Cardiac Electrophysiology II: Pacemaker Cells Flashcards
Sinus Node
- higher resting potential
- unstable baseline (pacemaker function)
- slower rate of rise (slow conduction due to Ca channels)
Atrial Muscle
- higher amplitude
- faster rate of rise
Example of heterogenous localization
What are the inherent characteristics of pacemaker cells?
Why is the SA node the dominant pacemaker cell? How does the speed of discharge compare to the speed of conduction of this node?
What are characteristics of potential pacemakers? What cells have this ability to take over?
Characteristics of pacemaker cells
unstable membrane potential
rhythmicity
_SA node - dominant_ fastest rhythm (discharge rate) slowest conduction
Potential (subsidiary) pacemakers
- slower inherent discharge
- usually suppressed but virtually all cells can take over if needed…or not (bad)
What are the intrinsic rates of the following potential pacemaker cells?
Which pacemaker cells have the fastest and slowest conduction rates?
SA node
fastest rate, slowest conduction
Purkinje system
slowest Rate, fastest conduction
Describe overdrive suppression in simplistic terms.
What is the main transporter involved in this mechanism?
Describe the mechanism in steps.
Overdrive suppression - hyperpolarizing cells “below” it so they are less excitable, taking over control of rhythm
Na/K ATPase huge role
- SA node driving cells at 70
- Purkinje wants to go at 25 - faster than they want - accumulate sodium
- as sodium accumulates Na/K ATPase upregulates - bringing more potassium in, hyperpolarizing
What etiologies can cause loss of SA node drive?
What occurs when this driving force of contraction is lost?
What is down regulated?
What is in charge of contraction then?
Loss of SA node drive
etiologies: SA block, AV block, sinus arrest, etc…
- hyperpolarizing current lost (Na/K ATPase downregulates)
- spontaneous depolarization at next cell’s intrinsic rate
- potential pacemaker can take over
What is a scary thing that occurs between loss of SA node drive and takeover of other conducting cells?
Sinus pause/arrest (2 seconds to minutes)
time for dissipation of hyperpolarizing (overdrive) current
allows escape beats/rhythm - subsidiary conduction taking over
can be life threatening
Overdrive suppression is a consequence of heart rate being greater than subsidiary cells inherent firing rate
The mechanism for overdrive suppression is hyperpolarization due to increased Na+ efflux
What enzyme is associated with overdrive suppression?
Na/K ATPase
What impact does the heterogenous tissue of the SA node have on conduction velocity?
When the SA node starts the electrical signal this is initially slow conduction, by the end however the velocity of conduction increases
What is the physiologycal response to sympathetic stimulation of the SA node?
AV node?
- Positive Chronotropic Effect (Nori, Epi, B1 receptor agonist)
- SA Node
- increased rate of rise of DD (Phase 4)
- If increased
- rapid decrease in gK
- increase gCa
- reach threshold sooner
- no change in MDP
- shorter duration AP
- as you can see in the graph, the slope of the slow diastolic depolarization changes so we reach threshold faster & that is what gives you a faster heart rate
- increased rate of rise of DD (Phase 4)
- AV node
- accelerated conduction due to increased gCa
- SA Node
- In image, top = SA node; bottom = AV node
What cells make up the SA node?
Describe the electrical coupling of the SA node. How well does it connect with surrounding cells?
Describe the quantities of desmosomes, gap junctions, and mitochondria in this region.
Describe the arrangement of sarcomere/myofibrils. How does this effect the force of contraction?
SA node made up of P cells
P cell - empty/pale cell, few desmosomes, few gap junctions
poor electrical coupling - surrounded by cells with high electrical coupling that can invade and mess things up - isolation is important
few mitochondria
few sarcomere/myofibrils in irregular arrangement (not productive)
multidirectional force is weak if any
Describe how surrounding cells could interfere with rhythmicity of SA node?
P - pale cell
W - working cell
(membrane potential is -90)
T - transitional cell
Should working cells invade the SA node (pale cells) this will interfere with action potentials and rhythmicity
Important that SA node and pale cells are isolated
(membrane potention is -50)
While moving from deep to superficial regions of the heart what characteristic of the heart changes action potentials allowing them to escape the isolation of the SA node?
Heterogeneity of the SA node allows for increasing amplitude of action potentials allowing the electrical signal to escape the confines of the SA node which is surrounding by muscle
What membrane voltage-gated, time-dependent currents lend to action potentials of pacemaker cells?
What electrogenic transporters carry current and contribute to action potentials of pacemaker cells?
Describe the location of sodium channels and IK1 channels in the SA Node.
What’s going on with Purkinje fibers and the AV node in regards to sodium channels and IK1 channels?
