Electrical Activity of the Heart I, II, and III

Question 1

Rhythmic Activity of the Heart

Answer 1

• Primary function of the heart: pump blood through arteries & veins to deliver nutrients & wash out breakdown products to the body
• Action potentials: control heart rate & initiate contractions
• SA node: pacemaker located above the right atrium that varies its rhythm & adjusts to different environmental conditions
• Bachman bundle: conduction pathway for rapid transmission/propagation of electrical signals within the atira
• AV node: pacemaker located b/n the atria & ventricles that propagates action potential from the right atrium, after a delay, to a specialized conduction system
• Specialized conduction system: rapidly transmits the signal from teh base to the apex of the ventricles
  
  • His bundle: between the AV node & the ventricular septum
  • Purkinje fibers: course along both sides of the ventricular septum, trigger action potentials in ventricular myocytes via electrical coupling
• Action potentials trigger contraction in ventricular myocytes –> atrial & ventricular contractions
  
  • Contractions: powerful enough to generate BP to the head, but gentle enough to avoid RBC hemolysis
• When the SA node fails, the AV node becomes the primary pacemaker

Question 2

Structure & function of cells comprising the heart

• Ventricular cells
• Purkinje fibers
• SA node cells
• AV node cells

Answer 2

• Ventricular cells
  
  • Precise actin, myosin, & z lines
  • 3D structure w/ branches
• Purkinje fibers
  
  • Largest cells
  • Fastest conduction velocity
• SA & AV node cells
  
  • Torturous network of small cells w/ sparse striations
  • Embedded in connective tissue w/ transitional, electrically non-excitable cells
  • Slower conduction velocity (velocity slows as diameter gets smaller & more torturous

Question 3

Gap Junctions, Gap Junction Protein, & Gap Junction Conductance

Answer 3

• Cell are coupled via gap junctions
  
  • ​Large channels that connect cardiac cells to provide electrical & ionic coupling between cells
  • Permit the diffusion of small molecules from one cell to a neighboring cell
• Gap junction protein: comprised of 2 hemichannels
  
  • Hemi-channel: comprised of 6 connexin protein monomers, linked by covalent disulfide bonds
  • Connexin 43: predominant connexin isoforms in ventricular cells
  • Connexin 40: predominant connexin isoforms in Purkinje fibers
• Gap junciton conductance: measure of how readily ions & small molecules diffuse from cell to cell across cardiac tissue
  
  • Decreases in the presence of high Ca2+ & low pH in ventricular cells
  • Accounts for electrical isolation of ischemic heart muscle from “heatlhy” muscle in pathologic conditions
  • Micro-injection of dyes like Fluorescein readily diffuse to adjacent cells

Question 4

Specialized Conduction Pathways

• Atria
• Ventricles

Answer 4

• Atria
  
  • Electrical impulses from the SA node (primary pacemaker) stimulate atrial myocytes to fire electrical impulses to the AV node
  • Bachman’s bundle: larger diameter myocytes w/ faster electrical prpoagation
• Ventricles
  
  • Endocardium (inner ventricular wall) is lined w/ Purkinje fibers (specialized conduction muscle fibers)
    
    • Emerge from the AV node to form the His bundle
      
      • _​_Form right & left bundle branches along the right & left sides of the septum
    • Course along both sides of the septum to reach the apex of the ventricles
    • Continue along the right & left endocardium of the ventricular free walls
    • Coupled to the papillary muscles & ventricular endocardial myocytes to increase the propagation velocity of electrical impulses
      
      • Ventricular cells: also transmit the electrical signal from cell to cell

Question 5

Amplifying and Controlling Station

Answer 5

• AV node is located at the AV junction of the right atrium
• All electrical impulses from the atria to the ventricles pass through the AV node
• The atria must fully contract to fill the ventricles before the ventricles contract
• AV node delays the signal 60-120ms to ensure that this occurs
• AV node may protect the ventricles from rapid arrhythmic beats

Question 6

The mass of ventricular muscle is the contracting tissue that pumps blood

• Heart cells
• Cardiac calcium-dependent adhesion molecules (N-Cadherin)
• Gap junctions
• Intercalated discs
• Functional electrical and mechanical syncytium

