![Page 1: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/1.jpg)
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
![Page 2: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/2.jpg)
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
![Page 3: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/3.jpg)
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
![Page 4: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/4.jpg)
The ECG and the action potential I.
![Page 5: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/5.jpg)
The ECG and the action potential II.
![Page 6: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/6.jpg)
Outline of membrane currents of sinus node cells: current profiles (drawn by hand) are time aligned with the action potential.
Diastolic depolarization
Purkinje fibre
![Page 7: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/7.jpg)
The main potassium currents in the ventricular and atrial muscle
And many other currents and mechanisms !!!
![Page 8: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/8.jpg)
Action potential and fast sodium current (INa) in atria and ventricle
![Page 9: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/9.jpg)
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
![Page 10: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/10.jpg)
Action potential and the L type calcium current (ICaL) in atria and ventricle
Atria
![Page 11: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/11.jpg)
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)
![Page 12: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/12.jpg)
Action potential and the transient outward potassium current (Ito) in atria and ventricle
Csatorna fehérje
![Page 13: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/13.jpg)
Virag et al, unpublished
100 ms
50 m
V
„Notch”
Transient outward potassium current (Ito)
ActivationResting potential
InactivationActivation kinetics Activation kinetics
![Page 14: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/14.jpg)
Effect of selective Ito blockade on the action potential
Virag et al, unpublished
The notch disappearsRepolarization lengthens
![Page 15: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/15.jpg)
Action potential and the rapid and slow componets of the delayed rectifier potassium currents (IKr and IKs) in atria and ventricle
![Page 16: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/16.jpg)
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
![Page 17: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/17.jpg)
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)
![Page 18: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/18.jpg)
Action potential and the inward rectifier potassium current (IK1) in atria and ventricle
![Page 19: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/19.jpg)
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
![Page 20: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/20.jpg)
Summary – the four main repolarizing current under the action potential
Dog
![Page 21: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/21.jpg)
?
Atria specific currents: The ultrarapid delayed rectifier potassium current (IKur)
![Page 22: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/22.jpg)
Atria specific currents: The ultrarapid delayed rectifier potassium current (IKur)
Gao et al, Br. J. Pharmacol, 2005; 144, 595-604
IKur
ActivationResting potential
Inactivation
![Page 23: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/23.jpg)
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
![Page 24: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/24.jpg)
Dobrev et al. Circulation 2005;112:3697-3706
Atria specific currents: The acetylcholine sensitive potassium current (IK,ACh)
![Page 25: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/25.jpg)
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)
![Page 26: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/26.jpg)
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
![Page 27: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/27.jpg)
![Page 28: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/28.jpg)
![Page 29: Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division](https://reader035.vdocuments.us/reader035/viewer/2022062503/5a4d1ae37f8b9ab0599782cb/html5/thumbnails/29.jpg)
THANK YOU FOR YOUR ATTENTION !