Cellular cardiac electrophysiology

AP

action potential

LMP

AV

atrioventricular

MDP

DAD

delayed after depolarisation

RMP

DFR

depressed fat response

SA

EAD

early after depolarisation

TMP

loss of membrane potential maximum diastolic potential resting membrane potential sinoatrial transmembrane potential

Terms

Action potential:

change in TMP after excitation of cell

Automaticity:

spontaneous diastolic depolarisation

Fast response fibre:

atrial, ventricular, or Purkinje fibres with AP upstroke dependent on fast Na+ current

Maximum diastolic

most negative diastolic TMP (automatic fibres)

potential:

Resting membrane

stable TMP during diastole (most fast response fibres)

potential:

Slow response fibre:

SA and AV node cells with AP upstroke mostly dependent on slow Ca current

Transmembrane potential:

electrical potential across cell membrane

responsible for generation of the APs, and ion exchange pumps that help to restore ion gradients during phase 4 are depicted in Fig 3.6.1 2 19 20

Resting membrane potential (phase 4)

K+ is the major ion determining RMP, because the cell membrane is quite permeable to K+ during phase 4, but relatively impermeable to other ions. A membrane bound, Na+/K+ exchange pump (Fig 3.6), fuelled by the hydrolysis of ATP, transports three Na+ out of the cell for two K+ into the cell during phase 4. As this pump generates a net outward movement of positive charges, it is "electrogenic''. As a result, [Na+jj and [K+]j are kept low and high, respectively, with the inside of the cell being negative with respect to the outside. Indeed, in most cardiac cell types, were it not for a small leak of Na+ ions (Fig 3.6), RMP would approach the equilibrium potential for a K+ electrode ( - 96 mV). Also, i i depending on TMP, and Na and Ca concentrations inside and outside the cell, a passive Na+/Ca2+ exchanger can run in the forward or reverse modes to move Na+ or Ca2+ into or out of cells (Fig 3.6). This exchanger depends partly on maintenance of the Na+ concentration gradient by the Na+/K+ exchange pump. Under normal conditions, one intracellular Ca2+ is exchanged for three or more external Na+ ions. If [Na+jj is abnormally high - for example, with digitalis toxicity - external Ca may be exchanged for internal

Action potential

The cardiac AP is a propagating wave of transient depolarisation, which begins when an excitatory stimulus (propagating AP, an external stimulus) depolarises the cell membrane beyond threshold potential. The AP is inscribed by the movement of Na+, K+, Ca2+, and Cl-ions through at least nine distinct voltage or ligand operated ion channels.1 The Na /K pump and

Na /Ca exchanger also contribute to the genesis of the AP by: (1) maintaining membrane ion gradients essential for excitability; (2) generating small currents as the result of net ion movements; and

Coronary Movement

Fig 3.4 Schematic representation of action potentials (APs) from various cardiac fibre types. Approximate timing of APs in relationship to events of surface ECG lead II and His bundle ECG (HBE) for one cardiac cycle is shown. Note that SA and AV nodal activation is electrically silent in both ECG II and HBE.

Table 3.2 Comparison of transmembrane potentials and other action potential characteristics from various cardiac fibre typesa

SA node Atrial AV node Purkinje Ventricular

SA node Atrial AV node Purkinje Ventricular

Table 3.2 Comparison of transmembrane potentials and other action potential characteristics from various cardiac fibre typesa

RMP or MDP

-50

to -

-80

to -

-60 to -

-90 to -

-80 to -90

(mV)

60

90

70

95

Amplitude (mV)

60-

-70

110-

-120

70-80

120

110-

-120

Overshoot (mV)

0-

10

100-

-200

5-15

30

30

Duration (ms)

100-

-300

100-

-300

100-300

300-500

200

-300

Upstroke (V/s)

1-

10

100-

-200

5-15

500-700

100-

200

Conduction (m/s)

<0

05

03-

-0 4

01

2-3

03-

-0 4

a Data from Sperelakis.18 SA, sinoatrial; AV, atrioventricular; RMP or MDP, resting membrane potential (quiescent fibres) or maximum diastolic potential (automatic fibres). Upstroke, maximum upstroke velocity.

(3) restoring normal intracellular ion concentration once the AP is inscribed.

By convention, inward (depolarising) currents during the AP reflect movement of positive charges into the myocyte. INa and ICa (below) are the major physiological inward currents. Outward currents reflect movement of positive charges out of the cell, and repolarise the cell during AP phase 3. K+ ions are the major charge carrier for outward current in heart.

Tmp Action Potential Phases

Fig 3.5 Terminology used to describe changes in transmembrane potential (TMP) during cardiac action potential (AP). Depolarisation is towards a more positive (low) level of TMP, and repolarisation towards a more negative (high) level of TMP. Note that action potential "B" arises from a depolarised membrane potential compared with action potential "A". As a result, some Na+ channels are inactivated, less Na+ current can flow, and action potential ''B" has a slower rate of rise and less overshoot compared with action potential "A". See text for further discussion.

