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4. Physiology and pathophysiology > Action potential and currents > Flashcards

Action potential and currents Flashcards

1
Q

Define resting membrane potential + normal value

A

Difference in electrical charges btwn extra and intra¢ = -80-90mV

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2
Q

What are the most important ion gradients for RMP

A

large resting ion gradient
o Intra¢ [Na+] = 150mmol/L vs extra¢ = 25
o Intra¢ [K+] = 4mmol/L vs extra¢ = 150

  • At rest, impermeable to Na+, partially permeable to K+ and Cl-
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3
Q

Relation of AP phases to ECG

A
  • Phase 0 = QRS
  • Phase 1 = J point
  • Phase 2 = ST segment
  • Phase 3 = T wave
  • Phase 4 = electrical diastole
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4
Q

Phase 0 key events

A

RAPID DEPOL
* Opening of voltage gated Na+ channels
* Influx of Na+ =>membrane potential to +20-30mV = inward current (INa)
* Rapid upstroke = fully depolarize the ¢

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5
Q

Describe Na+ channel gates

A

2 gates
o M: activation gate => open when threshold of -65mV is reached
o H: inactivation gate => time dependent property of the channel = close channel after a certain time
 Prevent any further exchange of Na+ during the rest of the AP

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6
Q

Phase 1 key events

A

EARLY REPOL
* When membrane potential reaches +30mV, triggers
o Closing of Na+ channels
o Slow opening of Ca2+ L-type
o Opening of voltage gated K+ channels = efflux of K+ = Ito
o Ca2+ activated Cl- current can also contribute to phase 1

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7
Q

More prominent phase 1

A

 Better defined in atrial and Purkinje ¢ AP
 Stronger in epicardium vs endocardium
 Can cause J wave on ECG in R wave downslope

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8
Q

Phase 2 key events

A

PLATEAU
* While K+ still open => formation of outward currents larger IKS and smaller IKR
* Voltage gated Ca2+ channels (L type) also open around -30 to -35mV
o Slower in how they open vs K+ channels = Ca2+ influx (ICa-L)
 Formation of a plateau: for every K+ out = Ca2+ in
o Plateau permits: small influx of Ca2+ => trigger larger release of Ca2+ => myocardial contraction
 Cross bridge cycle and shortening of sarcomere
o Allows full movement of blood from that chamber before relaxation
 If plateau is shorter and repolarization occurs beforehand = ejection of blood
* Final phase of plateau: membrane potential value => slowly 2nd to decr conductance of Ca2+ and incr K+

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9
Q

Phase 3 key events

A
  • Determine AP duration, complex origin
    o From initial depolarization, K+ currents activated w a delay (IKR, IKS, IKL)
     IKR = major contributor
     IKUR: K+ current in atrial myocytes responsible for shorter duration of AP
    o Closure of Ca2+ channels in response to incr intra¢ [Ca2+]
    o Inward current of Na+/Ca2+ exchanger becomes an inward current = Na+ entry
    o Inward Cl- flow may contribute
  • Closing of Ca2+ channels = stops Ca2+ influx
  • K+ channels still open = efflux of K+ => decr membrane potential = membrane potential decr to -90mV
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10
Q

Phase 4 key events

A
  • Membrane potential back to resting values
    o During diastole, activity of exchange systems maintain ionic balance
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11
Q

Which current maintain resting phase

A

Atrial, ventricular, His Purkinje ¢: value is mainly determined by conductance of K+ through IK1 channels

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12
Q

Atrial myocytes AP features

A
  • Shorter => lesser contraction force
    o decr inward Ca2+ flow
  • Short AP duration: rapid opening of IKUR → ↑K+ current
    o Ultrarapid delayed rectifier current
    o Lesser contraction force due to decr time for inward Ca2+ flow
  • Well defined phase 1: spiked and dome AP pattern
    o ↑ ITo : early repolarizing current
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13
Q

Ventricular myocytes AP features

A
  • Longer vs atrial potential but shorter vs Purkinje fibers
  • Differ according to layers of ventricular wall
    o Reflect different expression of ITO and IKS currents
     Epicardial myo¢: doming shape, prominent phase 1
     Mid myocardium myo¢: longer AP, prominent phase 1
     Endocardial myo¢: intermediate duration, small phase 1
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14
Q

