Cardiac action potential in conduction cells

• SA node: normal pacemaker, initiates each heartbeat
• AV node: delays the impulse before it enters ventricles
• His bundle, bundle branches, Purkinje fibers: rapidly transmit the impulse through ventricles

1. Slow-response action potential: SA and AV nodal cells
   This is usually what is meant by the action potential of pacemaker or nodal conduction cells.
2. Fast-response action potential: His-Purkinje cells
   It resembles the ventricular muscle-cell action potential, but Purkinje cells can also show slow spontaneous phase-4 depolarization.

---

1. Introduction: what is an action potential?

• At a negative voltage, the inside of the cell is more negative than the outside.
• Depolarization means the interior becomes less negative, then positive.
• Repolarization means the interior returns toward negativity.
• Hyperpolarization means it becomes more negative than its usual level.

---

2. Why nodal cells are special

• do not have a stable resting membrane potential
• have a maximum negative voltage of approximately -60 mV
• slowly depolarize during diastole
• use mainly Ca²⁺ influx, not fast Na⁺ influx, for the phase-0 upstroke
• do not have clear phases 1 and 2

Phase 4 → Phase 0 → Phase 3 → repeat

---

3. Diagram: SA nodal cell action potential

Membrane
potential
(mV)

 +10 |                         /\
   0 |                        /  \
 -10 |                       /    \
 -20 |                      /      \
 -30 |                     /        \
 -40 |--------------------|          \        Threshold
 -50 |                  /              \
 -60 |______/-----------                  \____
          ↑        ↑                         ↑
       Maximum   Phase 0                  Phase 3
       diastolic depolarization        repolarization
       potential
          \_______________________________/
                    Phase 4
          spontaneous diastolic depolarization
                 or pacemaker potential

             Time →

The phases and their common names

---

4. Phase 4: pacemaker potential

Other names

• Spontaneous diastolic depolarization
• Prepotential
• Pacemaker potential
• Automatic depolarization

Phase 4

 -60 mV                                     -40 mV
   │                                           │
   │          gradual depolarization           │
   └───────────────╱╱╱╱╱╱╱╱╱╱╱╱╱──────────────┘
       If current       ICa,T          ICa,L begins

Ionic basis of phase 4

A. Funny current, If

• Despite opening when the cell is very negative, If produces a net inward positive current.
• It is predominantly inward Na⁺ movement, with some K⁺ contribution.
• Na⁺ entering the cell makes the interior progressively more positive.

B. Decreased K⁺ efflux

• K⁺ channels progressively close
• less K⁺ leaves the cell
• the outward positive current decreases
• the membrane voltage gradually becomes less negative

C. T-type Ca²⁺ channels

• Ca²⁺ moves into the cell.
• This adds to depolarization.
• These channels help the membrane reach threshold.

D. L-type Ca²⁺ channels begin to open near threshold

Net charge movement during phase 4

Outside                     Membrane                     Inside

Na⁺  ───────────────────────►                         Positive charge enters
Ca²⁺ ───────────────────────►                         Positive charge enters
K⁺   ◄─────────────── less than before                Less positive charge exits

Result: inside becomes gradually less negative.

Importance of phase-4 slope

• Steeper phase-4 slope: threshold reached sooner, heart rate rises.
• Flatter phase-4 slope: threshold reached later, heart rate falls.

---

5. Phase 0: depolarization or upstroke

Common names

• Upstroke
• Depolarization
• Phase-0 depolarization

Phase 0

-40 mV                   0 to +10 mV
   │                         │
   └───────────────────────╱
                     Ca²⁺ enters
                   through ICa,L

Main ionic movement

Ca²⁺: extracellular fluid ───► nodal cell

Important contrast with ventricular muscle and Purkinje cells

• the nodal phase-0 upstroke is less steep
• nodal conduction is slow
• AV nodal delay occurs

---

6. Phase 3: repolarization

Common names

• Final repolarization
• Rapid repolarization
• Repolarizing phase

1. L-type Ca²⁺ channels inactivate, so inward positive charge falls.
2. K⁺ channels open.
3. K⁺ leaves the cell.
4. The interior becomes negative again.

Phase 3

 +10 mV
   │\
   │ \
   │  \
   │   \___________________ -60 mV
   │
   └── K⁺ exits cell
       Ca²⁺ entry stops

Ionic movement

Inside                           Membrane                  Outside

K⁺  ───────────────────────────────►                    Positive charge leaves
Ca²⁺ entry decreases or stops

Result: the cell interior becomes negative again.

