1. Cardiac action potential
Dr Shreetal Rajan Nair

2. Introduction Ions Channels/Pores/Carriers & Pumps
Channels- Aqueous channel/ Conformational change/ Action usually regulated/ Open to both environment/ Large number of molecules diffuse across
Pores- Continuously open to both environment/ No conformational changes/ Always open.
Carriers & Pumps- Not open simultaneously to both environments/ Binding sites/ Limited number of molecules diffuse across
Carriers & Pumps maintain the concentration gradients
Channels- contain an aqueous channel. Hydrophilic molecules of the right size and shape can diffuse through this channel. In many cases, whether a channel is open or closed can be regulated; they can be turned on and off. Channel is opened with a conformational switch, it is open to both environment simultaneously (extracellular and intracellular); channels are either in open state or closed state.
Pores-Pores are continuously open to these both environment, because they do not undergo conformational changes. They are always open.
Carriers & Pumps-Pathway in a carrier protein is not open smiltaneously to the both environment. Either its inner gate is open, or outer gate is open, or both gates are closed. Carrier has binding sites, but porins and channel proteins have not. When a channel is opened, thousands to millions of ions can pass through the membrane in one time, but only one or a small amount of molecules can pass through a carrier molecule. A carrier molecule can be a pump (active transport); cotransporter or antiporter
Biological membranes leak {since semipermeable}– without the constant addition of energy, the energy stored in concentration gradients across a membrane would dissipate over time, Carriers & Pumps maintain the concentration gradients

3. What makes ions to move across?
Steady state is reached when the magnitude of the chemical and electric gradients are equal

4. What makes ions to move across?
Nernst equation
EK =RT/ZF ln [K]2 / [K]1
Where,
T is temperature [370 C]
R is the gas constant
F is the Faraday constant
Z is the valence of ion [1]
[K]2 and [K]1 are the final concentrations of potassium in compartments 2 and 1,
respectively. [150mmol, 5 mmol]
EK is the equilibrium potential for potassium [-90mV]
At equilibrium potential net diffusion is 0
All ions try to reach equilibrium i.e., tries to drive the membrane potential towards its equilibrium potential
At RMP, membrane is permeable mostly to potassium , hence RMP is close to the EK

6. Membrane Action Potential
2 factors
Electromechanical gradient
Open Channels
MAP
Sum of AP generated by different channels [amplitude & direction]
Number of open channels

7. Action potential - definition
Action potential is the net product of mutiple distinctive time and voltage dependent ionic currents.
Complex interaction between depolarising inward currents and hyperpolarising outward currents

8. ACTION POTENTIAL Excitable tissues : Neurons Muscles
Action potential duration (APD)
Neurons and skeletal muscle cells (1–5 ms)
Cardiac myocytes ( ms)

10. Some terms
Strength of stimulus required to elicit a response or to produce an action potential.
Hyperpolarisation decreases excitability
Small reductions in RMP increase excitability
When RMP is less than the threshold potential the fibre becomes inexcitable
Threshold potential- potential at which net inward membrane current becomes large enough to initiate autoregenerative depolarization

11. Sites of action potential genesis in heart
Nodal tissue – AV node and SA node
His - Purkinje fibres -
Atrial muscle
Ventricular muscle

12. Refractory period Refractory Period-
- The interval of time during which the cell cannot be re-excited [Absolute RP]
- Relative RP
Effective refractory period : minimum interval between 2 propagating AP
- Supranormal Excitability

13. Cardiac AP
Pacemaker potential (slow channel) vs myocyte potential ( fast channel )
Pacemaker potential occurs in cells capable of producing spontaneous impulses – 1%
Myocyte potential occurs in all other cells – contractile cells – 99%

14. How a cardiac myocyte is stimulated ?
Spontaneous impulse generation
- automatic ( pacemaker) cells
Spread of depolarising current from neighbouring cells ( cardiac syncytium )

15. Ion channels in the heart
Sodium channels – voltage gated and ligand gated
Potassium channels - voltage gated, inward rectifier and background channels
Calcium channels – transient and long lasting

16. Non pacemaker cell – fast channel AP

17. Phase 4 Represents resting membrane potential
membrane potential when the cell is not stimulated.
this phase will be a horizontal line
caused by the difference in ionic concentrations and conductances across the cell membrane
normal resting membrane potential in the ventricular myocardium is about -85 to -95 mV

18. Phase 4
IK1 Current- Membrane stabilizing current [inward rectification
Others-TWIK-1/2 (KCNK1/6), TASK-1 (KCNK3), and TRAAK (KCNK4)
Na/K Pump- 3/2 outward; At fast HR RMP more negative
Low [K]o leads to less IK1 activity, more excitability

20. Action potential of a ventricular myocyte and how is it different from action potential of atrial myocyte
The membrane of the contractile cells remain essentially at rest at about -90mv until excited by electrical activity propagated by the pacemaker cells.

