1. CHAPTER 4 CIRCULATION Professor Pan Jing-yun Department of Physiology

3. SECTION 1 ELECTRICAL ACTIVITY OF HEART

4. I. BIOELECTRICAL PHENOMENA OF MYOCARDIAL CELL

7. Differences of AP configurations in different regions of the heart. Fast response potential Fast response cells: atrium cell and ventricle cells – working myocardium. Fast response automatic cells: Purkinje fiber and bundle of His. Slow response potential Slow response cells: S–A node and A–V node.

9. Basic concepts Depolarization –– cations influx ---- Na +, Ca + inward current Repolarization –– cations efflux ---- K + outward current Hyperpolarization: Vm → more negative than RMP Net current: inward ＜ outward repolarization inward ＞ outward depolarization inward ＝ outward no change in Vm

10. A.TRANSMEMBRANE POTENTIAL OF MYOCARDIAL CELL AND THEIR IONIC BASIS

11. ⒈ Typical features Resting membrane potential (RMP) Action potential (AP) Phase o (rapid depolarization) Phase 1(rapid initial repolarization) Phase 2 (plateau) Phase 3 (rapid late repolarization) Phase 4 (resting membrane potential)

13. ⒉ Ionic basis for RMP and AP of working myocardium a. Ionic concentration differences cross membrane b. Permeability to ions (conductance)

14. ⑴ Ionic basis for RMP K + permeability ↑, [K + ] i ＞ [K + ] o RMP ≌ K + equilibrium potential

15. ⑵ Ionic basis for AP Phase 0 (depolarization) Stimulation → partial depolarization → threshold potential (-70mV) →Na + Ch. opening →Na + influx into cell down electrochemical gradient → Vm less negative→0 mV → +30 mV (overshoot)

16. Features of fast Na + channel (1). Activated and inactivated very fast. Speed of depolarization: 120- 200 V / s; Fast response potential Fast response cell Fast channel

17. Regenerative process: depolarization caused by Na + influx induces more Na + Ch. to open and Na + influx. At same time, K + conductance falls and keeps Vm at depolarization state.

18. (2). Voltage dependent Activation -70mV Inactivation +30mV Recovery to reopen from -60mV (3). Blocked by TTX

19. Phase 1 (rapid repolarization) (1) Na + Ch. is inactivated at +30mV (2) Transient outward current (I to ) K + outward current, blocked by tetraethylammonium(TEA) and 4-aminopyridin.

20. Phase 2 (plateau) Ca 2+ Ch. activation at –40mV → Ca 2+ influx → Ca 2+ inward current I K Ch. Is activated slowly at phase o K + slowly efflux → K + outward current Inward Ca 2+ current = outward K + current at early stage of plateau Inward current ＜ outward K + current at late plateau, Vm → more negative → repolarization

21. Close of I K 1 Ch. at phase o and plateau prevents membrane potential from rapid repolarization Phase 2 is the integration of inward Ca 2+ current and outward K + current. The features of Ca 2+ channel:

22. (1).Slow channel, slow inward current, slow activation and inactivation and reactivation (2).Voltage dependent: Activated at –40mV, inactivated at 0mV (3).Blocked by Mn 2+ and verapamil (4).Low specialty: permeability to Na + also.

23. Phase 3 (late repolarization) Ca2+ channel is inactivated. ↑K + efflux via I K channel ↑K + efflux via I K1 channel →↑outward K + current → Vm → more and more negative → RMP.

26. Phase 4 (resting stage) During Phase 1-3, Na +, Ca 2+ and K + imbalance outside and inside cell. During Phase 4, Na +, Ca 2+ efflux against concentration gradient; K + influx against concentration gradient.

27. Na + -K + pump: 3 Na + out and 2 K + in Na + -Ca 2+ exchange – antiport 1 Ca 2+ out and 3 Na + in dependent of Na + concentration difference inside and outside cell. Ca 2+ pump: Ca 2+ out of cell.