Answer 6

• Heart cells: attached to each other end-to-end at intercalated discs
• Cardiac calcium-dependent adhesion molecules (N-Cadherin): part of the intercalated disc junction
  
  • Essential for the adherens junctions in myocytes
• Gap junctions: channels formed b/n adjacent cells
  
  • Low resistance pathways for the flow of current & movement of solutes
• Intercalated discs: tight mechanical coupling between cells
• Functional electrical and mechanical syncytium: heart muscle cells function as a unit
  
  • Cells that are part of the specialized conduction system also contain contractile protein & contract upon depolarization

Question 7

Pacemaker of the Heart

• SA node
• Neurotransmitters

Answer 7

• SA node: pace-setter of the heart
  
  • Conglomeration of flat mycoardial cells that act as the pace-setter of the heart
  • Located at the salcus terminalus near the junction of superior vena cava and the right atrium
  • Innervated by sympathetic & parasympathetic nerves
• Ach & adrenaline: high concentration in the micro environment of pacemaker cells
  
  • Modify the inherent rhythm of the pacemaker cells

Question 8

Cardiac Action Potential

• Recording
• Cardiac vs. Neuronal Action Potential
• Image

Answer 8

• Intracellular microelectrode measures the time course & magnitude of a ventricular action potential
  
  • Height: similar to nerve or skeletal muscle
  • Duration: 200-1500x longer
• Cardiac action potential is faster & lasts longer than neuronal action potentials
  
  • Issue w/ how many ions go through b/c cardiac action potentials last so long
• Image
  
  • A: both electrodes are extracellular, no difference in potential
  • B: one electrode is intracellular, resting potential = -90mV
  • C: apply small depolarization pulse, upstroke of action potential, peak = 30mV
  • D: repolarization
  • E: resting potential

Question 9

SA & AV node vs. atrial & ventricular action potentials

Answer 9

• SA & AV nodes
  
  • More positive resting potentials (-60 mV)
  • Slower rise-times
  • Shorter durations
  • “Unstable” resting (“pacemaker”) potential provides the signal for rhythmic pacemaking activity (continuously fire action potentials)
• Atrial & ventricular action potentials
  
  • More negative resting potentials (-80 to -100 mV)
  • Rapid upstrokes
  • Stable baselines

Question 10

Phases of Ventricular Action Potentials

Answer 10

• Rest: ventricular myocyte is quiescent
  
  • Resting potential = -90mV
• Phase 0: upstroke, Na+ flows in
  
  • Depolarization: change in membrane potential away from the resting potential toward 0
• Phase 1: reversal, overshoot, K+ transiently flows out
  
  • Peak potential = 30mV
• Phase 2: plateau, Ca2+ flows in
• Phase 3: rapid repolarization, K+ flows out
  
  • Hyperpolarizatoin: change in membrane potential that makes the inside of the cell more negative
• Refractory period
  
  • Action potential triggers contraction & controls its duration & magnitude
  • Duration is almost as long as duration of contraction
  • Long duration prevents initiation of another signal until contraction is terminated

Question 11

Nernst Equilibrium and Resting Potential w/ K+

Answer 11

• Nernst equilibrium: E_i = (RT / zF) ln(X_o / X_i)
  
  • R = Rygdberg constant
  • T = temperature in kelvin
  • z = ion valence
  • X₀ & X_i = concentrations of ion X outside & inside cardiac cells
• Cardiac muscle has high permeability to K+ at rest
  
  • EK = -90mV = value of membrane potential if membrane is only permeable to K+ and n oother ions
• At resting membrane potential, the dominant conductance for K+ is maintained by a K+ channel protein: Kir2.1
  
  • Kir2.1 is responsible for the K+ current (I_K1) & the K+ conductance (G_K1) at resting membrane potential

Question 12

Why the resting potential deviates from a perfect Nernst relation

Answer 12

• Low Na+ permeability
  
  • P_K / P_Na = 100 / 1
• Na/K-pumps transport 3 Na+ out for 2 K+ in the cell using ATP for energy
  
  • Hyperpolarizes membrane potential by 5-6mV
• Small conductances exist for anions through Cl- channels & non-specific cationic channels or low background leaks across the membrane

