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Cardiology > Electrical Activity of the Heart I, II, and III > Flashcards

Electrical Activity of the Heart I, II, and III Flashcards

1
Q

Rhythmic Activity of the Heart

A
  • 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
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2
Q

Structure & function of cells comprising the heart

  • Ventricular cells
  • Purkinje fibers
  • SA node cells
  • AV node cells
A
  • 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
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3
Q

Gap Junctions, Gap Junction Protein, & Gap Junction Conductance

A
  • 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
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4
Q

Specialized Conduction Pathways

  • Atria
  • Ventricles
A
  • 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
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5
Q

Amplifying and Controlling Station

A
  • 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
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6
Q

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
A
  • 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
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7
Q

Pacemaker of the Heart

  • SA node
  • Neurotransmitters
A
  • 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
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8
Q

Cardiac Action Potential

  • Recording
  • Cardiac vs. Neuronal Action Potential
  • Image
A
  • 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
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9
Q

SA & AV node vs. atrial & ventricular action potentials

A
  • 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
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10
Q

Phases of Ventricular Action Potentials

A
  • 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
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11
Q

Nernst Equilibrium and Resting Potential w/ K+

A
  • Nernst equilibrium: Ei = (RT / zF) ln(Xo / Xi)
    • R = Rygdberg constant
    • T = temperature in kelvin
    • z = ion valence
    • X0 & Xi = 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 (IK1) & the K+ conductance (GK1) at resting membrane potential
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12
Q

Why the resting potential deviates from a perfect Nernst relation

A
  • Low Na+ permeability
    • PK / PNa = 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
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13
Q

Permeability & Conductance

A
  • 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
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14
Q

Upstroke, Tetrodotoxin, & INa Threshold

A
  • 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 = ENa = 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
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15
Q

“All or None” Action Potential

A
  • 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 (INa)
  • 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
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16
Q

Plateau of the Cardiac Action Potential: GK1, TTX, & Ca2+ Channels

A
  • Total conductance of the membrane decreases by 300% during the plateau
  • GK1: 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, ICa,L (inward) = IK1 (outward)
    • Controls the duraiton of the action potential & msucle contraction
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17
Q

Inward and Outward Ionic Current during Ventricular Action Potentials

A
  • Inward current: movement of + charges from outside to inside the cell (depolarizing)
    • INa: dominant, greater amount
    • ICa(L): dominant, greater duration
    • ICa(T): weak
    • INa/Ca: weak, electrogenic exchanger (3 Na+ go in, 2 Ca go out)
  • Outward current: movement of + charges from inside to outside the cell (repolarizing)
    • Iss (Ito): brief, accounts for notch following upstroke
    • IK1: dominant, decreases during plateau phase
    • IKr & IKs: delayed K+ repolarizing current, important for downstroke
    • INa/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
18
Q

Repolarization Phase

A
  • 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 (IKr & IKs) contribute to repolarization
  • Brought about b/c membrane potential slowly decreases to the voltage range where the IK1 K+ current becomes larger
    • Drvies the voltage to the Nernst equilibrium potential for K+
19
Q

Refractory Period

A
  • 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
20
Q

Excitability during the Cardiac AP

  • Effective refractory period (ERP)
  • Relative refractory period (RRP)
  • Full recovery time (FRT)
A
  • 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
21
Q

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
A
  • 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
22
Q

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

  • Resting membrane potential
  • Electrical stimulation
  • Inactivation
  • Reset
A
  • Resting membrane potential
    • m gate is closed
    • h gate is open
    • Na+ conductance (GNa) = 0
  • Electrical stimulation
    • Vm passes through threshold voltage
    • m gate opens
    • GNa increases
  • Inactivation
    • m gate is still open
    • h gate closes within ms
    • GNa = 0
  • Reset
    • m gate resets
    • h gate remains closed until Vm returns to -90mV
23
Q

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

A
  • Na+
    • Activation: fast
    • Inactivation: fast
  • Ca2+
    • Activation: slower
    • Inactivation: slower
  • K+
    • Activation: delayed
    • Inactivaiton: fast or slow
24
Q

Voltage-Gated Ca2+ Channels

A
  • 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 ICa(L)
    • Ca2+ dependent negative feed-back system: when [Ca2+]i is high…
      • Ca2+ dependent inactivation turns off ICa(L) faster
      • AP duration becomes shorter
      • Total influx of Ca2+ via ICa(L) is suppressed
    • Voltage-dependent
  • Inactivation of Na+ channels
    • Voltage-dependent only
25
Protein & Current for the following Genes * KCNJ2 * KCNH2 * KCNQ1 * SCN5A * Kcnd2 * CACNA1C
* KCNJ2 * Protein: Kir2.1 * Current: IK1 * KCNH2 * Protein: HERG1 * Current: IKr * KCNQ1 * Protein: KvLQT1 * Current: IKs * SCN5A * Protein: Nav1.5 * Current: INa * Kcnd2 * Protein: Kv4.2 * Current: It.o * CACNA1C * Protein: Cav1.2 * Current: ICa(L)
26
Properties of Pacemaker Cells
* _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
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
* 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
28
How electrical activity triggers and controls force generation * Extracelluar Ca2+ * Intracellular Ca2+
* 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
29
How Ca2+ is transported out of cardiac cells * SR Ca2+ pumps * ATP-dependent Ca2+ transporters * Na+/Ca2+ exchanger
* 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
30
Ryanodine Receptors (RyRs) & Phospholamban (PLB)
* 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
31
Excitation-Contraction Coupling
* _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 ICa(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
32
The Staircase (Bowditch) Effect
* 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
33
Experimental Record of Diastolic Interval & AP Duration
* _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
34
Mechanisms involved in bringing about the shortening of AP w/ increasing HR * ICa(L) activation * ICa(L) inactivation * Positive vs. negative inotropic effect * Effect of increased HR on force
* ICa(L) activates when the membrane potential is depolarized to its threshold (-45mV) * ICa(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 ICa(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
35
Mechanisms underlying spontaneous pacemaker potential * Hyperpolarization-activated Cyclic-Nucleotide-gated (HCN) channel protein * Ca2+ clock
* 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 (If)_ * 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 ICa(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
36
Parasympathetic stimulation * Vagus nerve stimulation * Ach release * Vagal stimulation or Ach release on SA node * Vagal stimulation or Ach release on atrial AP
* Vagus nerve stimulation * Rate of diastolic depolarizaiton is suppressed --\> membrane hyperpolarizes * Increases K+ permeability & membrane conductance for K+ (GK) * 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
37
Action of adrenalin on pacemaker cells (sympathetic effects)
* _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
38
Graphs: Changes of frequency of pacemaker firing & Effects of sympathetic stimulation on SA node
* 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
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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...
* 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 GNa --\> increased INa --\> 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 ICa --\> increased plateau potential --\> increased Ca2+ entry * At K+ channels * Increases GK1 * Increases delayed K+ current IKs * 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 ICa(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
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Effects of Ach on ventricular cells
* 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
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Autonomic drugs * Beta-adrenoceptor agonists * Beta-adrenoceptor antagonists * Muscarinic receptor antagonists * Cardiac glycosides Cardiac glycosides
* 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)
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Drugs for arrhythmias that target ion channels * Class I * Class II * Class III * Class IV
* 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 (IKr blocker) * Class IV * Ca2+ channel blockers * Verapamil * Diltiazem * Nifedipine

Cardiology (40 decks)

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