Differences in cardiac atrial and ventricular ion channels

Transcription

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 The propagation of the stimulation in the heart Sinus node, discovered by Keith and Flack Left atria Sinus node His Bundle Left ventricle Conduction velocity in m/s AV node Left Bundle branch Time to arrive from AV to the respective place (ms) Right atria Right ventricle Right Bundle branch Purkinje fibres

3 The action potential in a ventricular myocyte 1. EXCITABILITY Small triggering stimulus Threshold and autogenerative large response Action Potential Action potential excitation 2. DEPOLARIZATION Na-channel / Na-current Ca- channel / Ca- current from extracellullar space 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 (I Na ) in atria and ventricle

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

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

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

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

13 Transient outward potassium current (I to ) Virag et al, unpublished Notch 50 mv Resting potential Activation kinetics Activation 100 ms Activation kinetics Inactivation

14 Effect of selective I to blockade on the action potential The notch disappears Repolarization lengthens Virag et al, unpublished

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

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

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 ) The inward rectification is regulated (inhibited) by intracellular cations (Mg 2+, Ca*, polyamines) under depolarization Control 10 µm BaCl 2 0 pa 1000 pa 60 mv 36 s -90 mv -120 mv 0 mv (mv) 200 ms 50 mv Control 10 µm BaCl 2 cycle length = 1000 ms Biliczki et al, Br. J. Pharmacol, 2002,137: Resting potential Activation kinetics Activation Deactivation kinetics Deactivation

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 Atria specific currents: The ultrarapid delayed rectifier potassium current (I Kur ) I Kur Gao et al, Br. J. Pharmacol, 2005; 144, Resting potential Activation Inactivation

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

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

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

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),

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29 THANK YOU FOR YOUR ATTENTION!