Question 13

Permeability & Conductance

Answer 13

• Permeability
  
  • Probability of diffusion of a particle across a diffusion barrier (ex. cellular membrane)
  • Applies to charged & neutral organic molecules
• Conductance (G)
  
  • Inverse of resistance (R) in units of Siemens (1 Ω = 1/S)
  • V = I * R
    
    • V = voltage in volts
    • I = current in amperes
    • R = resistance in ohms
  • G = 1 / R = I / V
  • Applies to charged particles or ions

Question 14

Upstroke, Tetrodotoxin, & I_Na Threshold

Answer 14

• Upstroke
  
  • Fast (1-5ms), abrupt increase in Na+ conductance / inward Na+ current
  • Max rate of rise depends on [extracellular N+] = 140mM
• Tetrodotoxin (TTX)
  
  • Toxin found in puffer fish
  • Blocks fast inward current & the upstroke
  • Has lower afifnity to cardiac than neuronal cells, so higher [TTX] is needed to fully block cardiac Na+ channels
• Threshold potential: voltage that must be reached to open the activation (m) gate of voltage-gated Na+ channels
  
  • Threshold for INa (current) = threshold for action potential generation = -65mV
  • Membrane potential max value = E_Na = 40mV
  • Once voltage-gated Na+ channels are activated, the channels automatically inactivate after a brief time-delay
  • Na+ channels close, & Na+ conductance drops back to its resting value

Question 15

“All or None” Action Potential

Answer 15

• Once some Na+ channales are activated, Na+ ions flow into the cell, causing further depolarization
  
  • Results in a positive feed-back, all-or-none effect
  • Only a small percentage of all the Na+ channels hav eto open to cause more to open
• Healthy hearts
  
  • Rapid upstroke of ventricular APs is entirely due to the Na+ current (I_Na)
• Ischemic hearts
  
  • Extracellular K+ becomes elevated
  • Resting membrane potential becomes depolarized
  • Na+ channels don’t fully recover from inactivation
  • Ca2+ influx contributes ot the AP upstroke via the activation of voltage-gated Ca2+ channels

Question 16

Plateau of the Cardiac Action Potential: G_K1, TTX, & Ca2+ Channels

Answer 16

• Total conductance of the membrane decreases by 300% during the plateau
• G_K1: controls dominant conductance
  
  • Decreases strongly at more + potentials b/c of Kir2.1 cardiac K+ channels
  • Voltage-dependent channel that’s never fully closed
  • Conductance varies w/ voltage
• Tetrodotoxin (TTX): Na+ channel blocker
  
  • Doesn’t affect duration or amplitude of the plateau b/c fast inward Na+ current contributes little
• In TTX blocked preparatoins, transient slow inward current (“secondary current”) is sensitive to varying [Ca]o
  
  • Current is inactivated to maintain the plateau potential
  • Addition of TTX abolishes the rapid upstroke so that the action potential is dependent on voltage-gated L-type Ca2+ channels
• Ca2+ channels
  
  • L (Large) Type: predominant isoforms in the heart
    
    • Can be blocked by other divalent cations (ex. Mn2+) and pharmacological Ca2+ channel blockers (ex. Diltiazem, Nifedipine, Verapamil)
  • T (Tiny) Type
  • N (Normal) Type
• During the plateau, I_Ca,L (inward) = I_K1 (outward)
  
  • Controls the duraiton of the action potential & msucle contraction

Question 17

Inward and Outward Ionic Current during Ventricular Action Potentials

Answer 17

• Inward current: movement of + charges from outside to inside the cell (depolarizing)
  
  • I_Na: dominant, greater amount
  • I_Ca(L): dominant, greater duration
  • I_Ca(T): weak
  • I_Na/Ca: weak, electrogenic exchanger (3 Na+ go in, 2 Ca go out)
• Outward current: movement of + charges from inside to outside the cell (repolarizing)
  
  • I_ss (I_to): brief, accounts for notch following upstroke
  • I_K1: dominant, decreases during plateau phase
  • I_Kr & I_Ks: delayed K+ repolarizing current, important for downstroke
  • I_Na/K: small, continuous repolarizing current
• Density associated with current: flow (pA) / capacitance (pF)
  
  • Because the capacitance is a measurement of the surface area of the cell’s membrane or the size of hte cell

