심장생리 1. cardiac muscle 의 특성 ; ec coupling 의 특성 ; 활동전압의 기능 ;...
TRANSCRIPT
심장생리
1. Cardiac muscle 의 특성 ; EC coupling 의 특성 ;활동전압의 기능 ; 활동전압의 component; 활동전압의 전도2,3. Ionic mechanism of action potentials; Cardiac Ion Channels;4. Mechanism of EKG 5. Mechanical properties; Cardiac cycle6. Autonomic control of cardiac function and the mechanism7. Pathophysiology: Arrhythmias; Ischemic heart disease;heart failure
Heart as a pump
• 250 - 300 g
• 70 - 75 beat/min, 5 l/min
• automaticity
• Regulated by: - autonomic nervous system - metabolic demand
• (right) atrium: - volume receptor - endocrine organ (ANP)
Contractility
Microscopic structure of a cardiac myocyte
• Myofibrils: cell volume 의 1/2 차지 ; thick filament 와 thin filament 의 규칙적 배열로 sarcomere 형성 ; I-band/A-band/Z-line
• Mitochondria: cell volume 의 1/3 차지 ; aerobic metabolism using fatty acid and lactate
• Tubular System- T-tubule: extension of the surface membrane into cell interior; located at Z-line- Sarcoplasmic Reticulum: surrounding myofilament; Ca 저장고 .
심장근의 구조적 특징- Multicellular tissue, but functional syncytium- Mechanical & electrical coupling via characteristic cell junction- gap junction in intercalated disc electrical synapse 형성
Spontaneous Rhythm generationConductionContraction
Cardiac Function
Initiated and Regulated by Action Potentials
Long Duration Long Refractory Period
심장근 활동전압의 특징
Long Refractory Period No Tetanus
수축 (Systole) : 세포내 Ca2+ 농도의 증가
이완 (Diastole) : 세포내 Ca2+ 농도의 감소
Cardiac Cycle
심장근 흥분 - 수축 연결 (E-C coupling) 의 특징
1. 활동전압과 수축과의 시간적 관계2. 세포밖 Ca2+ 에 의존적
활동전압과 수축과의 관계 특징
골격근
심장근
Ca2+ source for contraction
1. Ca2+ entry : Ca2+ channel during action potential
2. Ca2+-induced Ca2+ release (CICR) :from sarcoplasmic reticulum
Ca2+ removal during diastole
1. Reuptake to Sarcoplasmic Reticulum : Ca2+-ATPase (Ca2+ Pump)
2. Extrusion to extracellular space : Na/Ca Exchange
C ell M em brane S arcoplasm ic R eticu lum
C a channel
N a/C a Exchange
C a R elease
C a R euptake
R E G U LATIO N O F IN TR A C E LLU LA R C A LC IU M
S R
[C a ]2 +
심장근과 골격근의 비교
Spontaneous Rhythm generationConductionContraction
Cardiac Function
Initiated and Regulated by Action Potentials
Sino-Atrial Node
Atrial Track AM
Atrio-Ventricular Node
His Bundle
Purkinje fibre VM
Pacemaker and Specialized conduction system
Specialized conduction system
Leading pacemaker site in SA node
Atrial myocyteVentricular myocyte
15 m
Isolated cardiac myocytes
Sinoatrial node cell
Regional difference in cardiac action potentials
Resting or diastolic Potential (Phase 4)
Upstroke(Phase 0)
Phase of cardiac action potential
Repolarization
Phase 4
Phase 0
Phase 1
Phase 2
Phase 3
Three phases of repolarization
Phase 4 0
3
12
Important Factors of Action Potential
1. Resting Membrane Potential or Spontaneous Depolarization
2. Upstroke velocity (dV/dt)
3. Duration of AP (APD)
Resting Membrane Potential : VM, AM
Spontaneous Depolarization : SA, AV, PF
Dominent pacemaker/Latent pacemaker
Phase 4
Phase 0: - Upstroke velocity is determined by the negativity of RMP- Upstroke velocity determines the conduction velocity
Fast Action Potential : VM, AM, PF
Slow Action Potential : SA, AV
Action Potential Duration
APD
Related with 1. Refractory period 2. Contractile force
Early After Depolarization (EAD)
R epo larizationU pstroke
Pacem aker Depolarization ? ? ?
