1. 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

2. 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

3. 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 

4. The ECG and the action potential I.

5. The ECG and the action potential II.

6. Outline of membrane currents of sinus node cells: current profiles (drawn by hand) are time aligned with the action potential. Diastolic depolarization Purkinje fibre

7. The main potassium currents in the ventricular and atrial muscle And many other currents and mechanisms !!!

8. Action potential and fast sodium current (I Na ) in atria and ventricle

9. The fast sodium channel (I Na ) Wu et al, Heart Rhythm, 2008, 5(12):1726-34 100 ms 50 mV I Na m h + + Na outside Resting state inside - m h + + Na outside Active state inside - m + + Na outside Inactive state inside + h Activation kinetics  Inactivation kinetics  Re-activation kinetics

10. Action potential and the L type calcium current (I CaL ) in atria and ventricle Atria

11. Varro et al, Br. J. Pharmacol, (2001) 133, 625 – 634. m h + + Ca outside Resting potential inside - m h + + Ca outside Active inside - m + + Ca outside Inactive inside + h Activation kinetics  Inactivation kinetics  Re-activation kinetics 100 ms 50 mV I CaL L type calcium current (I Ca )

12. Action potential and the transient outward potassium current (I to ) in atria and ventricle Csatorna fehérje

13. Virag et al, unpublished 100 ms 50 mV „Notch” Transient outward potassium current (I to ) Activation Resting potentialInactivation Activation kinetics  Activation kinetics 

14. Effect of selective I to blockade on the action potential Virag et al, unpublished The notch disappearsRepolarization lengthens

15. Action potential and the rapid and slow componets of the delayed rectifier potassium currents (I Kr and I Ks ) in atria and ventricle

16. 25 pA 500 ms 2500ms 100 pA -40 mV 30 mV 5000 ms 2500 ms 50 pA -40 mV 30 mV 1000 ms There is a fast inactivation also ! The fast and slow delayed rectifier potassium currents (I Kr and I Ks ) Resting potential Activation Deactivation Activation kinetics  Deactivation kinetics 

17. 200 ms Difference current 50 pA 0 pA E-4031 sensitive (I Kr ) L-735,821 sensitive (I Ks ) 250 ms -80 mV -40 mV +30 mV Varro et al, J.Physiol. 2000; 523.1: 67-81 Controll 100 nM L-735,821 Controll 1 µM E-4031 200 ms 50 mV The fast and slow delayed rectifier potassium currents (I Kr and I Ks )

18. Action potential and the inward rectifier potassium current (I K1 ) in atria and ventricle

19. The inward rectifier potassium currents (I Kr and I Ks ) Biliczki et al, Br. J. Pharmacol, 2002,137:361-368 Control 10  M BaCl 2 -120 mV -90 mV 60 mV 36 s 1000 pA -120-80-40040(mV) 0 pA 0 mV 50 mV 200 ms cycle length = 1000 ms ------ Control 10  M BaCl 2 The ” inward” rectification is regulated (inhibited) by intracellular cations (Mg 2+, Ca*, polyamines) under depolarization Resting potential Activation Deactivation Activation kinetics  Deactivation kinetics 

20. Summary – the four main repolarizing current under the action potential Dog

21. ? Atria specific currents: The ultrarapid delayed rectifier potassium current (I Kur )

22. Gao et al, Br. J. Pharmacol, 2005; 144, 595-604 I Kur Activation Resting potentialInactivation

23. Wang et al. Circ. Res. 1993, 73: 1061 Wettwer et al. Circulation 2004;110:2299-2306 Effect of selective I Kur current blockade on action potential

24. Dobrev et al. Circulation 2005;112:3697-3706 Atria specific currents: The acetylcholine sensitive potassium current (I K,ACh )

25. Selective blockade of I K,ACh may be a new tretment for cAF ?!? Dobrev et al. Circulation 2005;112:3697-3706 Atria specific currents: The acetylcholine sensitive potassium current (I K,ACh )

26. Other ligand dependent current: the ATP sensitive potassium current (I KATP ) Iost N, et al, J Cardiovasc Pharmacol Ther, 8, 31-41, 2003 Németh M, J Cardiovasc Pharm Ther. 2 (4), 273-284. 1997

29. THANK YOU FOR YOUR ATTENTION !