).
• Extracellular current spread (extracell. current back).
• Propagation speed dependent on– Gap junction conductance: the larger – the faster.
– Fibre diameter: the larger – the faster (Ri↓).
Mod
ified
from
Raf
f & L
evitz
ky (
2011
)
CS 2015
II. AP in the Cardiac ICS
CS 2015
RMP and AP in SAN and AVN• Atrial ICS
– (Rabbit heart; ~ 96 BPM).
– RMP: variable, and much more
positive than in myocyte; when all
conductances blocked, ~ -35 mV.
– Slow rising phase: Not INa.
– Peak amplitude: ~20 mV (depends
on location within node; less positive
in centre).
– Duration: 200 – 250 ms.
– Threshold for AP: -50 – -40 mV.
• 3 Phases of AP (0 / 3 ± fixed; 4 var.)
0. Depolarisation (ICaL much
slower)
3. Repolarisation (slow)
4. Variable RMP (linear increase in
time to threshold).
CS 2015
Currents in Pacemaker Cells• Phase 0 (rise)
– Mostly Ca2+ spike.• Amplitude is [Ca2+]-dependent.
• ICaL (L-type) blocked by nifedipine; RMP).
– Not much INa involved (blocked by TTX).
• INa remains inactivated as hyperpolarisation not
sufficiently big and long – it is there…
• Phase 3
– Inactivation of ICa.
– Activation of IK (delayed rectifier, DR).
• Phase 4 (“Pacemaker potential” - PMP)
– Early de-activation of fast IK (del. rectifier).• Turning off an outward is seen as net inward
current.
– Followed by opening of a set of channels
that generate inward currents –
predominantly carried by Na+ (see next).
Kohnhardt et al. (1976), Basic Res Cardiol 71:17
CS 2015
Pacemaker Currents/Potential• = decay of “RMP” until Ca2+ spike.• Mixture of at least three currents:
– If - Current has “funny” properties – largest.• Hyperpolarisation-activated cation current (activated
during late phase 3).– Mixed cation current: largely Na+ inward current →
depolarisation; slow activation / deactivation.
– Erev = -20 – -10 mV.
• Tetrameric channel, gated via cyclic nucleotides (cAMP/cGMP bind to intracellular tail to close channel).
– cA/GMP↑: channel opened and vice versa.– Current modulated fast with cA/GMP↓↑ (see next lecture).
• 4 genes (HCN1 - 4).– In humans, mostly HCN4 – “sick sinus” if “blocked”.– HCN4 viral transfection in dogs can restore “sick sinus” to
normal pacing.
• Blocked by ivabradine – but PMP not fully blocked.
– ICaT – T-type Ca2+ current > -55 mV (late 4).• There is small amount of L-type current present, too.
– INCX – in reverse mode (3 Na+ vs 1 Ca2+) as
[Na+] high due to entry via HCN channels: hyperpolarisation → slows decay.
– Likely other Na+ conductance(s) involved.• IbNa (leak; TRPM4, NaV1.5; see next lecture).
Ber
ne &
Lev
y, 2
008
CS 2015
Hierarchy of Pacemakers• Normally, 3-tiered system for pacing
– SA node: 60 – 100 BPM• Natural rate around 100 BPM
• Slower due to ANS (parasympathetic innervation).
– AV node: 40 – 60 BPM
• Smaller If → slower depolarisation → HR↓.
• Is typically subservient to SA node; takes over if
not paced in time (supraventricular pacing).
• Delay of ~160 ms: gap junction coupling↓ and
small cells (delay line): impulse propagation slow.
– Purkinje cells: 20 – 40 BPM
• Even slower If than AV node; plus
• RMP much more hyperpolarised (-90 mV).– Cells have Na+ current in them (reactivated…).
• Cells with highest AP rate set heart rate as
all other ICS cells are depolarised by them
and functionally rendered “inactive”.
CS 2015
Spread of Excitation
• Atria excited within 80 – 90 ms (right earlier than left).
• First excitation seen with 140 ms delay in top septal areas: AV delay.
• Ventricles fully excited within 50 – 60 ms; right slightly earlier than left.– Compared to atria, speedup due to larger and better coupled Purkinje
fibres generating bigger currents → faster depolarisation wave.
Rho
ades
& B
ell (
2009
), 3
rd E
d.
CS 2015
AP Time-Courses in Heart
• Purkinje cells have longest AP: prevents ventric. arrhythmia.– Longest APs are subendocardial, shortest subepicardial.
• Last ventricular cells to depolarise are the first to repolarise.– Mechanism: ? – gradients of channel expression
Mod
ified
from
Bar
rett
et a
l. (2
010)
, 23rd
Ed.
CS 2015
III. Drug targets in AP
CS 2015
Currents as Therapeutic Targets
• Several currents involved in AP generation are targeted
via drugs used in clinical settings.
• Some drugs used for cardioversion may target several
currents unspecifically.
CS 2015
Take-Home Messages• Gap junctions are instrumental in spreading APs.
• Cardiac myocyte and ICS have different ionic currents.
• AP in myocytes has 5 phases during which specific currents are
activated/inactivated.
• AP propagation speeds up in larger fibres and when gap junction
conductance is large.
• Refractory period is determined by extent of repolarisation (re-
activation of Na+ channels).
• Pacemaker current is largely carried by HCN channels with no
NaV current.
• There is a 3-tiered hierarchy of pacemakers running at different
frequencies: SAN > AVN > Purkinje fibres.
• A multitude of drugs is used that affect AP.
CS 2015
MCQ
Joe Parsons, a 23 year-old very fit medical student participates in
a study by a drug company, which aims to block HCN channels.
Which of the following statements best describes the expected
effect of an HCN block on the heart?
A. Drop in heart rate (bradycardia).
B. Lengthening of the action potential in Purkinje cells.
C. Decreased depolarisation rate in atrio-ventricular cells.
D. Early delayed rectifier activation in sino-atrial node cells.
E. Increased T-type calcium current in sino-atrial node cells.
CS 2015
That’s it folks…
CS 2015
MCQ
Joe Parsons, a 23 year-old very fit medical student participates in
a study by a drug company, which aims to block HCN channels.
Which of the following statements best describes the expected
effect of an HCN block on the heart?
A. Drop in heart rate (bradycardia).
B. Lengthening of the action potential in Purkinje cells.
C. Decreased depolarisation rate in atrio-ventricular cells.
D. Early delayed rectifier activation in sino-atrial node cells.
E. Increased T-type calcium current in sino-atrial node cells.