2.1A. Impulse generation and conduction in the heart. Mechanism of pacemaker potential. Control of pacemaker activity and impulse conduction. Flashcards
I. Impulse generation in the heart
1/ What type of cells does the heart consist of?
Contractile cells and conducting cells
I. Impulse generation in the heart
2/ What is the role of conducting cells?
- Primarily responsible for impulse generation and pacemaker activity found in SA node in right atrium
I. Impulse generation in the heart
3/ What are the 2 main types of AP?
- Fast response AP
- Low-response AP
I. Impulse generation in the heart
4/ What are the 5 phases of AP?
Phase…
0: upstroke
1: partial repolarization
2: plateau
3: complete repolarization
4: resting membrane potential
I. Impulse generation in the heart
5/ Where does low-response AP occur?
In nodal cells
I. Impulse generation in the heart
6/ What are the differences between the fast and slow-response AP? What can you conclude about slow-response AP?
1/ Resting membrane potential (phase 4) is more negative in fast-response AP
2/ Slow-response AP does not have phase 1 and 2
3/ Slope of upstroke phase of AP is greater in fast-response AP
4/ Amplitude of AP is greater in fast-response AP
=> AP (conduction) is propagated more slowly and more likely to be blocked in the slow-response nodal tissues compared to fast-response myocardium
II. Mechanism of pacemaker potential
1/ What is the property of pacemaker cells (SA node)?
It has the property of automaticity, meaning it spontaneously depolarizes and generate AP
II. Mechanism of pacemaker potential
2/ What are the key ions in AP generation?
Na+, Ca2+, K+
II. Mechanism of pacemaker potential
3/ What are the 5 ion channels participate in the development of pacemaker potential?
1/ HCN (hyper-polarization activated cyclic nucleotide gated-cation channel)
2/ T-type VD Ca2+ channels
3/ L-type VD Ca2+ channels
4/ VD K+ channels
5/ GIRKs (G-protein coupled inwardly rectified K+ channels)
II. Mechanism of pacemaker potential
4/ What are the characteristics of HCN?
- Non-selective cation channel
- Activated by hyper polarization to around -50 mV
- An influx of Na+ slowly depolarizes nodal cells -> this will become pacemaker potential in nodal cells (This will create If)
- HCN does not inactivate
II. Mechanism of pacemaker potential
5/ What are the characteristics of T-type VGCC?
- Initial depolarization begins when the pacemaker potential reach around -45mV -> T-type VDCC opens and allows some Na+ and Ca2+ to come in
- It will close when the membrane potential reach around -25mV
II. Mechanism of pacemaker potential
6/ What are some characteristics of L-type VGCC?
- Activated when the membrane potential reach -25 mV (after the closing of T-type VGCC)
- An influx of Ca2+ further depolarizes the membrane until the membrane potential reach 20 mV
II. Mechanism of pacemaker potential
7/ What are the characteristics of VG K+ channels?
- At the peaks, various VGKCs open
- They allow an outflow of K+ channels, repolarizing the membrane potential
- Meanwhile, the L-type VGCC closes
II. Mechanism of pacemaker potential
8/ What are the characteristics of G-protein coupled rectified K+ channels (GIRKs)?
- Activated by PARA signal (ACh) through M2-receptors
- Responsible for hyperpolarizarion in response to ACh from vagal N. stimulation
- Lengthen the time for pacemaker to reach the threshold which leads to a decrease in heart rate
- Molecular mechanism: PARA signal -> GIRKs open -> hyperpolarization -> decreased AP-firing -> decreased heart rate
III. Control of pacemaker activity
1. Which systems control the pacemaker activity?
PARA and SYM nervous system
III. Control of pacemaker activity
2. Autonomic heart activity
a/ How is pacemaker activity controlled in sympathetic heart activity?
SYM signal
-> positive chronotropic effect -> increased HR
III. Control of pacemaker activity
2. Autonomic heart activity
b/ What is the molecular mechanism of pacemaker activity controlled in sympathetic heart activity?
Molecular mechanism:
- β1-AR (Gs) (NE) -> ↑[cAMP]
- Gs -> ↑adenylyl cyclase -> ↑[cAMP] -> ↑PKA -> HCN activated -> If↑-> I (Ca,L) ↑
- Increases the funny current, therefore increases the
rate of depolarization
-> Reaches threshold faster = time period between AP shorter = heart frequency↑
(SYM signal
-> positive chronotropic effect -> increased HR)
III. Control of pacemaker activity
2. Autonomic heart activity
c/ How is pacemaker activity controlled in PARA heart activity?
PARA signal -> negative chronotropic effect -> decreased HR
R. vagus nerve innervates SA node => decreased conduction frequency
L. vagus nerve innervates AV node => decreased conduction velocity
III. Control of pacemaker activity
2. Autonomic heart activity
d/ What is the molecular mechanism of pacemaker activity controlled in PARA heart activity?
M2 receptor (Gi)
1. Gi ->↓AC ->↓[cAMP] -> ↓PKA -> HCN not activated ->↓If +↑IK,ACh
2. Gβγ -> GIRKs open -> hyperpolarization -> ↓AP firing-> ↓HR
3. Increase in K+ leads to hyperpolarization
3. Decrease in Ca2+ channels = more depolarization needed to reach threshold
4. Threshold for AP is more positive = requires longer time to reach threshold
III. Control of pacemaker activity
3. How can circulating hormones regulate pacemaker activity?
- Hyperthyroidism => tachycardia (↑HR)
- hypothyroidism => bradycardia (↓HR)
- Circulating epinephrine -> tachycardia (similar mechanism to NE released by SYM)
III. Control of pacemaker activity
4. Drugs
a/ An example of a drug that can cancel PARA effect. Provide details about its mechanism
Cancelling PARA effects with the M2-receptor blocker atropine increased HR by about 50 bpm
III. Control of pacemaker activity
4. Drugs
b/ An example of a drug that can cancel SYM effect. Provide details about its mechanism
Cancelling SYM effects with β1-receptor blocker propanol only decreases the HR by about 10 bpm
III. Control of pacemaker activity
4. Drugs
c/ What happen of we use both β1-receptor blocker propanol and M2-receptor blocker atropine?
Using both drugs produced a HR of about 100bpm, the intrinsic pacemaking frequency of the SA node
IV. Extra
1. What happens if the pacemaker activity of the SA node fails?
- The other cells in the conducting system can also initiate pacemaker potential as they also contain HCN channels
- The region with the highest rate of depolarization (intrinsic frequency) can take over the pacemaker activity, in case of SA node failure
