Cardiac Action Potentials

Question 1

Phases of the Pacemaker Cell Action Potential (AP)

Answer 1

• Phase 4: slow, spontaneous depolarization caused by inward pacemaker current (I_f)
  
  • channels that carry the I_f current are activated and open during repolarization phase of previous AP
  • also modulated by voltage-gated Na⁺ channels in the SA node
  • accounts for automaticity of the SA node
• Phase 0: more rapid depolarization
  
  • voltage-gated Ca²⁺ channels open
• Phase 3: repolarization
  
  • voltage-gated Ca²⁺ channels close
  • K⁺ channels open

Question 2

Phases of the Ventricular Myocyte AP

Answer 2

• Phase 0: rapid depolarization
  
  • voltage-gated Na⁺ channels open (Na⁺ in)
• Phase 1: early phase of rapid repolarization
  
  • voltage-gated Na⁺ channels are inactivated (less Na⁺ in) → refractory period of AP (another AP can’t fire)
  • activation of transient K⁺ channels (K⁺ out)
• Phase 2: Plateau/contraction phase
  
  • Balance between activated T-type and L-type Ca²⁺ channels (Ca²⁺ in) and K⁺ channels (K⁺ out)
  • Mediates the influx of calcium needed to initiate contraction
• ​Phase 3: late phase of rapid repolarization
  
  • L-type channels are inactivated (less Ca²⁺ in)
  • K+ channels remain open (more K⁺ out), until they deactivate at -40 mV
• Phase 4: return to RMP (-90 mV)
  
  • time-dependent K+ channels are activated (more K+ out until RMP is reached)
  • equal inward and outward currents

Question 3

Differences between Ventricular Myocyte Calcium Channels

Answer 3

• Transient (T)-type calcium channels
  
  • inactivate with time
  • insensitive to block by dihydropyridines
• Long-lasting (L)-type calcium channels
  
  • activated at -30 mV
  • inactivates slowly
  • provides the dominant Ca²⁺ current in virtually all cardiac cells
  • sensitive to block by dihydropyridines, benzothiazepines, and phenylalkylamines

Question 4

Class I Anti-Arrythmics

Answer 4

Sodium channel blockers

Decrease SA nodal cell automaticity by:

1. Shifting the threshold to more positive potentials (⇡ threshold level)
2. Decreasing the slope of phase IV depolarization (so it takes longer to reach the threshold)

Examples: ACh and adenosine

Question 5

Different Class I Anti-Arrythmics

Answer 5

Differences are in the ventricular myocyte AP

• Class IA: moderate Na+ channel block
  
  • ⇣⇣ phase 0 upstroke rate
  • Leads to prolonged repolarization of myocytes; prolongs AP duration
• Class IB: mild Na+ channel block
  
  • These rapidly bind to/block the Na+ channels, but also rapidly dissociate from/unblock the Na+ channels
  • ⇣ phase 0 upstroke rate
  • Leads to shortened repolarization of myocytes; shortens AP duration
• Class IC: marked Na+ channel block
  
  • ⇣⇣⇣ phase 0 upstroke rate
  • Does not affect duration of repolarization of myocytes; no change in AP duration

Question 6

Class II Anti-Arrythmics

Answer 6

ß-adrenergic receptor antagonists (aka ß-blockers)

• ß1-adrenergic receptors are preferentially expressed in cardiac tissue
• ß-blockers block the sympathetic stimulation of ß1-adrenergic receptors in the SA and AV nodes
  
  • AV node is more sensitive to ß-blockers
• Useful in the treatment of supraventricular/ventricular arrythmias that are precipitated by sympathetic stimulation
• Overall effects:

1. Decrease the rate of phase 4 depolarization (especially important at SA node)
2. Prolong repolarization (phase 3 - especially important at AV node)

Question 7

Class III Anti-Arrythmics

Answer 7

K+ channel blockers

• Block the K+ flow outward in ventricular myocytes (including Purkinje fibers)
• Lead prolonged plateau phase and to markedly prolonged repolarization → prolongs AP
• ⇣ re-entry, however, can also predispose to early afterdepolarizations

Question 8

Class IV Anti-Arrythmics

Answer 8

Ca²⁺ channel blockers

• Act preferentially on SA and AV nodal tissue
• Slow AP upstroke in nodal tissue → ⇣ excitiability of SA nodal cells and prolonged AV nodal conduction
• Useful in arrythmias that involve re-entry through the AV node
• *However, high doses can prolong AV nodal conduction so much that heart block results