Purkinje AP features

A
  • Longest AP: large rapidly rising AP
    o ↓ internal resistance → favors rapid conduction
    o Long duration: safety against re-entrant arrhythmia
  • Well defined phase 1: spiked and dome AP pattern
    o ↑ ITo : early repolarizing current
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15
Q

Pacemaker cells AP features

A

Lower resting membrane potential: -40 to -70mV
* Absence of KIR2 channels responsible for IK1 current
* UNSTABLE MEMBRANE POTENTIAL = never goes to rest (because Na+ channels open at -60mV and repolarization takes the membrane to -60mV)
o Membrane/voltage clock: progressive decr of repolarizing currents at end of AP + initiation depolarizing currents
 IF => activate HCN channels => Na influx
 ICa-T & ICa-L => Ca influx
o Ca2+ clock: initiated by spontaneous release of Ca2+ by SR w ryanodine R => trigger Na influx and Ca efflux
* Pacemaker current IF: major contributor of spontaneous automaticity in SA and AV node

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16
Q

Steps of PM cells AP

A
  1. When membrane potential reach -60mV = opening of Na+ channel = slow influx of Na+
    * Membrane potential ¬from -60mV to -40mV
  2. When membrane potential reach -40mV
    * Opening of fast Ca2+ channels (T type) = rapid influx
    * Sharp rise in potential to around +10mV
  3. Closing of Ca2+ channels and opening of K+ channels = efflux of K+
    * Bring potential membrane back to -60mV
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17
Q

SA node automatic activity: which cells

A

P ¢
* Connected by each other by apposition of plasma membrane
* Coordination: transmembrane potential change almost simultaneously in all P¢
* Conductance from a dominant PM site => can shift in response to physiologic stimuli

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18
Q

Rate of spontaneous depolarization in SA node: 3 main factors

A

o Slope of phase 4: incr in slope => sooner reach of threshold => incr d/c rate
o Threshold potential: incr => delay onset of phase 0 => decr d/c rate and vice versa
o Membrane potential at initiation of phase 4: incr => easier to reach threshold => incr d/c rate

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19
Q

5 proposed PM currents to explain spontaneous depolarization in SA node

A

IK
IB
ICa-L and T
IF

o Safety factor: inhibition of 1 current leaves several others to carry depolarizing fct

  • Spontaneous depolarization in phase 4
  • Depolarization starts at -65mV => activation threshold -40mV => rapid depolarization initiate AP
    o Slower upstroke
     No fast Na+ current
    o No plateau phase
     Rapid onset of K+ repolarization from activation of delayed rectifier K+ current (Ik)
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20
Q

Normal spontaneous depol rates

A
  • SA node: 60-180bpm
  • AV node: 40-60bpm
  • Purkinje fibers: 20-40bpm
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21
Q

Delayed rectifier K+ current (Ik)

A
  • Major K+ current in PM ¢
  • Alteration of its rate => important governor of AP pattern
  • Activated when depolarization reach apex => contribute to repolarization
  • Time dependent
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22
Q

Background inward current (IP or IB)

A
  • Spontaneous inward Na+ current along [gradient]
  • Remains when all other are blocked
  • Role is controversial
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23
Q

Slow inward nodal Ca2+ current (ICa)

A
  • Essential for PM activity
  • Rising phases of AP
    o Transient component (ICa-T): threshold -60 to -50mV
     Open 1st (lower voltage)
    o Long lasting component (ICa-L): threshold -40mV
     Essential for the rapid upstroke
     Affected by Ca2+ antagonists and B adrenergic blocks  will slow but not arrest heart beat at clinical dosages
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24
Q

Inward current (If)

A
  • Activation at lower membrane potentials = -90 to -50mV
    o More negative than that usually found in P¢
    o May be fully operative when SA node is hyperpolarized
     Also named hyperpolarization-activated cyclic nucleotide-gated current (HCN)
  • N+ and K+ can carry => Na+ may be dominant
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25
Q

Overdrive suppression: mechanism and pathophys

A
  • Pacing at higher HR depresses activity of other PM ¢
  • Post pacing inhibition: PM activity is slow to resume after induced tachycardia
    o SSS: sudden decr in HR may result in cardiac arrest because of overdrive suppression of other PM ¢
  • Mechanism: slope of diastolic depolarization is decr => requires higher voltage to reach threshold
    o incr activity of Na+/K+ pump => incr outward Na+ current => hyperpolarization => prolong time needed to reach threshold
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26
Q

