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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. Left atria. Sinus node. His Bundle. Left ventricle.

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Differences in cardiac atrial and ventricular ion channels

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  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. Left atria Sinus node His Bundle 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 propagation of the stimulation in the heart Sinus node, discovered by Keith and Flack Conduction velocity in m/s

  3. Action potential REPOLARIZATION DEPOLARIZATION The action potential in a ventricular myocyte 1. EXCITABILITY Small triggering stimulus large response „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

  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. Purkinje fibre Diastolic depolarization

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

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

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

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

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

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

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„Notch” 50 mV Activation kinetics  Activation kinetics  Resting potential Inactivation Activation 100 ms Virag et al, unpublished

  14. Repolarization lengthens The notch disappears Effect of selective Ito blockade on the action potential Virag et al, unpublished

  15. Action potential and the rapid and slow componets of the delayed rectifier potassium currents (IKr and IKs) in atria and ventricle

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

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

  18. Action potential and the inward rectifier potassium current (IK1) in atria and ventricle

  19. The inward rectifier potassium currents (IKr and IKs) Activation kinetics  Deactivation kinetics  Resting potential Activation Deactivation The ” inward” rectification is regulated (inhibited) by intracellular cations (Mg2+, Ca*, polyamines) under depolarization 10 M BaCl2 Control 0 mV Control 0 pA 10 M BaCl2 1000 pA --- 60 mV 50 mV -90 mV 36 s -120 mV cycle length = 1000 ms -120 -80 -40 0 40 (mV) 200 ms Biliczki et al, Br. J. Pharmacol, 2002,137:361-368

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

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

  22. IKur Resting potential Inactivation Activation Atria specific currents: The ultrarapid delayed rectifier potassium current (IKur) Gao et al, Br. J. Pharmacol, 2005; 144, 595-604

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

  24. Atria specific currents: The acetylcholine sensitive potassium current (IK,ACh) Dobrevet al. Circulation 2005;112:3697-3706

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

  26. 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

  27. THANK YOU FOR YOUR ATTENTION !

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