_Membrane voltage-gated, time-dependent currents_ Sodium current (I<sub>Na</sub>) Funny current (I<sub>f</sub>) Calcium current (I<sub>Ca</sub>) Potassium current (I<sub>K</sub>)
Electrogenic transporters
Na+/Ca2+ Exchanger (INCX)
Na+/K+ ATPase
SA Node
heterogeneous, site specific sodium channels
sodium channels not in the center, but present in periphery
No Ik1 channels - which causes the unstable baseline
Purkinje fibers have sodium channels
AV Node does not have IK1 channels
What two “clocks” contribute to the rhythm and timing of action potentials formed by the center of the SA node?
Membrane clock
ensemble behavior of ion channels
time-dependent behavior
Calcium clock
spontaneous release of Ca from SR
local calcium release (LCR)
What membrane voltage gated ion channels contribute to pacemaker ticking functions? What activates these channels?
What SR function contributes to the ticking function of pacemakers?
Membrane ion channels
Funny channels - activated by cAMP and hypopolarization
Calcium channels - depolarization
Ca/K channel exchange channels - local calcium release
SR related
spontaneous local calcium release
What induces initial calcium influx through the calcium channels located on the membrane of pacemaker cells?
What is the initial influx of calcium called?
What does this induce?
Initial calcium influx through calcium channels is activated through depolarization
this initial influx is called the spark in pacemaker cells
this induces calcium induced calcium release
results in action potential and depolarization
What causes the activation of the following channels?
funny channels
calcium/potassium exchange channels
transient calcium channels
L type calcium channels
What causes repolarization of the SA nodal action potentials? What causes the difference between repolarization of muscle cells and the SAN cells?
What causes the slow unstable diastolic depolarization?
Funny channels opened around -55, during hyperpolarization - results in influx of sodium which prevents further hyperpolarization
Sodium/Calcium Exchange activated by calcium clock - results in further depolarization with influx of 3 sodium and efflux of 1 calcium
Transient Calcium channels opens during diastolic depolarization
L type calcium channels open when threshold is reached to cause slow depolarization
Repolarization of SA node
Potassium channels, specifically Ito1, open allowing rapid efflux of potassium leading to diving repolarization without a plateau phase that is present in muscle cells (due to high to1)
Slow unstable diastolic depolarization
caused by funny channels influx sodium - stopping hyperpolarization
caused by sodium/calcium exchange pumping out calcium and bringing in 3 sodium
What is the role of the Na/K ATPase during the action potential of SA node?
What goes in and out?
What does this lead to?
Is this pump responsible for phase 3 repolarization?
Na-K ATPase
maintains electrochemical gradient (3 Na out:2 K in)
net outward current leads to hyperpolarization
not responsible for phase 3
In pacemaker tissue can contribute to maximum diastolic potential - thus can influence pacemaking
How does the action potential change as it potentiates from the center of the SA node to the periphery?
Summarize the roles of the center cells and periphery cells of the SA node. Where is conduction fastest?
The center action potentials are low in amplitude and rely on calcium channels resulting in slow depolarization.
This expands breaking through the higher resting membrane potential of the outer cells which rely on sodium channels, and have action potentials which appear more similar to myocytes.
In short:
SAN center cells - ensure electrical isolation and automaticity, slow conduction
periphery cells - allow rapid exit of the AP, faster conduction, (more negative maximal diastolic potential?)
Unstable resting membrane potential
Relative absence or presence of Na+ channels
What do funny channels prevent?
Hyperpolarization
K currents overwhelm Ca currents
Opening of calcium channels
After the AP leaves the SA node where does it go? Specifically?
What is the conduction velocity?
What does the AP look like?
Goes to atrial muscle, specifically the intermodal pathways and inter atrial tract (Bachman’s bundle) to left atrium
Conduction velocity 1m/sec
When the AP leaves the atrial muscle where does it go?
What does this AP look like?
Conduction velocity?
What characteristics does this node have that are similar to the SA node?
What cell types will you find here?
Similar to SA node in
poor electrical coupling
low conduction velocity
long “natural” refractory period
automaticity
_Cell types_ P cells transition cells (slow) Purkinje cells (fast)
What are the three regions of the AV node and what cell types are found there?
What characteristics does this lead to?
How does the refractory period play with AP gone rogue?
_AN region (transitional region)_ no P cells no automaticity - an AP will not come from here, will be from lower down
N region
P and T cells
slow conduction with long refractory period
long refractory period stops rogue AP most of the time which is good
NH region
Purkinje and T cells
Where does the AP travel after the AV node?
What is the conduction velocity?
Where does the AP go from there?
Conduction velocity?
Bundle of His
Conduction velocity 1-2 m/sec
Right and Left Bundle Branch
Conduction velocity 2 m/sec
Where does the AP go from the left and right bundle branches?
