Cardiac Action Potentials

Origin of resting membrane potential of cardiac myocytes

• At rest, cardiac myocytes have a negative MP = -80 to -85 mV (negative inside relative to the outside)

• Made up of weighted average of equilibrium potentials of contributing ions (K⁺, Na⁺, Cl^-, Ca²⁺,)

• Each ions “weight” (how much it contributes to the MP) depends on how permeable the membrane is to it.

• Concentration gradient and permeability contribute to MP

Resting membrane ion permeability (most to least)

• K⁺ → Na⁺→ Cl^- → Ca²⁺

• Potassium is the most permeable at 30 while Calcium is the least permeable at 0

Steps to create a negative resting membrane potential

Step 1: Create concentration gradient

• Na+/K+-ATPase pumps 3 Na+ ions out of cell in exchange for 2 K+ ions in

• Energy-dependent

• Electrogenic: sets up net + charge outside cell

• More importantly: creates [K+]in >>[K+]out

Step 2: Let some ions move down concentration gradient

• K+ moves OUT along its concentration gradient (high membrane permeability)

• Unopposed negative ions left behind on the inner surface of membrane

• Effect: Negative membrane potential

• Ventricular myocytes: -80 to -85 mV

Phase 4 (Resting membrane potential)

• Cell is at its resting membrane potential (-80 to -85)

• Only K⁺ is permeable in the membrane the other ion channels are closed

• Plateau

Phase 0 (Rapid Depolarization)

• At threshold, voltage-gated fast Na+ channels suddenly open

• Na+ ions flood inward rapidly (down concentration gradient)

• Loss of membrane polarity (depolarization) as membrane voltage moves toward ENa+ (i.e., becomes more positive)

• After 1 msec, Na+ channels close and remain so until cell repolarizes in phase 3

Phase 1 (Early Repolarization)

• Na+ channels closed

• Voltage-gated K+ channels open and K+ moves out of cell (down concentration gradient)

• Membrane potential becomes more negative

• Voltage-gated, L-type Ca2+ channels start to open slowly (-20 mV)

Phase 2 (Plateu)

• Voltage-gated, L-type Ca2+ channels open

• Ca2+ moves into cell (down concentration gradient)

• Ca2+ induces more Ca2+ release from sarcoplasmic reticulum (excitation-contraction coupling) (contraction)

• K+ channels remain open. K+ out balances Ca2+ in = no net change in membrane potential

• Plateau ends as L-type Ca2+ channels slowly close

Phase 3 (Final Repolarization)

• L-type Ca2+ channels close

• K+ moves out of cell unopposed by Ca2+

• Membrane completely repolarizes (moves back toward EK+)

Phase 4 (Restoration of Ion Balance/Resting MP)

• Na+/K+-ATPase pump restores concentration gradients necessary for next beat, moving K+ in and Na+ out

• Ca2+ pumped out of cell (Ca2+/Na+ antiporter, Ca2+ ATPase)

Effective Refractory Period (ERP)

• Inactive Na+ channels can’t reopen, so another AP can’t be generated

• Allows heart to relax by preventing sustained, tetanic contraction, which facilitates intermittent pumping

Relative Refractory Period

• Na+ channels transitioning to ready state

• Cell can be stimulated to generate a new AP, but a larger-than-normal stimulus is required

RTRP

Ready for the next action potential

Non-autonomic cells

• Atrial/ventricular myocytes (contractile cells)

• Depolarize only in response to external stimulation

• Stable, flat phase 4 (resting phase) of action potential

Autonomic (Pacemaker) cells

• Sinoatrial (SA) node, Atrioventricular (AV) node, and Purkinje fibers (myoconductive cells)

• Depolarize independently of external stimulation

• Unstable phase 4 (resting phase) from inward “leak” of Na⁺ and Ca²⁺ ions causes spontaneous depolarization.

• This confers: Automaticity (heart can initiate its own beat), and Rythmicity (repetitive impulse generation)

Sinoatrial (SA, sinus) node

• Sits at the junction of cranial vena cava and right atrium

• Primary pacemaker site

Atrioventricular (AV) node

• On floor of right atrium, atop interventricular septum

• Can take over pacemaker duties if SA node fails

Bundle of His/Purkinje fibers

• Make up ventricular conduction system

• Can take over pacemaker duties if SA / AV nodes fail

Phase 4 (“Resting” membrane potential)

• At rest, cells less permeable to K+ than contractile myocytes, so “resting” MP is less negative

• Spontaneous phase 4 depolarization (gradual upslope) due to slow inward leak of Na+ and Ca2+ ions

• Main contributor = HCN (AKA “funny”) channel

• Na+ channel

• Hyperpolarization-activated, Cyclic Nucleotide gated channel (CN = 2nd messenger cAMP, which is increased in sympathetic stimulation)

• T-type Ca2+ channels also contribute

Phase 0 (Spontaneous Depolarization)

• Membrane potential drifts “upward” until threshold is reached

• At threshold, voltage-gated L-type Ca2+ channels open to generate action potential

• Ca2+ moves into the cell, causing depolarization

*Pacemaker cells to not contain fast Na+ channel

Phase 3 (Repolarization)

• K+ channels open, K+ moves out of cell

• Negative MP restored

Atrial / Ventricular myocytes summary

• Contractile

• Depolarize only in response to external stimulation

• Action potential traits:

  • RMP = -80 to 90 mV

  • Stable, flat phase 4 (no spontaneous depolarization)