RMP-90 mV
MDP-65 mV
UpstrokeRepolarization
Ventricular AP Sinoatrial AP
Ionic Basis of Action Potentials:
How to understand the generation of electrical signal (V)
from the characteristics of ion channels and currents (I)
I vs V
5 0 0 m s
0
- 2 0
0
- 0 .2
2 0 0 m s
m V
n A0
- 1
2 0 0 m s
n A
- 4 0
- 4 0
- 3 0
+ 5 0- 5 0
- 9 0
Recording of action potentials and ionic currents using patch clamp technique
-50 0 50 100 150 200 250 300 350
-80
-60
-40
-20
0
20
40
60
80
Act
ion
po
ten
tial (
mV
)
ms
Ventricular myocyte -80 mV
80 mV
-120 mV
-150 -100 -50 0 50 100
-5000
-4000
-3000
-2000
-1000
0
1000
2000
3000
pA
mV
Outward Current ;
Cause repolarization
or hyperpolarization
Cause depolarization
Inward Current:
I(Ca) I(Na/Ca)I(back)
I(Na)
I(K)I(to)I(pump)
Ionic Currents in Cardiac Myocytes
Inward>Outward Outward>Inward
Depolarization
Repolarization
Ventricular Action Potential
Resting
Depolarizing current conducted from neighbouring cells
Oscillation of the Balance between Inward and Outward Currents
Inward>Outward Outward>Inward
Depolarization
Repoarization
Oscillation of the Balance between Inward and Outward Currents in Sinoatrial Node
D epolarization R epolarization
Inw ard>O utw ard O utw ard> Inw ard
Ion Channels
Na channels
Ca channels:L-type
T-type
K channels: Inward rectifier
Delayed rectifier (rapid/slow)
Transient outward
ACh-activated
ATP-sensitive
Hyperpolarization-activated inward current
Cl channels
Electrogenic transporters Na-K pump
Na/Ca exchanger
5 nA
10 ms
-80mV -50mV
60mV
0 100 200 300 400 500-4000
-3000
-2000
-1000
0
1000
pA
ms
-35 mV40 mV
-80 mV-50 mV
-60 -40 -20 0 20 40
-2500
-2000
-1500
-1000
-500
0
pA
mV
-100 -80 -60 -40 -20 0 20 40 60
-5000
-4000
-3000
-2000
-1000
0
1000
pA
mV
Na current Ca current
Na Channel 활성화 (activation) 되면 전기화학적 경사에 의해 Na 이온이 세포내로 유입되어 내향전류가 발생 .
심실근 활동전압의 빠른 upstroke ( 수십 V/s) 는 Na 통로의 활성화에 기인 : fast action potential fast conduction velocity
Na 통로는 수 ms 내에 곧 비활성화 (inactivation) 되므로 지속적으로 내향전류를 발생하지는 않음 .
비활성화 (inactivation) 의 장애 -- 재분극 지연 -- APD 증가로 인한 long QT syndrome 의 원인 .
Na channel blocker: - TTX - 복어독 - local anesthetics (lidocain, quinidine 등 ) 은 Na 통로의 비활성화를 negative 로 shift -- 부정맥 치료에도 사용 (anti-arrhythmic drug)
Ca Channel 활성화되었을 때 Ca 이온이 세포내로 유입되며 내향전류가 발생한다 .
Na 통로에 비해 activation, inactivation 이 느림
심실근 , 심방근에서의 Ca 전류는 활동전압의 plateau 유지에 기여
동방결절이나 방실결절 같이 안정막전압이 낮아서 Na channel 은 비활성인 세포에서는 활동전압의 upstroke 에 기여 : upstroke dV/dt 느림 --- slow AP --- slow conduction
유입된 Ca 은 흥분 - 수축 연결에서 작용 : 수축의 유발 , 수축 크기 결정에 기여 .
Ca channel blocker-- inorganic blocker: Mn, Co, Ni -- organic blocker: verapamil, D-600, diltiazem, nifedipine 등 . 부정맥 , 고혈압 치료에 쓰임 .
0 200 400 600 800 1000
-60
-40
-20
0
20
40 Density : 0.05 -> controlDensity : 1
Density : 0 B C D
0 200 400 600 800 1000-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
Density : 1Density : 0.05Density : 0 B
C D
Ventricle SA node
0 200 400 600 800 1000-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
2
Density : 2
Density : 1
Density : 0 B C D
0 200 400 600 800 1000-100
-80
-60
-40
-20
0
20
40
60
Density : 2
Density : 1
Density : 0 B C D
Contribution of INa : Simulation study
-0.6
-0.4
-0.2
0.0
0.2
nA
1000 2000 3000 4000
-80
-60
-40
-20
0
20
40
Ac
tio
n P
oten
tia
l(m
V)
T im e(ms)
L-Ca density 0
L-Ca density 0.8
L-Ca density 1
A. SA-Node
B. Ventricle
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
nA
0 500 1000-100
-80
-60
-40
-20
0
20
40
60
Actio
n P
oten
tial(m
V)
Time(ms)
L-Ca density 0
L-Ca density 0.5
L-Ca density 1
Contribution of ICa : Simulation study
Effect of Ca channel blocker
K Channel
활성화되면 K 이온이 전기화학적 경사에 의해 세포외로 유출되어 외향전류가 발생되므로 , 활동전압을 재분극 시키는 역할 .