Question 18

Repolarization Phase

Answer 18

• Brought about by a time-delayed, rectifying K+ current
  
  • Similar to skeletal & nerve cells except for time delay
  • Time delay ensures the plateau phase is long & stable
  • Time-delayed rectifying K+ channels (I_Kr & I_Ks) contribute to repolarization
• Brought about b/c membrane potential slowly decreases to the voltage range where the I_K1 K+ current becomes larger
  
  • Drvies the voltage to the Nernst equilibrium potential for K+

Question 19

Refractory Period

Answer 19

• Duratio of plateau phase protects the myocardium from ectopic & aberrant stimulation
  
  • Protects against extra beats & arrhythmias
• Effective refractory period: electrical stimuli int eh range of physiological impulses aren’t able to elicit the firing of an additional AP
  
  • Occurs at a membrane potential around -50mV
• Strong defibrillation shocks overcome refctoriness
  
  • During relative refractory period, stronger stimuli are necessary to produce an AP
  • Refractory period protects against stimuli that can be generated by other cells in the heart, not paddle electrodes used in the ER

Question 20

Excitability during the Cardiac AP

• Effective refractory period (ERP)
• Relative refractory period (RRP)
• Full recovery time (FRT)

Answer 20

• Effective refractory period (ERP)
  
  • Most stimuli aren’t able to initiate a propagated AP
• Relative refractory period (RRP)
  
  • Only stimuli greater than those which normally reach threshold can cause a propagated AP
  • Na+ & Ca2+ channels havne’t fully recovered form inactivation so aren’t available to be activated or re-opened
  • APs generated propagate slower
• Full recovery time (FRT)
  
  • interval following depolarization
  • Threshold returns to normal
  • Stimulation produces a normal propagated AP

Question 21

Activation and Inactivation Properties of Voltage-Gated Na+ Channels

• Voltage-gated channels
• Threshold potential
• Voltage-sensor
• m gate
• Inactivaiton (h) gate
• Inactivation
• Recovery form inactivation

Answer 21

• Voltage-gated channels: triggered by an abrut change in membrane depolarizaiton or injection of + charge in the cell
  
  • Shifts the channel from closed to open
• Threshold potential: minimum membrane voltage needed to open/activate the channel
• Voltage-sensor: amino acid sequence linked to m gate
• m gate: a region of the channel protein that acts like a gate to open/activate the channel
• Inactivation (h) gate: internal mechanism to automatically close through a different gate
• Inactivation: shifts the conductance of hte channel back to a 0 conductance
  
  • m gate closes, so the pore of the channel remains blocked
  • h gate reamins in the closed position as long as the voltage across the membrane remains depolarized
  • Inactivaiton determines the excitability of the cardiac muscle, since firing an extra stimulus when the channel is inactivated can’t open the Na channels b/c the h gate hasn’t yet recovered
• Recovery from inactivation: resetting of the h gate when the voltage returns to -80mV to -90mV

Question 22

Activation (m gate) & Inactivation (h gate) of Voltage-Gated Na+ Channels

• Resting membrane potential
• Electrical stimulation
• Inactivation
• Reset

Answer 22

• Resting membrane potential
  
  • m gate is closed
  • h gate is open
  • Na+ conductance (G_Na) = 0
• Electrical stimulation
  
  • Vm passes through threshold voltage
  • m gate opens
  • G_Na increases
• Inactivation
  
  • m gate is still open
  • h gate closes within ms
  • G_Na = 0
• Reset
  
  • m gate resets
  • h gate remains closed until Vm returns to -90mV

Question 23

Activation and Inactivation for Voltage-Gated Na+, Ca2+, & K+

Answer 23

• Na+
  
  • Activation: fast
  • Inactivation: fast
• Ca2+
  
  • Activation: slower
  • Inactivation: slower
• K+
  
  • Activation: delayed
  • Inactivaiton: fast or slow

Question 24

Voltage-Gated Ca2+ Channels

Answer 24

• 3 types of Ca2+ channels
  
  • L (large): dominant isoform expressed in ventricular myocytes
  • N (normal)
  • T (tiny)
• L-type Ca2+ channels
  
