LIU Chuan Yong 刘传勇 Institute of Physiology Medical School of SDU Tel 88381175 (lab)

1. LIU Chuan Yong 刘传勇 Institute of Physiology Medical School of SDU Tel 88381175 (lab) 88382098 (office) Email: liucy@sdu.edu.cn Website: www.physiology.sdu.edu.cn

2. Section 2 Electrophysiology of the Heart

3. CARDIAC ELECTROPHYSIOLOGY

4. Two kinds of cardiac cells 1, The working cells. Special property: contractility

5. 2, Special conduction system including the Sinoatrial node, Atrioventricular node, Atrioventricular bundle (bundle of His), and Purkinje system. Special property: automaticity

6. Transmembrane Potentials of Myocardial Cells

7. 0 0 mv mv -90mv -90mv 0 mv -80mv ACTION POTENTIALS FROM DIFFERENT AREAS OF THE HEARTFast and Slow Response ATRIUM VENTRICLE SA NODE time

8. ELECTROPHYSIOLOGY OF THE FAST VENTRICULAR MUSCLE AMP +20 1 To oscilloscope 2 0 3 0 mv Cardiac Cell 4 -90 0 300 t (msec)

9. General description Resting potential: -90mv Action Potential Phase 0: rapid depolarization, 1-2ms Phase 1: early rapid repoarization, 10 ms Phase 2: plateau, slow repolarization, the potential is around 0 mv. 100 – 150ms Phase 3, late rapid repolarization. 100 – 150 ms Phase 4 resting potentials +20 1 2 0 3 0 mv 4 -90 0 300 t (msec)

10. Ion Channels in Working Muscle • Essentially same in atrial and ventricular muscle • Best understood in ventricular cells

11. Ion Channels in Ventricular Cells • Voltage-gated Na+ channels • Inward rectifier K+ channels • L-type Ca2+ channels • Several Voltage-gated K+ channels

12. Cardiac Na+ Channels • Almost identical to nerve Na+ channels (structurally and functionally) • very fast opening (as in nerve) • has inactivation state (as in nerve) • NOT Tetrodotoxin sensitive • Expressed only in non nodal tissue • Responsible for initiating and propagating the action potential in non nodal cells

13. +20 1 2 0 3 0 mv 4 -90 0 300 t (msec)

14. Inward Rectifier (Ik1) Structure Note: No “voltage sensor” P-Region Extracellular Fluid M1 M2 membrane Inside H2N HO2C

15. Inward Rectifier Channels 0 Ek

16. Inward Rectification K+ K+ K+ K+ Mg2+ Mg2+ Extracellular solution Intracellular Solution K+ K+ K+ -80 mV -30 mV K+ K+

17. Inward Rectifier Channels 0 Ek

18. Role for Inward Rectifier • Expressed primarily in non nodal tissues • Sets resting potential in atrial and ventricular muscle • Contributes to the late phase of action potential repolarization in non nodal cells

19. +20 1 2 0 3 0 mv 4 -90 0 300 t (msec)

20. Inactivating K channels (ITO) “Ultra-rapid” K channels (IKur) “Rapid” K channels (IKr) “Slow” K channels (IKs) Cardiac Voltage-gated K Channels • All structurally similar to nerve K+ channels • ITO is an inactivating K+ channel- rapid repolarization to the plateau • IKur functions like nerve K+ channel- fights with Ca to maintain plateau • IKr, IKs structurally and functionally complex

21. Cardiac Ca2+ Channels • L-type • Structurally rather similar to Na+ channels • Some functional similarity to Na+ channels • depolarization opens Ca2+ channels • Functionally different than Na+ channels • slower to open • very slow, rather incomplete inactivation • generates much less current flow

22. Role of Cardiac Ca2+ Channels • Nodal cells • initiate and propagate action potentials- SLOW • Non nodal cells • controls action potential duration • contraction

23. Ca2+CHANNEL BLOCKERS AND THE CARDIAC CELL ACTION POTENTIAL DILTIAZEM 地尔硫卓 ACTION POTENTIAL CONTROL 10 µMol/L 30 µMol/L 10 30 CONTROL 10 FORCE 30 TIME

24. 0 0 mv mv -90mv -90mv Ion Channels in Atrial Cells • Same as for ventricular cells • Less pronounced plateau due to different balance of voltage-gated Ca2+ and K channels ATRIUM VENTRICLE

