Cardiac action potentials

and excitation-contraction coupling

Gyorgy Szabadkai, 4th December, 2020

The lecture aims to explain:

generation of action potentials and spontaneous heartbeat
propagation of action potentials
excitation-contraction coupling
pathophysiology of EC coupling
The spontenous activity of the heart (Langendorff preparation)

Courtesy of Sean Davidson, Hatter Institute UCL

 Electrical systems of the heart

anatomy

SA node spontaneously depolarizes

Activation propagates through the atrial wall, AV node, bundle of His and Purkinje fibers
Spontaneous electric activity can start from any part of the system

SA node – highest frequency (100/min) – dominant pacemaker

secondary pacemaker - AV node

40-60/min spontaneous beat

tertiary pacemakers: anywhere below

lower frequency
Cardiac muscle forms a syntitium – thus able to propagate electric activity

Fibers branch and interconnect.

Fibers consist of individual cells attached end-to-end.
Nuclei (one per cell) are centrally located within each cell.
Intercalated discs are sites of attachment between cells.
Spontaneous activity of an isolated cardiac myocyte (loaded with a Ca2+ sensitive dye)

Courtesy of M. Duchen and S. Davidson

The cardiac action potential
Two types of action potentials (APs) exist in the heart

spontaneous, slow AP induced, fast AP

Phases of the APs

0 fast depolarization
1 small repolarization
2 plateau
3 repolarization
4 resting membrane potential – not stable in the SA node
Ionic currents underlying the APs

driving
depolarization

Na+
Ca2+
driving
repolarization

K+
Cl-
The significance of spontaneous depolarizations

triggers the excitatory wave of the heart

1. determines the dominant pacemaker
2. regulation of the frequency of heartbeat by changing the shape of APs in the SA node

: tachycardia
: bradycardia

change of slope of depolarization

change of threshold potential

change of ‘resting’ potential

The significance of ventricular action potentials

trigger of contraction
 Excitation-contraction coupling:
I. contraction

1. action potential 1.

2. Ca2+ signal 2.

3.
3. contraction
 Excitation-contraction coupling:
II. relaxation

1. Ca2+ signal OFF

2b.
2a. relaxation 2a.
1.

2b. repolarization
The refractory period

ERP: effective (absolute) refractory period

no new AP can be triggered

RRP: relative refractory period

new AP with lower amplitude can be
triggered
 The general structure of the contractile apparatus of muscle cells

Characteristic of
skeletal and cardiac
muscle
The sliding filament model of contraction
Ca2+ signal: the trigger of actin-myosin complex formation  contraction

Troponin complex:

TnT – troponin T
structural

TnC – troponin C
Ca2+
binding

TnI – troponin I
inhibits
actin- myosin
binding
where does Ca2+ come from?
 Sources of Ca2+

extracellular intracellular

Sarcolemma Sarcoplasmic reticulum (SR)

(plasmamembrane)
- Junctional
- T-tubule (at the T-tubule)

- Free

- Subsarcolemmal
 Integration of Ca2+ sources: 1. contraction

Ca2+

Ca2+

Ca2+

Ca2+

M. Scoote et al. Heart 2003;89:371-376

Integration of Ca2+ sources: 2. relaxation

Ca2+

Ca2+ ATPase, pump

Ca2+ Ca2+

Ca2+

M. Scoote et al. Heart 2003;89:371-376

 EC coupling as target of contractility regulation

parasympathetic sympathetic

- +
heart rate
+

contractile force
Regulation of contraction
Autonomic nervous system
Catecholamines (E, NE)
symphatic stimulation

R G
AC cAMP 
cAMP
Ca2+ PKA

protein kinase A
+++
Ca2+

+++

Ca2+ RyR L-type Ca2+

channel
 Regulation of relaxation
Catecholamines (E, NE)

R G
AC
cAMP + Ca2+ ATPase, pump

PKA
+
Ca2+
+++
Ca2+

 Ca2+ binding
Ca2+
 Increasing Ca2+ reuptake in the SR: mechanism of action

Ca2+ Phospholamban

‘resting’ ADP
SERCA
Ca2+ ATPase
ATP

Ca2+

Sarcoplasmic Reticulum

sympathetic stimulation
PKA Ca2+ ADP

p ATP

Ca2+
Relevance in diagnostics, pathology and therapy
Ionic currents underlying the APs

driving
depolarization

Na+
Ca2+
driving
repolarization

K+
Cl-
Voltage dependent ion channels involved:

slow (SA) fast (ventricle)

Na+ Ifunny fast voltage dependent

(spont. depol) (during peak)

L-type L-type
Ca2+
T-type

inwardly rectifying
K+ delayed rectifier
ATP sensitive
Acetyl-choline sensitive

Cl- - voltage dependent

Cl- channel

why is it important?
Ion channels and arrhythmias

channelopathies: mutations in ion channels (mostly K+ and Na+) responsible for AP

generation
usually no apparent problem with heart function
but responsible for 85% of Sudden Death Syndrome

long QT syndrome

idiopathic ventricular fibrillation

Voltage dependent ion channels as pharmacological targets:

slow (SA) fast (ventricle)

Na+ Ifunny fast voltage dependent

(during peak) lidocaine, procainamide
(spont. depol)

L-type L-type
Ca2+ verapamil, nifedipine
T-type

inwardly rectifying
K+ delayed rectifier dofetelide, ibutilide
ATP sensitive
Acetyl-choline sensitive

Cl- - voltage dependent

Cl- channel pharmacological
targets in
arrhythmias and
hypertension
The effect of Ca2+ channel inhibition on heart rate and contractility

reduced frequency reduced contraction

(SA node) (ventricle)
The effect of antiarrhythmic and antihypertensive drugs

1. inhibit spontaneous AP generation  frequency

2. inhibit ventricular  cardiac output  cardiac work

contraction

3. vasodilatation  peripheral resistance

 arterial blood pressure

The refractory period – relevance in pathology: reentry

ERP: effective (absolute) refractory period

no new AP can be triggered

RRP: relative refractory period

new AP with lower amplitude can be
triggered, leads to arrhythmias
The electrocardiogram (ECG)

The ECG records fluctuation of electrical potential in the chest

reflecting cardiac action potentials on the surface of the heart

lead potential vector lead

+
- -
heart +

field
galvanometer
The cardiac vector is projected onto different leads: the Einthoven triangle

_ I +
RA _ LA
_
_

II + III

+ +
LL

when the vector moves toward positive pole 

positive wave is recorded
The normal ECG
The ECG and the cardiac action potential

P wave

PQ interval

QRS complex
+
T wave
Deranged EC coupling in heart failure
 Cardiac action potentials
and excitation-contraction coupling

The lecture explained:

generation of action potentials and spontaneous heartbeat
propagation of action potentials
excitation-contraction coupling
pathophysiology of EC coupling