Propagation of impulse from SA node

A
  • Impulse form in SA node => spread to atrium => AV node
    o Impulse arrives to sarcolemma => opens Na+ & Ca2+ channels => + inward charges
    o Internal microzone of + charges attracted to negatively charged adjacent ¢
    o Adjacent sarcolemma tend to loose its polarity => open more Na+ voltage channels => impulse spread throughout sarcolemma
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27
Q

Pattern of atrial activation

A

Isochrone: equal travel time

  • Internodal tracts: ¢ histologically similar to Purkinje fibers
    o Insensitive to incr in extra¢ [K+]
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28
Q

AV node electrophysio properties

A
  1. Spontaneous slow diastolic depolarization: can serve as subsidiary PM
  2. Delay the rate of impulse conduction to V
    o Ensure relaxed V at the time of A kick
    o Max reduction of impulse velocity occurs in compact node
  3. Decremental conduction: progressive delay of impulse propagation with incr HR
  4. Concealed conduction: alteration of AV node conduction by previous event not visualized on ECG
  5. Conduction can occur anterograde or retrograde
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29
Q

Decremental conduction mechanism

A

o Affect slope of subsequent AP
o Cumulative effect can lead to block impulse
o Control # and order of SV impulses

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30
Q

AV node slow impulse conduction by 2 mechanism

A

 Low amplitude and slow rate of rise of AP
* Absence of fast inward Na+ current
* AP depend on slow inward Ca2+ currents
 High internal resistance
* Small AV nodal cell diameter
* Small # of gap jcts

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31
Q

3 AV node functional regions and AP features

A
  1. Atrionodal region
    * Shortest AP duration (close to atrial myocytes)
  2. Nodal region
    * Longer AP duration vs AN region
    * ↓ resting potential: slowest spontaneous PM activity
    * ↑ contribution of Ca2+-L channels
    i. ↑ effect of Ca2+ channel blockers (verapamil, dilt)
  3. Nodal-His bundle
    * Longest AP duration
    * Fastest spontaneous PM activity
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32
Q

Effect of adenosine

A
  • Inhibit L type Ca2+ current
  • Hyperpolarization by adenosine-sensitive K+ channel
  • Occurs w adenosine A1 R
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33
Q

His bundle AP

A
  • ¢ in the common bundle = Purkinje ¢
    o Rapid conduction of electrical impulse
    o Rate of firing is slower

FEATURES
* Phase 0: greater positive value
 rapid conduction of impulse
* Phase 1: more rapid repolarization before plateau phase
* Phase 3: slower repolarization
 longer AP
 longer refractory period = prevent from reentry

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34
Q

Autonomic nervous system control: intracell effects

A

Denser innervation in SA node = ↑ influence vs AV node

  • ∑ and p∑: opposite effects on formation of cAMP
    o ∑ → ↑cAMP → direct and indirect effects
     Catecholamines
    o p∑ → ↓cAMP
     Ach
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35
Q

SA node: B stim (catecholamines)

A
  • incr probability of opening ICa-L + IF
  • incr Ca2+ current by phosphorylation of Ca2+ channels
    o ↑ membrane conductance to Ca2+
    o incr rate of diastolic depolarization = incr HR
  • ↑ K+ current by phosphorylation of IK channels
    o ↑ rate of repol → shorten AP duration
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36
Q

SA node: vagal stim (Ach)

A

releases NO => liberates Ach => decr HR
* ↓ rate of diastolic depolarization = lengthen AP
o incr K+ conductance: outward K+ current (IKAch)
 Activates Ach-regulated K+ channel
 Also activated by adenosine
o decr Ca2+ current ICa-L
o Activation of If current → ↓ d/c rate
* Intense vagal stimulation => hyperpolarization effects
o Hyperpolarization decr rate at which the threshold is reached
o Can induce PM shift from normally dominant P ¢ to peripheral T ¢
o Change PM potential in zone of activity of IF = incr rate of spontaneous depolarization

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37
Q

AV node: B stim (catecholamines)

A

↑ conduction velocity
o incr Ca2+ current by phosphorylation of Ca2+ channels
 incr rate of diastolic depolarization