---

7. Complete ionic-current graph

Phase:       4                   0                  3
             │                   │                  │
Voltage:    -60 mV ──► -40 mV ──► +5 mV ──► -60 mV

If:          ↑ early             ↓                  off
             Na⁺ inward

ICa,T:       ↑ late phase 4      ↓                  off
             Ca²⁺ inward

ICa,L:       begins near          ↑↑↑                closes
             threshold            Ca²⁺ inward

IK:          progressively        low initially      ↑↑↑
             declining                                K⁺ outward

---

8. Stages of depolarization and repolarization

Depolarization stages

1. Slow diastolic depolarization

• Corresponds to phase 4
• If current begins
• K⁺ efflux decreases
• T-type Ca²⁺ influx assists
• Cell moves from around -60 mV toward threshold

2. Threshold

• Approximately -40 mV
• L-type Ca²⁺ channels activate

3. Rapid depolarization

• Corresponds to phase 0
• Ca²⁺ influx causes the upstroke
• The cell interior becomes positive

Repolarization stage

Final repolarization

• Corresponds to phase 3
• L-type Ca²⁺ channels inactivate
• K⁺ exits
• Membrane returns toward approximately -60 mV
• A new pacemaker cycle begins

---

9. Why phases 1 and 2 are absent in nodal cells

• Phase 1 is initial repolarization, largely due to transient outward K⁺ current.
• Phase 2 is the plateau, produced by balance between Ca²⁺ entry and K⁺ exit.

Nodal cell:          4 → 0 → 3

Fast-response cell:  4 → 0 → 1 → 2 → 3

---

10. Comparison: nodal versus Purkinje action potentials

---

11. Autonomic effects

Sympathetic stimulation

• increases cAMP
• increases If
• increases Ca²⁺ current
• steepens phase 4
• threshold is reached earlier
• increases heart rate: positive chronotropy
• increases AV nodal conduction: positive dromotropy

Steeper phase 4 = more action potentials per minute

Parasympathetic stimulation

• decreases cAMP
• decreases If and L-type Ca²⁺ current
• increases K⁺ conductance through acetylcholine-sensitive K⁺ channels
• makes the cell more negative
• flattens phase 4
• slows SA-node firing and AV-nodal conduction

Flatter phase 4 + more negative maximum diastolic potential
= slower heart rate

---

12. High-yield clinical correlations

• Ivabradine blocks the funny current, If. It slows phase-4 depolarization and lowers heart rate.
• Beta blockers reduce sympathetic stimulation, flatten phase 4, and slow heart rate and AV nodal conduction.
• Verapamil and diltiazem block L-type Ca²⁺ channels. They slow nodal phase 0 and AV nodal conduction.
• Adenosine increases K⁺ conductance and suppresses Ca²⁺-dependent AV nodal conduction. It can terminate many AV-node-dependent supraventricular tachycardias.
• Hyperkalemia makes membrane potential less negative and can impair excitability and conduction.

---

One-line summary

SA and AV nodal cells spontaneously depolarize during phase 4 because of If, reduced K⁺ efflux, and Ca²⁺ entry; phase 0 is caused by L-type Ca²⁺ influx; phase 3 is caused by K⁺ efflux. They have phases 4, 0, and 3 only.

Simplified diagrams

NODAL CELL: slow-response AP

mV
 +10 |                    /\
 -40 |-------------------/  \---------------- threshold
 -60 |______/────────────      \______
          Phase 4       0         3
       pacemaker      Ca²⁺ in    K⁺ out
       If, Ca²⁺ in

VENTRICULAR CELL: fast-response AP

mV
 +20 |              /──────────\
   0 |             /            \
 -90 |____________/              \__________
              0    1     2        3     4
            Na⁺ in  K⁺   Ca²⁺ in    K⁺ out
                         plateau

High-yield memory aid

• Nodal cells:
  Funny Na⁺ in during phase 4 → Ca²⁺ in during phase 0 → K⁺ out during phase 3.
• Ventricular cells:
  Na⁺ in during phase 0 → brief K⁺ out during phase 1 → Ca²⁺ in creates phase-2 plateau → K⁺ out during phase 3.

• Nodal cells, SA and AV node: phase 4 is spontaneous pacemaker depolarization, phase 0 depends on L-type Ca²⁺ influx, and phase 3 is due to K⁺ efflux. Phases 1 and 2 are absent.
• Ventricular myocytes: phase 0 is fast Na⁺ influx; phase 1 is brief K⁺ efflux; phase 2 is the Ca²⁺-dependent plateau; and phase 3 is K⁺-mediated repolarization.