Differences in cardiac atrial and ventricular ion channels Norbert Jost, PhD Department of...

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

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

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

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.

Diastolic depolarization

Purkinje fibre

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)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

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

Atria

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)

Action potential and the transient outward potassium current (Ito) in atria and ventricle

Csatorna fehérje

Virag et al, unpublished

100 ms

50 m

V

„Notch”

Transient outward potassium current (Ito)

ActivationResting potential

InactivationActivation kinetics Activation kinetics

Effect of selective Ito blockade on the action potential

Virag et al, unpublished

The notch disappearsRepolarization lengthens

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

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

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)

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

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

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)

Gao et al, Br. J. Pharmacol, 2005; 144, 595-604

IKur

ActivationResting potential

Inactivation

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

Dobrev et al. Circulation 2005;112:3697-3706

Atria specific currents: The acetylcholine sensitive potassium current (IK,ACh)

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)

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

THANK YOU FOR YOUR ATTENTION !