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Na-channel / Na-currentfrom extracellullar space Ca- channel / Ca- current to intracellular space 2. DEPOLARIZATION K- channel / K- current from intracellular space to extracellullar space 3. REPOLARIZATION Action potential REPOLARIZATION DEPOLARIZATION The action potential in a ventricular myocyte 4. Re-establish of the diastolic (resting) membrane potential 1. EXCITABILITY Small triggering stimulus large response „Action Potential” Threshold and autogenerative excitation
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Differences in cardiac atrial and ventricular ion channels
Norbert Jost, PhD
Department of Pharmacology & Pharmacotherapy, University of SzegedDivision for Cardiovascular Pharmacology, Hungarian Academy of Sciences
Szeged, Hungary
Right ventricle
AV node
Right atria
Sinus node
His Bundle
Left atria
Left ventricle
Left Bundle branch
Right Bundle branch
Purkinje fibres
The propagation of the stimulation in the heart
Conduction velocity in m/s
Time to arrive from AV to the respective place (ms)
Sinus node, discovered by Keith and Flack
Na-channel / Na-current from extracellullar spaceCa- channel / Ca- current to intracellular space
2. DEPOLARIZATION
K- channel / K- current from intracellular space
to extracellullar space
3. REPOLARIZATION
Action potentialREPOLARIZATION
DEP
OLA
RIZ
ATI
ON
The action potential in a ventricular myocyte
4. Re-establish of the diastolic (resting) membrane potential
1. EXCITABILITY
Small triggering stimulus large response „Action Potential”
Threshold and autogenerative excitation
The ECG and the action potential I.
The ECG and the action potential II.
Outline of membrane currents of sinus node cells: current profiles (drawn by hand) are time aligned with the action potential.
Diastolic depolarization
Purkinje fibre
The main potassium currents in the ventricular and atrial muscle
And many other currents and mechanisms !!!
Action potential and fast sodium current (INa) in atria and ventricle
The fast sodium channel (INa)Wu et al, Heart Rhythm, 2008, 5(12):1726-34
100 ms
50 m
VINa
m
h
++Na Na
outside
Resting state
inside -
m
h
++Na Na
outside
Active state
inside -
m
+
+
Na
Na
outside
Inactive state
inside +
h
Activation kinetics Inactivation kinetics
Re-activation kinetics
Action potential and the L type calcium current (ICaL) in atria and ventricle
Atria
Varro et al, Br. J. Pharmacol, (2001) 133, 625 – 634.
m
h
++Ca Ca
outside
Resting potential
inside -
m
h
++Ca Ca
outside
Active
inside -
m
+
+
Ca
Ca
outside
Inactive
inside +
h
Activation kinetics Inactivation kinetics
Re-activation kinetics
100 ms
50 m
V
ICaL
L type calcium current (ICa)
Action potential and the transient outward potassium current (Ito) in atria and ventricle
Csatorna fehérje
Virag et al, unpublished
100 ms
50 m
V
„Notch”
Transient outward potassium current (Ito)
ActivationResting potential
InactivationActivation kinetics Activation kinetics
Effect of selective Ito blockade on the action potential
Virag et al, unpublished
The notch disappearsRepolarization lengthens
Action potential and the rapid and slow componets of the delayed rectifier potassium currents (IKr and IKs) in atria and ventricle
25 p
A
500 ms
2500ms
100
pA
-40 mV
30 mV5000 ms
2500 ms
50 p
A
-40 mV
30 mV1000 ms
There is a fast inactivation also !
The fast and slow delayed rectifier potassium currents (IKr and IKs)
Resting potential Activation Deactivation
Activation kinetics Deactivation kinetics
200 ms
Difference current
50 p
A
0 pA
E-4031 sensitive (IKr)
L-735,821 sensitive (IKs)
250 ms-80 mV
-40 mV
+30 mV
Varro et al, J.Physiol. 2000; 523.1: 67-81
Controll100 nM L-735,821
Controll1 µM E-4031
200 ms50 m
V
The fast and slow delayed rectifier potassium currents (IKr and IKs)
Action potential and the inward rectifier potassium current (IK1) in atria and ventricle
The inward rectifier potassium currents (IKr and IKs)
Biliczki et al, Br. J. Pharmacol, 2002,137:361-368
Control 10 M BaCl2
-120 mV
-90 mV
60 mV
36 s
1000 pA
-120 -80 -40 0 40 (mV)
0 pA
0 mV
50 m
V
200 mscycle length = 1000 ms
---
Control10 M BaCl2
The ” inward” rectification is regulated (inhibited) by intracellular cations (Mg2+, Ca*, polyamines) underdepolarization
Resting potential Activation Deactivation
Activation kinetics
Deactivation kinetics
Summary – the four main repolarizing current under the action potential
Dog
?
Atria specific currents: The ultrarapid delayed rectifier potassium current (IKur)
Atria specific currents: The ultrarapid delayed rectifier potassium current (IKur)
Gao et al, Br. J. Pharmacol, 2005; 144, 595-604
IKur
ActivationResting potential
Inactivation
Wang et al. Circ. Res. 1993, 73: 1061 Wettwer et al. Circulation 2004;110:2299-2306
Effect of selective IKur current blockade on action potential
Dobrev et al. Circulation 2005;112:3697-3706
Atria specific currents: The acetylcholine sensitive potassium current (IK,ACh)
Selective blockade of IK,ACh may be a new tretment for cAF ?!?
Dobrev et al. Circulation 2005;112:3697-3706
Atria specific currents: The acetylcholine sensitive potassium current (IK,ACh)
Other ligand dependent current: the ATP sensitive potassium current (IKATP)
Iost N, et al, J Cardiovasc Pharmacol Ther, 8, 31-41, 2003 Németh M, J Cardiovasc Pharm Ther. 2 (4), 273-
284. 1997
THANK YOU FOR YOUR ATTENTION !