28. II. Transmembrane potential of rhythmic cell and their ionic basis Automatic fast response cell –– Purkinje cell. Automatic slow response cell in S-A node and A-V node

29. Spontaneous, phase 4 depolarization the cause of automaticity pacemaker potential ⑴ Maximal repolarization potential at the end of phase 3. ⑵ Phase 4 depolarizes automatically and slowly.

30. ⑶ When depolarization reaches threshold level, excitation (AP) appears..

32. 1. Slow response cell -- P cell in S-A node

33. (1) Features of P cell in S-A node a. Slow depolarization of phase 0, 7ms, 10V ／ s,magnitude 70mV Due to Ca 2+ channel opening, blocked by Verapamil or Mn 2+. b. No distinct phase 1 and phase 2

34. c. Smaller overshoot (+15mV) d. Maximum diastolic potential –70mV, firing level – 40mV. f. Repolarization –– K + outward current. g. Faster spontaneous phase 4 depolarization.

36. (2) Ionic basis for spontaneous phase 4 depolarization in P cell

37. a. Inward current, i f b. Inward Ca 2+ current, i Ca c. Outward K + current, i K

39. a. Inward current, i f Features of i f : (a) Carried by Na +, blocked by Cs, but not TTX (b) Activation at -60mV,full activation at –100mV (c) Noradrenalin → ↑i f Acetylcholine →↓i f

40. b. Inward Ca 2+ current, i Ca Activation at -55mV Noradrenalin → ↑i f Acetylcholine →↓i f Blocked by Ca ch.blockade

42. C. Gradually diminishing outward K + current, I k

43. With time the inward current (i Ca ， if ） ＞ outward current （ I k ), causing phase 4 diastolic depolarization to reach firing level results in a new action potential.

44. 2. Ionic basis of AP of rapid response automatic cells as the same as that of AP of working cells except phase 4.

45. Ionic basis of spontaneous phase 4 depolarization in fast response cell-Purkinje cell

46. (1) Gradual increase in inward current ， i f (2) Gradually diminishing outward K + current, i K I f ＞ I K, depolarization →threshold potential → a new AP

48. III. Electrophysiological properties of cardiac muscle Excitability; Automaticity (autorhythmicity); Conductivity.

49. ⒈ Excitability and its affecting factors (1).Excitability: 1 ／ threshold strength. Affecting factors: a.Excitation is caused by depolarization reaching threshold level, so affecting factors are:

50. 1. Excitability and its affecting factors 1).Excitability index: 1 ／ threshold strength. Affecting factors: a. Excitation is caused by depolarization reaching threshold level, so affecting factors are:

51. (a). RMP level: the lower the RMP, the larger the distance from RMP to threshold potential, the larger the threshold strength needed to induce excitation →↓excitability, [K + ] o ↓

52. (b) Threshold level: Threshold level moves upward, the distance between it and RMP becomes larger, excitability decreases.

53. (c). Behavior of Na + channel Resting activation inactivation stage stage stage reactivation stage

54. Voltage-dependent Na + Ch. Resting stage: - 90 mV Activation stage: - 70mV Inactvation stage: + 30mV Reactivation stage: - 60mV Time-dependent Na + Ch.

55. B. Cyclic changes in excitability in a cardiac cycle (a).Effective refractory period (ERP) 0 – -60mV Absolute refractory period (ARP) 0 – -55mV Local response (no AP) -55 – -60 mV

58. (b) Relative refractory period (RRP) -60 – -80mV Excitability lower than normal, Na + channel is reactivation, but not fully reactivated. Stronger stimulation than normal induces a premature potential.

59. (c) Supra-normal period (SNP) -80 – -90mV Excitability is higher than normal, Vm at this period is less negative than normal RMP, and its distance to threshold potential is shorter than normal. The new AP is still smaller than normal.

60. Feature of premature potential: A propagated AP, but smaller than normal AP Low speed of phase 0; Low amplitude of phase 0; Low conduction; Shorter duration of AP.

61. The speed and amplitude of depolarization are determined by RMP. The recovery of ability of Na + Ch. to reopen depends on membrane potential (Vm).