  • Rapid phase 0 (“fast-response”)

SA and AV nodal cells summary

• Myoconductive

• Can depolarize independently of external stimulation

• Action potential traits:

  • Less negative RMP (-60 mV)

  • Unstable phase 4 from inward “leak” of Na+ and Ca2+ ions causes spontaneous depolarization

  • Slow phase 0 (“slow-response”)

Purkinje fiber cells summary

• Myoconductive

• Can depolarize independently of external stimulation

• Action potential traits:

  • RMP = -80 to -90 mV

  • Unstable phase 4 from inward “leak” of Na+ and Ca2+ ions causes spontaneous depolarization

  • Rapid phase 0 (“fast-response”)

Sympathetic activation of heart

• Norepinephrine, epinephrine via B1 adrenergic receptors

• Increase Na, Ca leak (increase slope of phase 4)

• Changes rate of phase 4 depolarization to be steeper

• Faster/steeper slope = faster HR

• Physical exertion, anxiety, illness, emotional stress

Parasympathetic activation of heart

• Acetylcholine via muscarinic receptors

• Decreases Na, Ca leak (decrease phase 4 slope and increases K permeability to hyperpolarize)

• Changes phase 4 starting point

• Takes longer to reach threshold

• Slower/flatter slope = slower HR

• Rest, relaxation

Pacemaker “Hierarchy”

• Any cardiac cell with pacemaker activity can initiate a heartbeat

• The pacemaker firing with greatest frequency will trigger an action potential that will propagate throughout the heart

• The fastest pacemaker sets heart rate and overrides/ resets all slower pacemakers

Order of Pacemaker “hierarchy”

• Sinoatrial (SA) nodal cells: 60-250 bpm

• Atrioventricular (AV) nodal cells: 40-60 bpm

• Purkinje fibers: 20-40 bpm

Cardiac tissue is excitable

• When a cell is stimulated to reach its threshold potential, it rapidly loses its negative membrane polarity (this is called depolarization)

• When a cell is depolarized, adjacent cells are then stimulated to do the same

  • Depolarization (“cardiac impulse”) spreads QUICKLY as a wave

  • Depolarization triggers myocyte contraction – wave propagation must be carefully timed to synchronize ventricular contraction and optimize ejection of blood

  • Extracellular currents associated with this wave are detected by the electrocardiogram (ECG)

Propagation of the cardiac action potential steps

1. Depolarizing stimulus arrives

2. Na+ ions (or Ca in SA and AV nodal cells) at border zone flow toward negatively-charged adjacent membrane, creating a local electrical current that reduces membrane polarity (i.e., makes it less negative

3. At threshold (-70 mV), voltage-gated Na+ channels open; adjacent membrane depolarizes; AP generated

4. AP propagation continues down length of fiber as “wave of depolarization)

Rapid conductors

• Atrial/ventricular myocytes, Purkinje fibers

• “Fast response” AP: Rapid phase 0 depolarization (steep-up- stroke) = rapid impulse conduction velocity

• Conduction depends on fast Na+ channels

• Cells are larger/broader and have more gap junctions (decreased resistance = faster conduction)

Slow conductors

• SA and AV nodes

• “Slow response” AP: slower up-stroke of phase 0 = slow impulse conduction velocity

• Conduction depends on slow Ca²⁺ channels

• Smaller cells + fewer gap junctions

Phase 4 vs. Phase 0 characteristics

• The slope of phase 4 determines whether a cell can be a pacemaker

• The slope of phase 0 determines how fast a cell can pass along an impulse (conduction speed)

Normal Cardiac activation sequence

1. SA node- Slowest conduction and fastest pacemaker

2. Atrial muscle

3. AV node

4. Purkinje fibers- Fastest conduction and slowest pacemaker

5. Ventricular muscle

Propagation of impulse (SA node)

• Spontaneous phase 4 depolarization initiates depolarization wave that activates entire heart

• Because SA node discharge rate is fastest of all pacemakers, it almost always controls rhythm in the normal heart

• Rate (slope) of phase 4 depolarization determines heart rate (HR)

  • HR in isolated (denervated) heart = 100 bpm

  • Slope of phase 4 altered by:

    • Autonomic nervous system inputs (β1/M)

    • Temperature (e.g., fever increases)

    • Metabolic rate

Propagation of impulse (Atrial muscle)

• Impulse moves outward (“ripple in a pond”) from SA node, depolarizing atria in right-to-left, cranial-to-caudal direction

• Once upper right atrium is depolarized, there is rapid conduction of impulse cell-to-cell through the atrial syncytium

Propagation of impulse (AV node)

• Atrial wave converges on AV node

• Area of slowest conduction in the heart

  • Delays transmission of impulse from atria to ventricles

  • Delay allows atrial contraction (which occurs right after depolarization) to push blood into ventricles immediately before ventricular contraction

• AV node has long refractory period

  • Impulses easily conducted in other areas may be blocked here (good thing! “filter” function

• Autonomic inputs affect conduction velocity

Propagation of impulse (His-Purkinje system)

• His-Purkinje system - extensive subendocardial network of rapidly conducting cells

• The rapid conduction activates the large ventricular myocardium nearly simultaneously

  • Provides efficiency needed for synchronous ventricular contraction

• Once signal reaches ends of Purkinje fibers, it travels cell-by-cell in endocardial-to-epicardial direction through the myocardium