Anesthesia Pharmacology: The Cardiac Transmembrane Potential and Action Potential

Anesthesia Pharmacology: Antiarrhythmic Agents

Transmembrane potential -- determined primarily by three ionic gradients
- Na⁺, K⁺, Ca ²⁺
  - Water-soluble, i.e. not free to diffuse through the membrane in response to concentration or electrical gradients: depended upon membrane channels (proteins)
- Movement through channels depend on controlling "molecular gates"
  - Gate-status controlled by:
    - Ionic conditions
    - Metabolic conditions
    - Transmembrane voltage
- Maintenance of ionic gradients depends on the Na⁺/K⁺ ATPase pump.
  - This pump is described as "electrogenic" as net current flows as a result of transport (e.g., three Na⁺ exchange for two K⁺ ions).
- Initial permeability state defined the resting membrane potential.
  - In this permeability state the membrane is relatively impermeable to Na⁺ and relatively permeable to K⁺ ions.
- Cardiac cell permeability and conductance:
  - Conductance is determined by characteristics of ion channel protein.
  - Current flow equals voltage X conductance
  - Voltage in the resting state is the actual membrane potential minus the membrane potential at which no current would flow, even with channels open.
- Sodium
  - Concentration gradient: 140 mmol/L Na⁺ outside: 10 mmol/L Na⁺ inside;
  - Electrical gradient: 0 mV outside; -90 mV inside
  - Driving force, both electrical and concentration, tend to move Na⁺into the cell.
  - In the resting state: sodium ion channels are closed therefore no Na⁺ flow through the membrane
  - In the active state: channels open causing a large influx of sodium which accounts for phase 0 depolarization

**Cardiac Cell Phase 0 and Sodium Current**
	Note the rapid "upstroke" characteristic of Phase 0 depolarization. This abrupt change in membrane potential is caused by rapid, synchronous opening of Na⁺ channels. Note the relationships between the the ECG tracing and phase 0

Potassium:

Concentration gradient (140 mmol/L K⁺ inside; 4 mmol/L K⁺outside)

Concentration gradient tends to drive potassium out

Electrical gradient tends to hold K⁺ in.

Some K⁺ channels ("inward rectifier") are open in the resting state; however, little K⁺ current flows because of the balance between the K⁺ concentration and membrane electrical gradients.

Cardiac resting membrane potential is mainly determined by:

the extracellular potassium concentration and by the

inward rectifier channel state

Spontaneous Depolarization (pacemaker cells)-- phase 4 depolarization

Spontaneous Depolarization occurs because:

Gradual increase in depolarizing currents due to increasing membrane permeability to sodium or calcium.

and a Decrease in repolarizing potassium currents (decreasing membrane potassium permeability)

Both factors are important.

Ectopic pacemaker,not normal SA nodal pacemakers, may be pathological and is:

Facilitated by hypokalemic states

Increasing potassium: tends to slow or stop ectopic pacemaker activity

Channel Activation Sequence:

Depolarization to threshold voltage by increasing Na⁺ conductance.

m gate activation (activation gate); assuming inactivation (h) gates are not closed then

Sodium permeability dramatically increased; intense sodium current

Depolarization

h gate closure; Na⁺ current inactivation, resetting membrane potential towards the resting state.

**Ca^2+: Channel Activation Sequence similar to sodium; but occurring at more positive membrane potentials (phases 1 and 2)**
	Following intense inward Na⁺current (phase 0), Ca²⁺currents: Phases 1 & 2, are slowly inactivated. (Ca²⁺channel activation occurred later than for Na⁺)

**Channel Inactivation, Re-establishing the Resting Membrane Potential**
	Final repolarization (phase 3): Complete Na⁺and Ca²⁺channel inactivation Increased potassium permeability Membrane potential approaches K⁺ equilibrium potential -- which approximates the normal resting membrane potential

Five Phases: Cardiac action potential associated with HIS-purkinje fibers or ventricular muscle

Phase 0 corresponds to Na⁺ channel activation.

The maximum upstroke slope of phase 0 is proportional to the sodium current.

Phase 0 slope is related to the conduction velocity in that the more rapid the rate of depolarization the greater the rate of impulse propagation.

Phase 1 corresponds to an early repolarizing K⁺ current.

Rapidly inactivated.

Phase 2 is the combination of an inward, depolarizing Ca²⁺ current balanced by an outward, repolarizing K⁺ current (delayed rectifier).

Phase 3 is also the combination of Ca²⁺ and K⁺ currents.

Phase 3 is repolarizing because the outward (repolarizing) K⁺ current increases while the inward (depolarizing) Ca²⁺ current is decreasing.

Phase 4 in normal His-Purkinje and ventricular muscle cells is characterized by a balance between outward Na⁺ current and inward K⁺ current.

As a result, the resting membrane potential would normally be flat.

In disease states or for other cell types (SA nodal cells) the membrane potential drifts towards threshold.

This phenomenon of spontaneous depolarization is termed automaticity and has an important role in arrhythmogenesis.

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton & Lange, 1998, pp 216-241.