  • Threshold potential is more positive (-45mV) than Na+ channels (-65mV)
  • Voltage-gated activation is slower than for Na+ channels
• Inactivation of I_Ca(L)
  
  • Ca2+ dependent negative feed-back system: when [Ca2+]_i is high…
    
    • Ca2+ dependent inactivation turns off I_Ca(L) faster
    • AP duration becomes shorter
    • Total influx of Ca2+ via I_Ca(L) is suppressed
  • Voltage-dependent
• Inactivation of Na+ channels
  
  • Voltage-dependent only

Question 25

Protein & Current for the following Genes

• KCNJ2
• KCNH2
• KCNQ1
• SCN5A
• Kcnd2
• CACNA1C

Answer 25

• KCNJ2
  
  • Protein: K_ir2.1
  • Current: I_K1
• KCNH2
  
  • Protein: HERG1
  • Current: I_Kr
• KCNQ1
  
  • Protein: KvLQT1
  • Current: I_Ks
• SCN5A
  
  • Protein: Na_v1.5
  • Current: I_Na
• Kcnd2
  
  • Protein: Kv4.2
  • Current: I_t.o
• CACNA1C
  
  • Protein: Ca_v1.2
  • Current: I_Ca(L)

Question 26

Properties of Pacemaker Cells

Answer 26

• Pacemaker cells: exhibit spontaneous oscillatory electircal activity around the resting potential
  
  • APs are generated spontaneously w/o an external electrical stimulus
  • Pacemaker current depolarizes until the threshold potential is reached
  • When the AP recovers towards baseline, the membrane potential doesn’t remain stable & slowly depolarizes until it reaches the threshold
• Pacemaker potential (slow diastolic depolarization): slow depolarizatoin of the resting potential
• Maximum diastolic potential (depolarization): most negative value of SA node cells
  
  • More negative = longer time for pacemaker potential to reach threshold = slower HR
  • Less negative = shorter time for pacemaker potential to reach threshold = faster HR
• SA & AV node cells v.s ventricular cells
  
  • More positive threshold (-45mV)
  • Slower upstroke b/c of an inward Ca2+ current generated by L-type (& T-type) voltage-gated Ca2+ channels

Question 27

Effect of interventions on SA nodal pacemaker potential

• Increase temperature
• Decrease temperature
• Increase Ach
• Increase epinephrine
• Increase [Ca]_o
• Decrease [Ca]_o
• Increase [Na]_o
• Decrease [Na]_o
• TTX

Answer 27

• Increase temperature
  
  • Increase rate diastolic depolarization & HR
• Decrease temperature
  
  • Decrease rate diastolic depolarization & HR
• Increase Ach
  
  • Decrease rate diastolic depolarization & HR
• Increase epinephrine
  
  • Increase rate diastolic depolarizatoin & HR
• Increase [Ca]_o
  
  • Increase rate diastolic depolarization & HR
• Decrease [Ca]_o
  
  • Decrease or no effect on rate diastolic depolarization & HR
• Increase [Na]_o
  
  • No effect on rate diastolic depolarization or HR
• Decrease [Na]_o
  
  • No effect on rate diastolic depolarization or HR
• TTX
  
  • No effect on SA node

Question 28

How electrical activity triggers and controls force generation

• Extracelluar Ca2+
• Intracellular Ca2+

Answer 28

• Extracellular Ca2+ is required for normal force generation
  
  • Ca2+ entry into heart cells via voltage-gated Ca2+ channels provides Ca2+ to activate force generation by sarcomeres (actin-myosin system)
  • Extracellular Ca2+ is necessary for heart contractions but not skeletal contractions
• Advantage of SR as a store for intracellular Ca2+
  
  • Ca2+ release occurs near myofibrils, so diffusion distances & times are short
    
    • Cardiac muscle contractions depend on external & internal Ca2+
  • SRs are also near transverse tubules
    
    • Less well-developed in cardiac than skeletal muscle

Question 29

How Ca2+ is transported out of cardiac cells

• SR Ca2+ pumps
• ATP-dependent Ca2+ transporters
• Na+/Ca2+ exchanger

Answer 29

• SR Ca2+ pumps
  
  • Pump 2 Ca2+ out for 1 ATP hydrolyzed to ADP
  • Replenishes internal Ca2+ in the SR
  • Resets the SR for Ca2+ release at the next AP
  • Serca2: Ca2+, Mg2+-ATPase responsible for translocating Ca2+ across the SR membrane
• ATP-dependent Ca2+ transporters
  
