Download NJ_Differences in cardiac atrial and ventricular ion channels

Differences in cardiac atrial and
ventricular ion channels
Norbert Jost, PhD
Department of Pharmacology & Pharmacotherapy, University of Szeged
Division for Cardiovascular Pharmacology, Hungarian Academy of Sciences
Szeged, Hungary
The propagation of the stimulation in the heart
Sinus node, discovered by Keith and Flack
Left atria
Sinus node
His Bundle
Conduction velocity
in m/s
Left ventricle
AV node
Left Bundle
branch
Time to arrive from AV
to the respective place (ms)
Right atria
Right ventricle
Right Bundle
branch
Purkinje
fibres
The action potential in a ventricular myocyte
1. EXCITABILITY
Small triggering stimulus

large response
„Action Potential”
Action potential
Threshold and autogenerative
excitation
2. DEPOLARIZATION
Na-channel / Na-current
from extracellullar space
Ca- channel / Ca- current
to intracellular space
3. REPOLARIZATION
K- channel / K- current
from intracellular space
to extracellullar space
4. Re-establish of the diastolic (resting) membrane potential
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.
Purkinje fibre
Diastolic
depolarization
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)
50 mV
Wu et al, Heart Rhythm, 2008, 5(12):1726-34
INa
100 ms
Resting state
Na
+
Activation kinetics  Active state
+
Na
Na
+
outside
outside
m
inside
-
Re-activation kinetics
inside
Na
+
h
h
m
-
+
Na
outside
m
inside
+
Inactivation kinetics Inactive state
+
Na
Action potential and the L type calcium current (ICaL) in atria and ventricle
Atria
L type calcium current (ICa)
50 mV
ICaL
Varro et al, Br. J. Pharmacol, (2001) 133, 625 – 634.
100 ms
Activation kinetics 
Resting potential
+ Ca
Ca
+
outside
Inactivation kinetics 
Active
Ca
+
outside
-
Re-activation kinetics
m
inside
inside
Ca
+
h
h
m
-
+
Ca
outside
m
inside
+
Inactive
+
Ca
Action potential and the transient outward potassium current (Ito) in atria and ventricle
Csatorna fehérje
Transient outward potassium current (Ito)
50 mV
Virag et al, unpublished
100 ms
Activation kinetics 
Resting potential
Activation
Activation kinetics 
Inactivation
„Notch”
Effect of selective Ito blockade on the action potential
Repolarization lengthens
The notch disappears
Virag et al, unpublished
Action potential and the rapid and slow componets of the delayed rectifier potassium
currents (IKr and IKs) in atria and ventricle
The fast and slow delayed rectifier potassium currents (IKr and IKs)
1000 ms
5000 ms
30 mV
30 mV
-40 mV
-40 mV
100 pA
50 pA
There is a fast inactivation also !
2500 ms
Activation kinetics 
Resting potential
Activation
25 pA
2500ms
Deactivation kinetics 
Deactivation
500 ms
The fast and slow delayed rectifier potassium currents (IKr and IKs)
Controll
1 µM E-4031
+30 mV
-40 mV
-80 mV
250 ms
Difference current
50 pA
E-4031 sensitive (IKr)
Controll
100 nM L-735,821
0 pA
L-735,821 sensitive (IKs)
Varro et al, J.Physiol. 2000; 523.1: 67-81
50 mV
200 ms
200 ms
Action potential and the inward rectifier potassium current (IK1) in atria and ventricle
The inward rectifier potassium currents (IKr and IKs)
The ” inward” rectification is regulated (inhibited) by intracellular cations (Mg2+, Ca*, polyamines) under
depolarization
10 M BaCl2
Control
0 mV
Control
0 pA
60 mV
-90 mV
36 s
-
50 mV
1000 pA
10 M BaCl2
-120 mV
cycle length = 1000 ms
-120
-80
-40
0
40 (mV)
200 ms
Biliczki et al, Br. J. Pharmacol, 2002,137:361-368
Activation kinetics 
Resting potential
Activation
Deactivation kinetics 
Deactivation
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)
IKur
Gao et al, Br. J. Pharmacol, 2005; 144, 595-604
Resting potential
Activation
Inactivation
Effect of selective IKur current blockade on action potential
Wang et al. Circ. Res. 1993, 73: 1061
Wettwer et al. Circulation 2004;110:2299-2306
Atria specific currents: The acetylcholine sensitive potassium current (IK,ACh)
Dobrev et al. Circulation 2005;112:3697-3706
Atria specific currents: The acetylcholine sensitive potassium current (IK,ACh)
Dobrev et al. Circulation 2005;112:3697-3706
Selective blockade of IK,ACh may be a new
tretment for cAF ?!?
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
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ATTENTION !