Fig 3.5 Terminology used to describe changes in transmembrane potential (TMP) during cardiac action potential (AP). Depolarisation is towards a more positive (low) level of TMP, and repolarisation towards a more negative (high) level of TMP. Note that action potential "B" arises from a depolarised membrane potential compared with action potential "A". As a result, some Na+ channels are inactivated, less Na+ current can flow, and action potential ''B" has a slower rate of rise and less overshoot compared with action potential "A". See text for further discussion.

Fast Response Action Potential

Fig 3.6 Transmembrane currents, ion exchange pumps, and refractory periods in a typical fast response fibre. Inward currents (black) include the fast Na+ current (INa); transient or tiny Ca2+ current (ICa T); long-lasting or large Ca2+ current (ICa L); and a non-selective cation current (INS) carried by a channel activated by intracellular Ca2+ loading. Outward currents (grey) include the inward rectifier current (IK1); delayed rectifier current (IK - shown as the sum of its two components); a rapidly activated, time dependent, non-Ca2+ dependent K+ current (Ito 1); a transient current that is dependent on [Ca2+]i, and carried by C1- in some species (Ito2); and a hyperpolarising K+ current activated by acetylcholine (IACh). A chloride conductance (ICl) dependent protein kinase A can be activated in some species. Typical intra- and extracellular ion concentrations during phase 4 are shown (top right). The predominant intracellular anions (A-) are large, impermeable proteins. The ATP dependent Na+/K+ pump maintains the steep outwardly and inwardly directed gradients for K+ and Na+, respectively, and also generates a small net outward current. The passive Na+/Ca2+ exchanger generates a small net inward current. The resting membrane potential (Vr) results from high membrane permeability to K+ relative to other ions and the transmembrane concentration gradient for K+. A small inward "leak" of Na+ ions keeps Vr slightly positive to the K+ equilibrium potential. Finally, the fibre cannot be excited during the absolute refractory period (ARP). During the relative refractory period (RRP), excitation produces action potentials with reduced amplitude, slower upstrokes, and no overshoot (AP "a"). These either fail to propagate or do so slowly. Following the RRP, the threshold potential (TP) returns to normal, so that a fully regenerative AP (AP "b") occurs with excitation. See the text for further discussion.

Finally, we must define the term "rectification'' before describing ionic mechanisms for the AP. Rectification describes the voltage dependence of resistance to ion flow through some ion channels. For example, the delayed rectifier K+ current (IK) and transient outward currents (/tol and I^) (Fig 3.6) exhibit outward going rectification, that is, more current flows with increasing depolarisation. In contrast, current flow progressively decreases with increasing depolarisation for the inward rectifier K+ current (Iki).

Phase 0: AP upstroke (rapid depolarisation)

There are two types of fibres, depending on the primary mechanism for generation of the

AP upstroke - "fast" (Na ) and slow (Ca ) response fibres. The first includes atrial, Purkinje, and ventricular muscle fibres, and the second SA and AV nodal cells.

In fast response fibres, depolarisation increases the probability of Na+ channel activation. It must be sufficient to bring the membrane to threshold potential (TP), where enough inward Na+ current is activated to overcome the repolarising influence of the outward K+ conductances. TP ranges from - 70 to - 65 mV in normal Purkinje fibres. Once reached, the escalating influx of Na+ ions causes regenerative depolarisation - whereby movement of a little Na+ into the cell further depolarises the cell membrane, allowing more and more Na+ to enter the cell. Depolarisation approaches, but never actually reaches, the Na+ equilibrium potential (+ 70 mV). Purkinje fibres, with the highest AP upstroke velocities (see Table 3.2), have a significantly higher density of Na+ channels than atrial or ventricular muscle fibres. AP upstroke velocity and amplitude are major determinants of myocardial conduction velocity. Finally, smaller depolarising stimuli that do not bring fast response fibres to threshold for regenerative excitation can result in non-propagated APs (local or "electrotonic effects"). Non-propagated APs, however, may impair conduction of subsequent propagating APs.

Slow response fibres have a lower RMP, slower upstrokes, and little or no overshoot (see Table 3.2 and Fig 3.4). Depolarisation during phase 0 is dependent primarily on the slow

inward current (I^) carried predominantly by Ca (Ica). Its threshold for activation is about -30 to -40 mV. In fast response fibres, this current is activated during phase 0 by regenerative depolarisation caused by INa. Although current flows through both the fast

(INa) and slow channels (Isi) during the second half of phase 0, Isi is much smaller than peak INa, and therefore contributes little to the AP until after inactivation of INa (following completion of phase 0). In addition, Is^ can be activated and may play a prominent role in incompletely depolarised fast response fibres ("depressed fast response" - see below) in which INa has been inactivated, provided that conditions are appropriate for Isi activation.