  • Transports Ca2+ to external spaces
  • Homologous to transporters on the SR membrane
• Na+/Ca2+ exchanger
  
  • Pumps 1 Ca2+ out for 3 Na+ in
  • Electrochemical gradient of Na+ out-to-in drives Ca2+ against its electrochemical gradient in-to-out
  • Influx of Na+ is balanced by the ATP-driven Na+/K+ pump

Question 30

Ryanodine Receptors (RyRs) & Phospholamban (PLB)

Answer 30

• Ryanodine receptors (RyRs)
  
  • Ca2+ release channels on SR membranes
    
    • RyR1: skeletal muscles
    • RyR2: cardiac muscle
    • RyR3: brain & other cells
  • In muscle, the close juxtaposition of Ca2+(L) channels to RyR2s accounts for the effective trigger of Ca2+ entering via the channels to raise local [Ca]_i near the RyR
• Phospholamban (PBL)
  
  • Interacts with Ca2+, Mg2+-ATPase or Ca2+ pumps to suppress Ca2+ uptake by SRs
  • cAMP-depenent phosphorylation of PLB reverses inhibition
    
    • Increases rate of Ca2+ uptake by the SR
    • Greater SR Ca2+ filling –> increased Ca2+ release next time

Question 31

Excitation-Contraction Coupling

Answer 31

• Excitation-contraciton coupling: AP firing at the cell membrane releases Ca2+ from the SR to produce contraction
• APs propagate along cell membrane & in T-tubules
• Depolarization of T-tubules reaches threshold potential to activate Ca2+(L) channels across the sarcolemma
• Entry of Ca2+ at the triadic junction (T-tubule + terminal cisternae of the SR) triggers release of Ca2+ from the SR
• Terminal cisternae of the SR contain Ca2+ release channels (ryanodine receptors, RyR2) that open when [Ca2+] rises, releaseing more Ca2+ from the SR I_Ca(L) channels
  
  • Ca2+-induced Ca2+-release: entry of low [Ca2+] elicits further relase of Ca2+ from the SR stores
• [Ca2+]_i activates myofibrils to generate force
• Ca2+ is removed by the Na+-Ca2+ exchanger and ATP-dependent Ca2+ pumps on the SR

Question 32

The Staircase (Bowditch) Effect

Answer 32

• Cardiac muscle changes the AP duration as a function of HR
  
  • Allows AP & force of contractions to adapt to ranges of HRs
  • Explains how force of contractions adjusts to physiological conditions
• Increase HR –> increase force of cardiac contractions
  
  • Increase HR –> gradual step-wise increase in force
  • The instant HR is increaesd, the force begins to increase by steps, levels-off, then remains steady but elevated at the new higher HR
• If HR is increased…
  
  • & AP duration remains constant…
    
    • Resting phase decreases
  • & AP can’t remain constant b/c HR is too high…
    
    • AP duration shortens
• AP duration is dependent on the diastolic interval b/n repolarization of hte previous AP & depolarizaiton of the next AP

Question 33

Experimental Record of Diastolic Interval & AP Duration

Answer 33

• APD restitution curve: duration of AP vs. diastolic interval
  
  • Stimulus pulse (S1) is applied continuously to elicit APs
  • Second stimulus (S2) is applied w/ a shorter delay or diastolic interval to produce APs w/ shorter duration
• APD restitution by pacing the heart at different rates or cycle lengths
  
  • Longer cycle lengths = longer AP durations = longer diastolic intervals
  • Shorter cycle lengths = shorter AP durations = shorter diastolic intervals
  • As cycle length decreases, AP durations continue to decrease until the stimulus fails to capture

Question 34

Mechanisms involved in bringing about the shortening of AP w/ increasing HR

• I_Ca(L) activation
• I_Ca(L) inactivation
• Positive vs. negative inotropic effect
• Effect of increased HR on force

Answer 34

• I_Ca(L) activates when the membrane potential is depolarized to its threshold (-45mV)
• I_Ca(L) inactivates…
  