내향전류와의 balance 에 의해 action potential duration(APD) 가 결정됨 .
다양성이 특징이라 할 수 있을 정도로 종류가 많음 . - Inward rectifier (IRK, IK1) : resting membrane potential
- Transient outward (Ito): phase 1 repolarization
- Delayed rectifier : rapidly activating -- IKr
slowly activating --- IKs
- ATP-dependent K channel (KATP)
- Acetylcholine-activated K channel (KACh)
200 400 600 800 1000 1200 1400
-6000
-5000
-4000
-3000
-2000
-1000
0
1000
2000
3000
4000
5000
6000
pA
ms
0
-0.2
200 ms
nA
-40 -30
+50
ICa
IKr
-70
+50
-80
Ito
0 50 100 150 200 250
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
mV
ms
0 50 100 150 200 250
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
nA
ms-100 -80 -60 -40 -20 0 20 40 60 80 100 120
0.0
0.5
1.0
1.5
2.0
nA
mV
IV-curve
Transient outward K current in ventricle
-Phase 1 repolarization 에 주로 기여 .-Myocardium region 에 따라 density 가 다름 : Purkinje fiber, epicardial, midmyocardial region 에 phase 1 notch 가 prominent, endocardial region 은 less prominent.
Epicardial cell
M cell
Endocardial cell
0 50 100 150 200
-100
-80
-60
-40
-20
0
20
40
60
80 Density 0.1
Density 1
Density 5
mV
ms
0 50 100 150 200
-0.20.00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.03.23.43.6
Density 0.1
Density 1
Density 5
mV
ms
Ventricle
Phase 1 repolarization 에 중요
Contribution of Ito : Simulation study
0 200 400 600 800 1000
-100
-80
-60
-40
-20
0
20
40
60
Density : 10Density : 1Density : 0 B
C D
Ventricle
Contribution of IK : Simulation study
0 200 400 600 800 1000
-80
-60
-40
-20
0
20
40Density : 2Density : 1.5 -> control
Density : 1 B C D
SA node
Contribution of IK : Simulation study
0 200 400 600 800 1000
-2.0
-1.5
-1.0
-0.5
0.0
0.5
0 200 400 600 800 1000
-140
-120
-100
-80
-60
-40
-20
0
20
40
-160 -140 -120 -100 -80 -60 -40 -20 0 20 40 60
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
Step pulse
Current IV - Curve
Inward rectifier K+ channel
I-V relationship of inward rectifier K current, IK1
-Large conductance at RMP-Allow little outward current at plateau
0 200
-100
-80
-60
-40
-20
0
20
40
60
80
100
Density : 5Density : 1Density : 0 B
C DVentricle
SA node
0 200 400 600 800 1000
-80
-60
-40
-20
0
20
40 Density : 1Density : 0.03 -> controlDensity : 0 B
C D
Contribution of IK1 : Simulation study
Effect of external K concentration
Acetylcholine-activated K current
IN Gi/o
OUTACh
m2
KACh channel
2 min
500 pA
ACh ACh
a b c d
-120 -80 -40 0 40
-2000
-1000
0
1000
I (pA)
cb
a, d
mV
R epo larizationU pstroke
Pacem aker Depolarization ? ? ?
RMP-90 mV
MDP-65 mV
UpstrokeRepolarization
Ventricular AP Sinoatrial AP
RMPIK1
UpstrokeINa
Ventricular AP
ICa
IK
ICa
Ito
IK and IK1
Balance betweenIK and ICa INa/Ca
IK
5 0 0 m s
0
- 2 0
0
- 0 .2
2 0 0 m s
m V
n A0
- 1
2 0 0 m s
n A
- 4 0
- 4 0
- 3 0
+ 5 0- 5 0
- 9 0
SA node cell
Pacemaker current (If, Ih) : hyperpolarization-activated inward currents
ICa
IK
R epo larizationU pstroke
Pacem aker Depolarization ? ? ?
MDP
Sinoatrial Node
ICaIK
IK decay, If , ICa, Ib
Ib, IK,Absence of IK1
Ionic Currents contributing to AP
Simulation study: contribution of each current
Cardiac Ion Channels
Electrical properties (Resting Membrane Potential, Action Potential) 를 결정지을 뿐 아니라 , 수축의 발생 및 조절과도 밀접한 관계 .
Pathophysiology of Diseases, 또는 side effect of drug 와 관련됨 .
Target of therapeutics: Ion channel blocker, Ion channel opener 들이 부정맥 , 고혈압의 치료제로 쓰임 .
Target of therapeutics:
Antiarrhythmic drug: Class I : Na channel blocker Class II: sympathetic blocker Class III: K channel blocker Class IV: Ca channel blocker
Antihypertensive drug: Ca channel blocker KATP channel opener