CHAPTER 4

CIRCULATION

Professor Pan Jing-yun

Department of Physiology

SECTION 1

ELECTRICAL ACTIVITY

OF HEART

I. BIOELECTRICAL

PHENOMENA OF

MYOCARDIAL CELL

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.

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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

A. TRANSMEMBRANE POTENTIAL

OF MYOCARDIAL CELL AND

THEIR IONIC BASIS

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)

⒉ Ionic basis for RMP and AP

of working myocardium

a. Ionic concentration differences

cross membrane

b. Permeability to ions

(conductance)

⑴ Ionic basis for RMP

K+ permeability ↑, [K+]i ＞ [K+]o

RMP ≌ K+ equilibrium potential

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)

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

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.

(2). Voltage dependent

Activation -70mV

Inactivation +30mV

Recovery to reopen from -60mV

(3). Blocked by TTX

Phase 1 (rapid repolarization)

(1) Na+ Ch. is inactivated at +30mV

(2) Transient outward current (Ito)

K+outward current, blocked by

tetraethylammonium(TEA) and

4-aminopyridin.

Phase 2 (plateau)

Ca2+ Ch. activation at –40mV → Ca 2+ influx → Ca2+ inward current

IK Ch. Is activated slowly at phase o

K+ slowly efflux → K+ outward current

Inward Ca2+ current = outward K+ current at early stage of plateau

Inward current ＜ outward K+ current at late plateau, Vm → more negative → repolarization

Close of IK1 Ch. at phase o and plateau prev

ents membrane potential from rapid repola

rization

Phase 2 is the integration of inward

Ca2+current and outward K+current.

The features of Ca2+ channel:

(1).Slow channel, slow inward current, slo

w activation and inactivation and reacti

vation

(2).Voltage dependent:

Activated at –40mV, inactivated at 0mV

(3).Blocked by Mn2+ and verapamil

(4).Low specialty: permeability to Na+ also.

Phase 3 (late repolarization)

Ca2+ channel is inactivated.

↑K+ efflux via IK channel

↑K+ efflux via IK1 channel →↑outward

K+ current → Vm → more and more

negative → RMP.

Phase 4 (resting stage)

During Phase 1-3, Na+, Ca2+ and K+

imbalance outside and inside cell.

During Phase 4, Na+, Ca2+ efflux

against concentration gradient;

K+ influx against concentration gradient .

Na+-K+ pump:

3 Na+ out and 2 K+ in

Na+-Ca2+ exchange – antiport

1 Ca2+ out and 3 Na+ in dependent of

Na+ concentration difference inside and

outside cell.

Ca2+ pump: Ca2+ out of cell.

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

Spontaneous, phase 4 depolarization

the cause of automaticity

pacemaker potential

Maximal repolarization potential ⑴ at the end of phase 3.

Phase 4 depolarizes automatically ⑵ and slowly.

⑶ When depolarization reaches

threshold level, excitation (AP)

appears.

.

1. Slow response cell -- P cell in

S-A node

(1) Features of P cell in S-A node

a. Slow depolarization of phase 0,

7ms, 10V ／ s ,magnitude 70mV

Due to Ca2+ channel opening,

blocked by Verapamil or Mn2+.

b. No distinct phase 1 and phase 2

c. Smaller overshoot (+15mV)

d. Maximum diastolic potential

–70mV, firing level – 40mV.

f. Repolarization –– K+ outward

current.

g. Faster spontaneous phase 4

depolarization.

(2) Ionic basis for spontaneous

phase 4 depolarization in P

cell

a. Inward current, if

b. Inward Ca2+ current, iCa

c. Outward K+ current, iK

a. Inward current, if

Features of if:

(a) Carried by Na+, blocked

by Cs, but not TTX

(b) Activation at -60mV,full

activation at –100mV

(c) Noradrenalin → ↑if

Acetylcholine →↓if

b. Inward Ca2+ current, iCa

Activation at -55mV

Noradrenalin → ↑if

Acetylcholine →↓if

Blocked by Ca ch.blockade

C. Gradually diminishing outward

K+ current, Ik

With time the inward current (iCa ， if ）

＞ outward current （ Ik), causing phase 4

diastolic depolarization to reach firing

level results in a new action potential.

2. Ionic basis of AP of rapid

response automatic cells

as the same as that of AP of

working cells except phase 4.

Ionic basis of spontaneous

phase 4 depolarization in fast

response cell-Purkinje cell

(1) Gradual increase in inward

current ， if

(2) Gradually diminishing outward

K+ current, iK

If ＞ IK , depolarization →threshold

potential → a new AP

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III. Electrophysiological properties

of cardiac muscle

Excitability;

Automaticity (autorhythmicity);

Conductivity.

⒈Excitability and its affecting factors

(1).Excitability: 1 ／ threshold strength.

Affecting factors:

a.Excitation is caused by depolarization

reaching threshold level, so affecting

factors are:

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:

(a). RMP level: the lower the RMP,

the larger the distance from RMP

to threshold potential, the larger t

he threshold strength needed to in

duce excitation →↓excitability, [K+]o↓

(b) Threshold level:

Threshold level moves upward,

the distance between it and RMP

becomes larger, excitability

decreases.

(c). Behavior of Na+ channel

Resting activation inactivation stage stage stage reactivation stage

Voltage-dependent Na+ Ch.

Resting stage: - 90 mV

Activation stage: - 70mV

Inactvation stage: + 30mV

Reactivation stage: - 60mV

Time-dependent Na+ Ch.

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

(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.

(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.

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.

The speed and amplitude of depol

arization are determined by RMP.