  • as a function of [Ca2+]_i
    
    • High [Ca2+]_i increases inactivation, limiting the influx of Ca2+ during an AP by shortening the AP duration
    • High HRs = more APs = elevated [Ca2+]_i = accelerated I_Ca(L) inactivation = shorter AP duration
    • Low HRs = reduced force of contraction
  • as a funciton of membrane potential
• Inotropic effects
  
  • Positive –> increased force of contraction
    
    • Higher HR = increase in Ca2+ load in cells b/c of increase of Ca2+ influx : Ca2+ efflux ratio
    • Ca2+ enters during AP duration and exits during diastole
    • As HR increases, diastole decrease more than AP duration decreases
    • Ca2+ entry is slightly reduced per AP but removal is greatly reduced so [Ca2+]_i rises
    • Force of contraction increases for 12 beats until Ca2+ influx = Ca2+ efflux
  • Negative –> decreased force of contraction
• Effect of increased HR on force
  
  • Increased HR –> increased diastolic & systolic Ca2+ –> increased force in contraction
    
    • Increase in Ca2+ during diastole has minimal effect b/c it remains below mechanical threshold
  • Increased force of contraction is due to increased force generated by myofibrils w/ increased [Ca2+]_i
  • Increased in [Ca2+]_i gets next cycle closer to threshold so the new influx of Ca2+ produces a greater force

Question 35

Mechanisms underlying spontaneous pacemaker potential

• Hyperpolarization-activated Cyclic-Nucleotide-gated (HCN) channel protein
• Ca2+ clock

Answer 35

• Hyperpolarization-activated Cyclic-Nucleotide-gated (HCN) channel protein
  
  • Channel in SA nodal cells that causes pacemaker potential
  • 4 isoforms
  • HCN2 & HCN4: dominant in the SA node
  • HCN4: responsible for slow inward funny current (I_f)
    
    • Cationic inward current carried by Na+ & Ca2+
    • Activated by negative membrane potentials
    • Modulated by cAMP-dependent phosphorylation
• Ca2+ clock
  
  • Caused by the rhythmic, spontaneous releae of Ca2+ from the SR via RyR2
  • [Ca2+]_i oscillations produce transients of Na/Ca exchange current which produces slow, diastolic potential or pacemaker potential
    
    • Elevation of [Ca2+]_i increases the Na/Ca exchange current (3 Na+ in, 1 Ca2+ out)
    • Membrane depolarization triggers opening of I_Ca(L) to produce an AP
    • Speed of clock or [Ca2+]_i oscillations increases w/ higher [Ca2+]_i
  • Re-uptake of Ca2+ by SERCA2 Ca2+ pumps on the SR reduces [Ca2+]_i
  • When the SR is reloaded w/ Ca2+, the cycle repeats

Question 36

Parasympathetic stimulation

• Vagus nerve stimulation
• Ach release
• Vagal stimulation or Ach release on SA node
• Vagal stimulation or Ach release on atrial AP

Answer 36

• Vagus nerve stimulation
  
  • Rate of diastolic depolarizaiton is suppressed –> membrane hyperpolarizes
  • Increases K+ permeability & membrane conductance for K+ (G_K)
• Ach release
  
  • Reduces pacemaker potential (diastolic depolarization) –> slows HR
  • Increased rate of loss of K+ from cells
• Vagal stimulation or Ach release on SA node
  
  • Pacemaker activity slows
  • Resting potential becomes more negative
  • Rate of diastolic depolarization is reduced
• Vagal stimulation or Ach release on atrial AP
  
  • Duration of AP shortens
  • Slow inward current is reduced
  • Outward potassium currents that cause repolarization are increased

Question 37

Action of adrenalin on pacemaker cells (sympathetic effects)

Answer 37

• Dominant action: increase slope of pacemaker potential –> increase firing frequency & HR
• Decrease max diastolic potential –> decrease firing frequency
• Increase overshoot
• Threshold potential for upstroke doesn’t change so doesn’t affect firing frequency
• Mechanism: activation of all ionic channels & ATP-driven transport pumps in the cell

Question 38

Graphs: Changes of frequency of pacemaker firing & Effects of sympathetic stimulation on SA node