Isi passes through protein membrane channels that are selective for Ca . Two types of i

Ca inward current exist in cardiac fibres:

1 A slowly inactivating, high threshold, dihydropyridine sensitive current (long lasting,

large or "L type" Ca current - Ic L). /Ca L contributes to depolarisation and impulse propagation in slow response fibres. In fast response fibres, IcaL contributes to the AP

plateau and triggering the release of Ca2+ from the sarcoplasmic reticulum.2 Ca2+ channel blockers block I^l, but it is stimulated by drugs that increase cyclic AMP

levels (^-adrenergic agonists and phosphodiesterase inhibitors).

2 A fast inactivating, low threshold, dihydropyridine insensitive current (transient, tiny, or "T type" - I ca T). Ica t is activated at thresholds intermediate between those for INa and

IcaL. It probably contributes inward current to the later stages of phase 4 depolarisation in SA node cells and Purkinje fibres.2

Phase 1: early rapid repolarisation

In fast response fibres, the AP upstroke peak is followed by rapid, early repolarisation (phase 1). This brings the membrane potential back to + 10 ± 10mV.1 2 Phase 1 results from ZNa along with activation of Ito. Ito inactivation of INa along with activation of Ito. Ito consists of at least two components:21

1 /tol is a voltage dependent, rapidly activating K+ current with outward going rectification.

It undergoes voltage and time dependent inactivation, and its channels are notably slow to recover from inactivation - diminishing its importance to phase 1 at fast heart rates.

2 /to2 is believed to be a Ca2+ dependent Cl- current.22 Ito2 activation correlates with Ca2+

2+ 2 + release from the sarcoplasmic reticulum, triggered by Ca influx from L type Ca channels.

There is marked regional variation in the prominence of I^. For example, AP of ventricular epicardial cells have prominent Ito2 and phase 1 repolarisation. In contrast, Ito2 is small and phase 1 negligible in endocardial cells.23 Cl- ions, along with Ito2, may contribute to early rapid repolarisation during adrenergic stimulation via rapidly activating-non-inactivating Cl-current.24

Phase 2: AP plateau

The AP plateau phase (phase 2) may last several hundred milliseconds. Membrane conductance for all ions falls to rather low levels.1 2 Decreased Na+ conductance (caused by inactivation of I^) along with decreased outward K+ conductance (consequent to I^

inward going rectification - so that little K+ leaves the cell) are primarily responsible. Minor currents during phase 2 include:

1 Ca current (I^ t, Iqh i): current through T type channels, activated at cell membrane potentials positive to - 70 mV, is negligible, but may contribute to the pacemaker potential (see below). Current through the

L type channels, activated at cell membrane potentials positive to - 40 mV, inactivates

slowly. Its primary role is to trigger the release of Ca from the sarcoplasmic reticulum to initiate contraction.

2 ATP dependent Na+/K+ pump: this does not turn on and off with each AP, but instead restores the ionic gradient over a cumulative time period. It pumps 3 Na+ ions out for 2 K+ ions into the cell.

3 Cl- current: Ca2 dependent Cl- current (/to2) also contributes to phase 2.22

4 Slowly inactivating or "late" Na+ current: a small, persistent inward Na+ current that continues to flow during phase 2 in ventricular muscle and Purkinje fibres.25 It is unknown whether it results from delayed or failed inactivation of some Na+ channels (^Na), or is carried by a distinct subpopulation of Na+ channels that open with long latencies.1 Inhibition of this "late'' Na+ current is thought to be responsible for the shortening of the ventricular AP duration by lidocaine (lignocaine) and other class IB antiarrhythmic drugs.26

5 Passive Na /Ca exchanger: this exchanger generates a small membrane current by

virtue of its 3:1 Na :Ca2 transport ratio.27 The direction of the current flow is

determined by the relationship of the membrane potential to the Na /Ca equilibrium potential. Inward current (Na influx/Ca2 efflux) flows at rest because RMP is negative

to ^Na-Ca (- 30 to -40mV). Outward current flows (Na efflux/Ca influx) towards the

end of phase 0 and during phase 1 because RMP is positive to E^.Ca-As [Ca increases (phase 2), E^.f

influx/Ca efflux mode.

increases (phase 2), ENa-Ca becomes more positive and the exchanger reverts to its Na+

Phase 3: final rapid repolarisation

Progressive decay of I^ L with increased outward K+ current terminates phase 2 and initiates phase 3.1 2 Outward current is generated by Ik (early phase 3) and I^, along with a small contribution from the ATP dependent Na+/K+ pump. I^ channels, closed during phase 2, progressively reactivate during phase 3 to cause regenerative repolarisation back to the RMP.

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