The recovery of ability of Na+ Ch.

to reopen depends on membrane

potential (Vm).

Extrasystole and compensatory pause

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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

Atrioventricular delay permits

optimal ventricular filling

Atrioventricular(AV) block

complete AV block

AV conduction is affected by auton

omic nerve system

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;

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(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 t

o reach firing level.

⑵ Factors determining automaticity

Frequency of excitation of pacemaker

cell determinates the time for maximum

diastolic potential to reach threshold

potential.

a. Rate of spontaneous, phase 4

depolarization.βreceptor activa

tion, If↑ HR↑

b. Maximum diastolic potential l

evel , gK+↑ HR↓

c. Threshold potential level

⑶ Conductivity

a. Index of conductivity – speed of

conduction of AP

b. Factors determining conductivity

of cardiac muscle

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 ↑.

(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

More negative RMP → ↑speed of Na+

channel opening → ↑speed of phase d

epolarization → ↑speed of local curre

nt stimulation to reach to threshold p

otential → ↑speed of conduction

More negative RMP → ↑number of

Na+ channel opening → ↑amplitude of

phase 0 depolarization → ↑ amplitude

of local current → speed of

conduction↑

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.

Local current stimulus conducts to

area which is more negative RMP,

excitability decreases and

conductivity also decreases.

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

Contraction or relaxation of heart →

changes in pressure → opening or

closing of valves → direction of blood

flow

The opening or closing of valves

is a passive process resulting from

pressure differences across the

valves

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

⒊ Ventricular diastole:

(1) Isovolumic relaxation phase

(2) Rapid filling phase

(3) Reduced filling phase

Importance of rapid ventricular

filling.

Primary pump of atrium:

(a) increase in ventricular

filling

(b) decrease in atrial pressure

B. Atrial pressure changes of

cardiac cycle

a wave, c wave, v wave

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 / m2

Ejection fraction (EF):

SV EDV-ESVEF = ——— = —————— EDV EDV

ESV: residue blood volume

Cardiac work pressure–volume work + kinetic energya. Stroke work

pressure–volume work / beat = Force ×Distance

F×D = (P×A) ×D =P(A×D)

= P×ΔV

Stroke work(g-m) =

SV(cm3)× （ 1/1000)×(MAP –

mean atrial P)× （ 13.6g/cm3)

Minute cardiac work （ Kg-m/min)=

SV(g-m)×heart rate×(1/1000)

b. Kinetic energy: 1/2mV2

2-4% of cardiac work

Pressure work consumes more

oxygen than volume work

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

Cardiac output = SV × HR Determinants of stroke volume ： （ 1 ） initial length (pre-load)

（ 2 ） contractility

（ 3 ） after-load

(1) Initial length

Ventricular function curve

SV increases as LVEDV

increases at no changes in other

factors.

Frank-Starling mechanism(1918)

EDV is at the left to optimal initial

length, SV increases as EDV

increases. This feature means that

ventricle has larger initial length

reserve.

Sarcomere length 2.0-2.2m is opti

mal initial length.

Overlap between thick and thin file

ments in a sarcomere is very well

Number of cross-bridge linkages is

the biggest

Factors influencing EDV

a. Venous return blood volume

b. Duration of filling (diastole)

a. Venous return blood volume

depends on velocity of venous

return, which is determined by

difference between peripheral

venous pressure and end-diastolic

pressure.

b. Duration of filling (diastole)

Increase in HR results in short

filling period, distolic filling

decreases, therefore, EDV

decreases.

B. contractility1.Sympathetic nerve and catecholamine

→↑contractility

ventricular function curve shifts to

upward and the left

Contractility is depended by

Number of activated cross-

bridge linkage /total number of

cross-bridge linkage:

Intracellular free [Ca2+]

Affinity of troponin to Ca2+

Cardiac sympathetic nerve ending

→ noradrenaline → binds to β-

adrenergic receptor→↑permeability

to Ca2+ leads to:

↑Contractility due to ↑[Ca2+]i:

↑Ca2+ influx → calcium-induced

release of calcium →↑Release

Ca2+ from sarcoplasmic

reticulum

↑Speed of relaxation during diastole:

a.↓Affinity of Ca2+ to troponin

↑dissociation Ca2+ from troponin

b.↑Uptake Ca2+ of sadrcoplasmic

reticulum → ↓[Ca2+]i

c.↑Na+-Ca2+ exchange → ↓[Ca2+]i

The role of cAMP-dependent prote

in kinase:

Increase in contractile force and s

peed of contraction

Increase in the speed of relaxation

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↑.

2. Effect of heart rate on cardiac output

cardiac output = HR×SV

↑HR, ↑CO.

HR ＞ 200bpm, CO↓due to diasto

le too short, venous return too sma

ll.

Autonomic nervous system controls heart rate Vagal tone Sympathetic tone

(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:

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

↓conductivity due to: ACh →↓

Ca2+ influx →↓amplitude of

phase 0 depolarization → ↓

conductivity at A-V junction

(2) Effects of cardiac sympathetic n

Cardiac sympathetic ending →NE

binds to βreceptor →↑permeability

to Ca2+ leads to:

↑Automaticity:

↑If at phase 4 in automatic cell.

↑Conductivity: ↑Ca2+ influx

at phase 0 in A-V junction →

↑Speed and amplitude of

phase 0 depolarization → ↑

conductivity

Autonomic nervous system controls

heart rate

Vagal tone predominates in normal

person

Intrinsic heart rate 100 beats/min

⒌ Cardiac reserve

Heart rate reserve

Stroke reserve

Diastolic reserve

Systolic reserve

Measurement of myocardia contractility