Download Phase 4

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.
4
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: 120200 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
prevents membrane potential from rapid
repolarization
Phase 2 is the integration of inward
Ca2+current and outward K+current.
The features of Ca2+ channel:
(1).Slow channel, slow inward current, slow
activation and inactivation and
reactivation
(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
⑴ Maximal repolarization potential
at the end of phase 3.
⑵ Phase 4 depolarizes automatically
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
2+
Ca
b. Inward
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
21
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
the threshold strength needed to
induce 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
stage
activation inactivation
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
depolarization are determined by
RMP.
The recovery of ability of Na+ Ch.
to reopen depends on membrane
potential (Vm).
Extrasystole and compensatory
pause
33
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
autonomic 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;
21
(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.
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
activation, If↑ HR↑
b. Maximum diastolic potential
level , 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
depolarization → ↑speed of local
current stimulation to reach to
threshold potential → ↑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-ESV
EF = ——— = ——————
EDV
EDV
ESV: residue blood volume
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
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 2.0-2.2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
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. contractility
1.Sympathetic nerve and catecholamine
→↑contractility
ventricular function curve shifts to
upward and the left
Contractility is depended by
Number of activated crossbridge linkage /total number of
cross-bridge linkage:
Intracellular free [Ca2+]
Affinity of troponin to Ca2+
Cardiac sympathetic nerve ending
→ noradrenaline → binds to βadrenergic receptor→↑permeability
to Ca2+ leads to:
↑Contractility due to ↑[Ca2+]i:
↑Ca2+ influx → calcium-induced
release of calcium →↑Release
2+
Ca 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
protein kinase:
Increase in contractile force and
speed 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
diastole too short, venous return
too small.
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