25. OVERVIEW OF SPECIFIC EVENTS IN THE VENTRICULAR ACTION POTENTIAL

26. Activation & Fast Inactivation

27. Na+ Na+ m m m A B h h -65mv -90mv Na+ Na+ m m C D h h 0mv +20mv Na+ m E h +30mv PHASE 0 OF THE FAST FIBER ACTION POTENTIAL Chemical Gradient Electrical Gradient

28. Inactivating K channels (ITO) “Ultra-rapid” K channels (IKur) “Rapid” K channels (IKr) “Slow” K channels (IKs) Voltage-gated Na Channels Voltage-gated Ca Channels 200 msec IK1 Ion Channels in Ventricular Muscle 0 Ventricular muscle membrane potential (mV) -50

29. Ion Channels in Ventricular Muscle Current Na Current Ca Current IK1 ITO IKur IKr IKs

30. 2. Transmembrane Potential of Rhythmic Cells

31. Ion Channels in Purkinje Fibers • At phase 4, the membrane potential does not maintain at a level, • but depolarizes automatically – the automaticity • (Phase 0 – 3) Same as for ventricular cells • (Phase 4) Plus a very small amount of If (pacemaker) channels

32. Activated by negative potential (at about -60 mv during Phase 3) • Not particularly selective: allows both Na+ and K+

33. The SA node cell • Maximal repolarization (diastole) potential, –70mv • Low amplitude and long duration of phase 0. • not so sharp as ventricle cell and Purkinje cell. • No phase 1 and 2 • Comparatively fast spontaneous depolarization at phase 4 A, Cardiac ventricular cell B, Sinoatrial node cell

34. SA Node Action Potential Voltage-gated Ca channels Voltage-gated K channels 0 SA node membrane potential (mV) No inward-rectifier K channels -50 If or pacemaker channels 200 msec

35. SA Node Cells Current Ca Current K currents If (pacemaker current)

36. CAUSES OF THE PACEMAKER POTENTIAL K+ if iCa OUT IN iK Na+ Ca++

37. LOOKING AT THE PACEMAKER CURRENTS voltage iK if ionic currents iCa

38. AV Node Action Potentials • Similar to SA node • Latent pacemaker • Slow, Ca+2-dependent upstroke • Slow conduction (delay) • K+-dependent repolarization 0 AV node membrane potential (mV) SA node -50 AV node 200 msec

39. Fast and slow response, rhythmic and non-rhythmic cardiac cells • Fast response, non –rhythmic cells: working cells • Fast response, rhythmic cells: cells in special conduction system of A-V bundle and Purkinje network. • Slow response, non-rhythmic cells: cells in nodal area • Slow response rhythmic cells: S-Anode, atrionodal area (AN), nodal –His (NH)cells

40. II Electrical Properties of Cardiac Cells Excitability, Conductivity and Automaticity

41. 1. Excitability of Cardiac Muscle

42. (1) Refractory Period +25 1 RRP 0 -25 2 3 0 -50 Transmembrane Potential 4 ARP -75 -100 -125 0 0.1 0.2 0.3 Time (msec) • Absolute Refractory Period – regardless of the strength of a stimulus, the cell cannot be depolarized. • Relative Refractory Period – stronger than normal stimulus can induce depolarization.

43. Refractory Period • Absolute Refractory Period (ARC): Cardiac muscle cell completely insensitive to further stimulation • Relative Refractory Period (RRC): Cell exhibits reduced sensitivity to additional stimulation

44. Na+ Channel Conformations Another Non-conducting conformation (a while after more depolarized potentials) Non-conducting conformation(s) (shortly after more depolarized potentials) Conducting conformation (at negative potentials) Open Inactivated Closed Outside IFM Inside IFM IFM

45. Refractory Period • The plateau phase of the cardiac cell AP increases the duration of the AP to 300 msec, • The refractory period of cardiac cells is long (250 msec). • compared to 1-5 msec in neurons and skeletal muscle fibers.

46. Refractory Period • Long refractory period prevents tetanic contractions • systole and diastole occur alternately. • very important for pumping blood to arteries.

47. Comparison of refractory period and summation in cardiac and skeletal muscle fibers

48. Absolute S.N. Rel Supranormal period: • Occurs early in phase 4 and is usually accompanied by negative after-potentials as some potassium channels close. • The membrane potential is about -80 mv - -90 mv, near threshold potential

50. Skeletal Vs. Cardiac muscle contraction • Impulse generation: Intrinsic in cardiac muscle, extrinsic in skeletal muscle • Plateau phase: Present in cardiac muscle, absent in skeletal muscle • Refractory period: long in cardiac muscle, shorter in skeletal muscle • Summation: Impossible in cardiac muscle, possible in skeletal muscle