What cell types do you find here?
Purkinje fibers
Pale cells (like SA node) but more gap junctions
glycogen rich
few more myofibrils - slightly more organized
Describe the speed of conduction and intrinsic rhythm of purkinje cells.
What characteristics of the purkinje cells lead to the conduction speed?
What channels are the most important to prevent hyperpolarization?
The action potentials of purkinje cells are appear similar to what other type of cell? What channels contribute to the stable baseline?
What function of the purkinje cells is due to the conduction speed?
Purkinje cells
Fast conduction (2-4m/sec), slowest intrinsic rhythm
More gap junctions and Na channels - fast conduction
funny channels very important - prevent hyperpolarization at lower membrane potential
AP like working cells - stable phase 4 due to IK1
rapid activation of entire endocardial surface of ventricles (due to fast conduction)
long refractory periods - good to stop irritation sending more APs
Where does the action potential go after Purkinje fibers?
What does this action potential look like?
What path does this take?
What is the conduction velocity?
Action potential goes from purkinje fibers to the ventricular muscle.
Path goes from endocardial to epicardial
Conduction velocity 0.3-1 m/sec
(slow intrinsic rhythm - 25/bpm)
Purkinje cells have rapid conduction because
They have large cells
phase 0 is carried by sodium channels
many gap junctions
stable baseline
What advantage is conferred by the relative long refractory period of Purkinje cells?
Block premature impulses that get through the AV node
What is the normal range of human heart rate?
What factors influence extrinsic modulation?
- Heart rate 30-240 b/min
- rate or rise of diastolic depolarization; Phase 4
- Changing the Maximum Diastolic Potential (MDP)
- funny channels prevent hyperpolarization, so they determine the maxiumu diastolic potential;
- Also the role of Na/K ATPase in suppression & can play a role in determining MDP
- Phosphorylation state of the cell (impacted by autonomic nervous system)
- L-type Ca2+, and various K+ channel activation
- funny channels - cAMP
Describe the molecular response of the SA node to sympathetic stimulation
- When agonist of B1 binds, see stimulation of adenylate cyclase
- increased concentration cAMP
- directly binds to If & accelerate function
- increase in PKA so phosphorylation state of hte cll increases
- ICa,L - increased rates Ca entering cell
- faster depolarizaion
- affecting time it takes to get to threshold
- IK - increased rates of K exiting the cell
- faster repolarizaion
- changes duration of refractory period & thus heart rate
- RYR - Can can move out of SR faster
- Phospholambam (inhibits the inhibitor – cannot inhibit SERCA) - faster Calcium uptake into the SR
- ICa,L - increased rates Ca entering cell
- increased concentration cAMP
Describe the molecular response of th SA node to parasympatheti stimulation
- Ach binding to M2 receptor
- gBy : binds with IK,Ach
- leads to potassium leaving the cell –> hyperpolarizaion & plays an important role in slowing things down
- gai : inhibits AC = less cAMP = less PKA & If slower
- cell gets dephosphorylated & slow everythign down
- Lengthen refractory period b/c IK dephosphorylated
- If not stimulated by cAMP = slow diastolic depolarization rate
- gBy : binds with IK,Ach
What is the physiological respons of SA node stimulation by the parasympathetic nervous system?
AV node?
- Negative Chronotropic Effect (Acetylcholine; M2 receptors)
- Reduction of heart rate
- SA Node
- decreased rate of rise of DD
- decreased If and ICa (Phase 4)
- MDP more negative
- increased gK durign Phase 3 & 4
- you can see the slowing of the diatolic depolarization by the decreae in slope
- decreased rate of rise of DD
- AV Node
- slowed conduction due to decreased gCa
What is the bowditch effect?
The link between chronotropic & ionotripc effects
increased contractility associated with increased rate
- When you have changes in you local calcium currents
-
LCR - Ca2+ release for timing (sparks) - rate
- Na+ “accumulates” with increased rate
- Na+-Ca2+ exchanges favors Na+ efflux, [Ca2+]i influx
-
Ca2+- induced Ca2+ release - SR release via RYR - in nodal cells = timing function; ventricular cells = force
- increased [Ca2+]i
- increase inotropic state - increased contractility
-
LCR - Ca2+ release for timing (sparks) - rate
- When heart is beating faster, you will typically see an increase in contractility due to the impacton the rate of Ca influx; the reverse is true when the hear is beating slower
- Synchronization of RYR activation spark and trigger Ca2+
[B1]
b. phosphorylating L-type Ca2+ channels
[B1]
b. increasing the rate of diastolic depolarization
[M2]
b. opening Ik,Ach channels
c. decreasing the rate of diastolic depolarization (cAMP affects funny current)