62. Extrasystole and compensatory pause

63. ⒉ Automaticity (Autorhythmicity) ⑴ Index of automaticity: frequency of discharge of pacemaker cell in S-A node. 100 ／ min: dominant pacemaker A-V junction 50 ／ min, Purkinje fiber 25 ／ min latent or subordinary pacemaker

64. Atrioventricular delay permits optimal ventricular filling Atrioventricular(AV) block complete AV block AV conduction is affected by autonomic nerve system

66. S-A node controls latent pacemaker due to: a. S-A node drives latent pacemaker b. Overdrive suppression: (a) The longer overdrive, the stronger suppression;

68. (b) The larger difference of excitation frequency between two pacemakers, the stronger suppression. Active Na + pump: 3 Na + out, 2 K + in → hyperpolarization → need more time to reach firing level.

70. ⑵ Factors determining automaticity Frequency of excitation of pacemaker cell determinates the time for maximum diastolic potential to reach threshold potential.

72. a. Rate of spontaneous, phase 4 depolarization.βreceptor activation, I f ↑ HR↑ b. Maximum diastolic potential level, g K+ ↑ HR↓ c. Threshold potential level

73. ⑶ Conductivity a. Index of conductivity – speed of conduction of AP b. Factors determining conductivity of cardiac muscle

74. a. Speed and amplitude of phase 0 depolarization (a) ↑ speed of phase 0 depolarization → ↑rate of generation of local current →↓time for depolarization to reach threshold potential → conductivity ↑.

75. (b)↑amplitude of phase 0 depolarization → ↑amplitude of local current → ↑distance of depolarization of nearby membrane → ↑conductivity. (c) Speed and amplitude of phase 0 depolarization is determined by Vm

76. More negative RMP → ↑speed of Na + channel opening → ↑speed of phase depolarization → ↑speed of local current stimulation to reach to threshold potential → ↑speed of conduction

77. More negative RMP → ↑number of Na + channel opening → ↑amplitude of phase 0 depolarization → ↑ amplitude of local current → speed of conduction↑

80. b. ↓excitability of nearby membrane area → ↓conductivity Local current stimulus conducts to area which is in effective refractory period of premature potential. The stimulus can’t induce a new AP and conduction block occurs.

81. Local current stimulus conducts to area which is more negative RMP, excitability decreases and conductivity also decreases.

84. Section 2 Cardiac pump function Cardiac cycle ⒈ Order of contraction and relaxation of atrium and ventricle ⒉ Diastole ＞ systole ⒊ ↑HR → ↓↓diastole, ↓systole ↓HR → ↑↑diastole, ↑systole

85. Contraction or relaxation of heart → changes in pressure → opening or closing of valves → direction of blood flow

86. The opening or closing of valves is a passive process resulting from pressure differences across the valves

88. I. Mechanical events of the cardiac cycle A, Left ventricular ejection and filling 1. Atrial systole 2. Ventricular systole: (1) Isovolumic contraction phase (2) Rapid ejection phase (3) Reduced ejection phase

89. ⒊ Ventricular diastole: (1) Isovolumic relaxation phase (2) Rapid filling phase (3) Reduced filling phase

91. Importance of rapid ventricular filling. Primary pump of atrium: (a) increase in ventricular filling (b) decrease in atrial pressure

92. B. Atrial pressure changes of cardiac cycle a wave, c wave, v wave

93. Ⅲ. Evaluation of cardiac pump function : Stroke volume = EDV – ESV, 70ml Cardiac output = stroke volume × heart rate 5L / min (4.5 - 6.0) Cardiac index = cardiac output / area of body surface, 3.0 – 3.5 L / min / m 2

94. Ejection fraction (EF): SV EDV-ESV EF = ——— = —————— EDV EDV ESV: residue blood volume

96. Cardiac work pressure–volume work + kinetic energy a. Stroke work pressure–volume work / beat = Force ×Distance F×D = (P×A) ×D =P(A×D) = P×ΔV

97. Stroke work(g-m) = SV(cm 3 )× （ 1/1000)×(MAP – mean atrial P)× （ 13.6g/cm 3 ) Minute cardiac work （ Kg-m/min)= SV(g-m)×heart rate×(1/1000) b. Kinetic energy: 1/2mV 2 2-4% of cardiac work