Answer 38

• Mechanisms involved in changes of frequency of pacemaker firing
  
  • Reduction in slope of pacemaker potential diminishes frequency
  • Increase in threshold or increae in magnitude of resting potential diminishes frequency
• Effects of catecholamines or sympathetic stimulation on the SA node
  
  • Increased rate of diastolic depolarization accelerates pacemaker activity due to increased inward current

Question 39

Effects of adrenalin on ventricular cells

• Sequence of events
• At the level of the SR
• At voltage-gated Na+ channels
• At the Na/K pump
• At the plateau phase
• At K+ channels
• At AP
• In intact hearts, adrenalin causes…

Answer 39

• Sequence of events
  
  • Noradrenalin/Adrenalin binds to beta1-adrenergic receptors
  • Ligand-receptor interaction stimulates adenylate cyclase
  • Increase in cAMP in the cytosol
  • Activation of protein kinases
  • Widespread signaling mechanism that activates virtually all channels & transporters
• At the level of the SR
  
  • Phospholamban: protein that binds to Ca2+ pump on the SR membrane (SERCA2) –> inhibition of rate of Ca2+ uptake by SR
  • Adrenergic activation phosphorylates Phospholamban –> dissociation from SERCA2 –> increase in rate of Ca2+ uptake by SR
    
    • –> increase in rate of muscle relaxation
    • –> increaes in amount of SR Ca2+ release due to increased Ca2+ load in the SR
• At voltage-gated Na+ channels
  
  • Increase in probability of channel opening upon membrane depolarization
  • Increased G_Na –> increased I_Na –> increased upstroke velocity –> increased propagation of AP across ventricular muscle
• At the Na/K pump
  
  • Phosphorylation increases rate of transport
  • Hyperpolarizes resting potential
• At the plateau phase
  
  • Increaased I_Ca –> increased plateau potential –> increased Ca2+ entry
• At K+ channels
  
  • Increases G_K1
  • Increases delayed K+ current I_Ks
  • Accelerates repolarizatoin
  • Decreases AP duration
  • Force of contraction increases
  • Duration of contractions decreases
• At AP
  
  • Increases rate of upstroke & rate of repolarization of downstroke
  • Raises plateau potential
  • Increases I_Ca(L)
  • Increases peak & relaxation rates
  • Increases HR by increasing slope of pacemaker potential
• In intact hearts, adrenalin causes a positive inotropic effect by…
  
  • Direct action of adrenalin on cardiac cells
  • Action of adrenalin on the SA node –> increased HR –> additional positive inotropic change through the Staircase Effect

Question 40

Effects of Ach on ventricular cells

Answer 40

• Increases K+ conductance
  
  • Negligible b/c Ach receptors are sparse on mammalian ventricles
• Negligible except when muscle has been exposed to adrenalin
  
  • Ach activates G inhibitory proteins to increase cGMP & inhibit cAMP
  • Exerts opposite effects to reduce the positive inotropic action of adrenalin
• Inhibits adrenalin release from nerve terminals embedded in the ventricular tissue
  
  • Counteracts positive inotropic actions of adrenalin

Question 41

Autonomic drugs

• Beta-adrenoceptor agonists
• Beta-adrenoceptor antagonists
• Muscarinic receptor antagonists
• Cardiac glycosides

Cardiac glycosides

Answer 41

• Beta-adrenoceptor agonists
  
  • Adrenaline
  • Dobutamine
  • Isoproterenol
• Beta-adrenoceptor antagonists
  
  • Propranolol
  • Atenolol
• Muscarinic receptor antagonists
  
  • Atropine
• Cardiac glycosides
  
  • Digoxin
  • Ouabain
  • Actions in increasing force of contraction & slowing HR (higher concentrations)

Question 42

Drugs for arrhythmias that target ion channels

• Class I
• Class II
• Class III
• Class IV

Answer 42

• Class I
  
  • Na+ channel blockers
  • Lidocaine
  • Flecainide
• Class II
  
  • Beta-adrenoceptor antagonists
• Class III
  
  • Drugs that prolong the refractory period of cardiac muscle
  • Amiodarone (non-selective block)
  • D-sotalol (I_Kr blocker)
• Class IV
  
  • Ca2+ channel blockers
  • Verapamil
  • Diltiazem
  • Nifedipine