21. Phase 0 Rapid depolarisation phase
Opening of the fast Na+ channels causing a rapid increase in the membrane conductance to Na+
Rate of membrane depolarisation corresponds to conduction velocity

22. Na+ channels
3 States
Open
Closed
Inactivated
Depends on the RMP

23. Gating & Inactivation Closing and opening of channels
Voltage, Metabolic, Stretch

24. Gating & Inactivation m gate h gate
The N-terminal or “ball and chain” mechanism of Na channel inactivation

25. video

26. RMP and Na channels
The slope of phase 0 represents the maximum rate of potential change and is known as dV/dtmax
 If the membrane potential is at its baseline (about -85 mV) all fast Na+channels are closed and excitation will open all of them
When membrane potential is less negative some of the fast Na+ channels will be in an inactivated state insensitive to opening
lesser response to excitation of the cell membrane and a lower Vmax

27. When the resting membrane potential becomes too positive the cell may not be excitable and conduction through the heart may be delayed

28. SODIUM CHANNEL BLOCKERS
IA – decrease conduction velocity and increase refractoriness
I B – only increase refractoriness
I C - decrease only conduction velocity

29. Phase 1
Phase 1 of the myocyte action potential occurs with the inactivation of the fast Na+ channels
The transient net outward current causing the small downward deflection of the action potential is due to the movement of K+ and Cl- ions, carried by the Ito1 and Ito2 currents respectively

30. Ito currents determine the amplitude and the timing of Ca2+ release from the SR.
In advanced HF Ito currents are downregulated and indirectly affect the Ca currents in phase 2
Ito currents express differentially at different parts of heart
Maximum in RV, basal region and
epicardium
Ito current – ACE inhibitors

31. Phase 2
"plateau" phase of the cardiac action potential (absent in pacemaker cells)
sustained by a balance between inward movement of Ca2+ (ICa) through L-type calcium channels and outward movement of K+ through the slow delayed rectifier potassium channels - IKs

32. Phase 3 L-type Ca2+ channels close
slow delayed rectifier (IKs) K+ channels are still open.
more types of K+ channels open.- Ikr,Ikur,Ik1
the rapid delayed rectifier K+ channels (IKr)
 inwardly rectifying K+ current, IK1
Additional channel in atrial muscle ( I kur )
Vernakalant has action on this channel
RESULT IN REPOLARISATION

33. Potassium channels

34. Source :Zipes textbook of electrophysiology

35. Refractory period - explanation
Absolute refractory period - Sodium channels are in an inactivated state -
Relative refractory period - sufficient number of sodium channels have transitioned back to their resting state – a stronger stimulus can generate AP

36. Refractory period Absolute refractory period
- beginning of phase 0 until nearly the end of phase 2
Relative refractory period
- phase 3 and phase 4
- caused by changes in the state of sodium and potassium channel molecules

37. Afterdepolarisations
Positive potentials that occur during the repolarisation phase of the action potential
Types :
Early – phase 2 and phase 3
Delayed – phase 4
Important in the genesis of arrhythmias

38. Afterdepolarisations

39. Mechanism of arrhythmogenesis in DAD

40. AP in pacemaker cells

41. Action Potential of the pacemaker cells
The pacemaker cells do not have a stable resting membrane potential like the nerve and the skeletal muscles.
Instead they have an unstable membrane potential that starts at – 60mv and slowly drifts upwards towards threshold.
Because the membrane potential never rests at a constant value, it is called a Pacemaker Potential rather than a resting membrane potential.
Phase 1 and 2 typically absent.

42. IONIC BASIS OF ACTION POTENTIAL OF PACEMAKER CELLS
Phase 4: Pacemaker Potential:
Opening of voltage-gated Sodium channels called Funny channels (If or f channels ).
Closure of voltage-gated Potassium channels.
Opening of Voltage-gated Transient-type Calcium (T-type Ca2+ channels) channels .
Phase 0: The Rising Phase or Depolarization:
Opening of Long-lasting voltage-gated Calcium channels (L-type Ca2+ channels).
Large influx of Calcium.
Phase 3: The Falling Phase or Repolarization:
Opening of voltage-gated Potassium channels
Closing of L-type Ca channels.
Potassium Efflux.

43. Phase 4 Diastolic depolarisation
Chronotropism or the rate of heart beat depends on the slope of pacemaker potential
modulation by the autonomic system of the cardiac SAN rate also takes place in this phase
 Sympathetic stimuli induce the acceleration of rate by increasing the slope of the pacemaker phase
Parasympathetic stimuli has opposite effect

44. Regulation by autonomic nervous system
Parasympathetic activation
- c AMP levels decrease and open additional K channels and produce more hyperpolarisation.
- phase 4 takes longer to reach the threshold voltage
Sympathetic activation
- increase c AMP levels and this in turn open calcium channels

45. Autonomic nervous system modulates the frequency of depolarization of pacemaker
Sympathetic stimulation (neurotransmitter = ); binds to b1 receptors on the SA nodal membranes
Parasympathetic stimulation (neurotransmitter = ); binds to muscarinic receptors on nodal membranes; increases conductivity of K+ and decreases conductivity of Ca2+

46. Clinical aspects

49. Summary

50. Refractory period In fast channels ERP/APD < 1 :
Na channels recover in a voltage dependent manner above the threshold potential
In slow channels ERP/APD > 1 :
Ca channels recover only in a time dependent manner progressively after the fiber has fully repolarised

51. CARDIAC AP – types Fast channel AP Slow channel AP Site
Atria , Ventricle, Purkinje fibre
SA node, AV node, around AV ring and coronary sinus opening
Predominant ion in
phase 0
Sodium
Calcium
Activation potential
-60 to -70
-40 to -55
Conduction velocity
m/s
0.01 – 0.1 m/s
ERP- APD relationship
ERP<APD
ERP>APD

52. Summary Potassium ion is the main determinant of RMP
AP - fast channel ( Na mediated ) and slow channel ( Ca mediated )
Phase 0 – sodium
Phase 1 – I to
Phase 2 and 3 – potassium
Pacemaker potential – funny channels

53. Summary

54. Phase 0
Phase 2&3
Phase 2&3
Phase 1
Phase 2&3
Phase 2&3
Phase 2&3
Phase 4