98. Pressure work consumes more oxygen than volume work

99. Ⅳ Control of cardiac output significance: To meet the need of tissues under different conditions To keep cardiac output balance with cardiac filling To match the output of the right and left ventricle

100. Cardiac output = SV × HR Determinants of stroke volume ： （ 1 ） initial length (pre-load) （ 2 ） contractility （ 3 ） after-load

101. (1)Initial length Ventricular function curve SV increases as LVEDV increases at no changes in other factors. Frank-Starling mechanism (1918)

103. EDV is at the left to optimal initial length, SV increases as EDV increases. This feature means that ventricle has larger initial length reserve.

104. Sarcomere length 2.0-2.2  m is optimal initial length. Overlap between thick and thin filements in a sarcomere is very well Number of cross-bridge linkages is the biggest

106. Factors influencing EDV a. Venous return blood volume b. Duration of filling (diastole)

107. a. Venous return blood volume depends on velocity of venous return, which is determined by difference between peripheral venous pressure and end-diastolic pressure.

108. b. Duration of filling (diastole) Increase in HR results in short filling period, distolic filling decreases, therefore, EDV decreases.

109. B. contractility 1.Sympathetic nerve and catecholamine →↑contractility ventricular function curve shifts to upward and the left

114. Contractility is depended by Number of activated cross- bridge linkage /total number of cross-bridge linkage: Intracellular free [Ca 2+ ] Affinity of troponin to Ca 2+

115. Cardiac sympathetic nerve ending → noradrenaline → binds to β- adrenergic receptor→↑permeability to Ca 2+ leads to:

116. ↑Contractility due to ↑[Ca 2+ ] i : ↑Ca 2+ influx → calcium-induced release of calcium → ↑Release Ca 2+ from sarcoplasmic reticulum

117. ↑Speed of relaxation during diastole: a.↓Affinity of Ca 2+ to troponin ↑dissociation Ca 2+ from troponin b.↑Uptake Ca 2+ of sadrcoplasmic reticulum → ↓[Ca 2+ ] i c.↑Na + -Ca 2+ exchange → ↓[Ca 2+ ] i

118. The role of cAMP-dependent protein kinase: Increase in contractile force and speed of contraction Increase in the speed of relaxation

120. ⒊ Effect of after-load on cardiac output After-load –– aortic pressure ↑Aortic pressure →↓stroke volume → blood accumulates in ventricle →↑EDV→ recovery of stroke volume by Frank-Starling mechanism recovery of EDV through ↑contractility → cardiac work↑.

122. 2. Effect of heart rate on cardiac output cardiac output = HR×SV ↑HR, ↑CO. HR ＞ 200bpm, CO↓due to diastole too short, venous return too small.

123. Autonomic nervous system controls heart rate Vagal tone Sympathetic tone

124. (1)Effect of cardiac vagal nerve:↓HR Vagal nerve ending → ACh binds to M cholinergic receptor → ↑permeability to K + results in: ↓automaticity of S-A node:

126. a. More negative maximum diastolic potential b. ↓Speed of phase 4 depolarization due to ↑K + efflux during phase 4, i.e. decrease in diminishing K + outward current

128. ↓conductivity due to: ACh →↓ Ca 2+ influx →↓amplitude of phase 0 depolarization → ↓ conductivity at A-V junction

129. (2) Effects of cardiac sympathetic n Cardiac sympathetic ending →NE binds to βreceptor →↑permeability to Ca 2+ leads to:

130. ↑Automaticity: ↑I f at phase 4 in automatic cell. ↑Conductivity: ↑Ca 2+ influx at phase 0 in A-V junction → ↑Speed and amplitude of phase 0 depolarization → ↑ conductivity

132. Autonomic nervous system controls heart rate Vagal tone predominates in normal person Intrinsic heart rate 100 beats/min

134. ⒌ Cardiac reserve Heart rate reserve Stroke reserve Diastolic reserve Systolic reserve

135. Measurement of myocardia contractility