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38
Q

AV node: vagal stim (Ach)

A

↓ conduction velocity
o Same mechanisms as SA node
 AV node sensitive to p∑ inhibition (physio AVB)
o Inhibit Ca2+ channel opening

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39
Q

Atrial myocytes: vagal stim

A

↓ AP duration and refractory period
o Activation of outward K+ currents → shorter plateau phase
o ↓ duration of Ca2+ channel opening → ↓ inotropy

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40
Q

Electrical properties of myocardium

A

Excitability
Automaticity
Refractoriness
Conduction

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41
Q

Factors influencing cardiac activity

A
  • Body temperature: incr slope of phase 4 => incr HR
    o incr in 1˚ => incr 10bpm
  • Hyper Ca2+: decr AP duration and accelerate repolarization
    o Vice versa for hypoCa2+
  • HyperK+: incr resting membrane potential => slows conduction velocity and velocity of incr of phase 0
    o Atrial ¢ can reach state of constant depolarization and lose ability to depolarize
  • HypoK+: decr resting membrane potential => decr excitability
    o Prolongation of AP associated w decr in IKR and IK1
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42
Q

Def excitability

A
  • Ability to generate an AP from a stimulus = or > the membrane potential threshold
  • Depends on availability of Na+ channels
43
Q

Def automaticity

A
  • Ability to spontaneously generate an AP
    o Characteristic of the SA node and subsidiary PM
  • Subsidiary PM
    o Include: various area in atria, PVs, coronary sinus, AV valves, His Purkinje system
    o Usually latent because overdrived by SA node depolarization
44
Q

Def refractoriness

A
  • Period of time where myocytes are not excitable
    o From phase 0 to 3: inactivation of Na channels
45
Q

Def total RP

A
  • Total refractory period = effective + relative
    o Effective: phase 0 => ½ phase 3 (QRS to endo of T wave)
     Progressive reactivation of Na+ channels
     Membrane potential return below -50mV
    o Relative: end of effective refractory period => end of AP (1/2 phase 3 => end phase 3)
     Progressive reactivation of Na channels
     Myocytes can respond to a very intense stimulus: decr # of Na channels available
46
Q

Def supernormal excitability

A
  • Supernormal excitability: phase after relative refractory period
    o Stimulus under threshold can initiate AP
    o Period where membrane potential is close to threshold value during diastolic repolarization
47
Q

How changes in cardiac cycle length alter RP

A

o Fast HR  shorter cycle  shorter AP duration and refractory period
o Currents responsible for this mechanism: IKS & ITO

48
Q

Polarization of sarcolemma

A

o Capacity to maintain vast ion gradients btwn intra/extra¢ environment
o Capacity to respond to the depolarization wave by brief opening of specific channels

  • Intra¢ is normally negative, extra¢ is positive
    o Sarcolemma is polarized
    o Polarity is reversed w depolarization
49
Q

Voltage gated channels role

A

Open with change in membrane potential => membrane depolarization
o Allow entry of positively charged ions (Na+, Ca2+)
o Outward flux of K+ permit repolarization

50
Q

Which pumps are responsible for restoration of ion balance

A

Ca2+ ions are pumped out by Na+/Ca2+ exchanger

Na+/K+ pump Na+ out to restore [gradient]

51
Q

Ions determining RMP

A

Na+, K+, Cl-
o Ca2+ not considered = low permeability
o Membrane is permeable to Na+, K+

52
Q

Role of Na+/K+ pump

A

actively pump
o K+ inward => accumulate on inner surface
 high intra¢ [K+]
 As gradient gets higher, some of pumped K+ will passively move out
o Na+ outward => accumulate on outer surface
 low intra¢ [Na+]
 As gradient gets higher, some of pumped Na+ will passively move in
* Slower diffusion (vs K+) because membrane < permeable to Na+

53
Q

Driving force of current flow through channels

A

o Potential across membrane
o Concentration gradient for that ion

54
Q

Structure of channels

A
  • Pore-forming membrane proteins
    o Highly selective pathway into the ¢
    o Guarded by 2 or > gates that control opening and closing
     Activation gate = m
     Inactivation gate = h
    o Ions can pass only if 2 gates are open
55
Q

Molecule structure of channels: which segment responsible for voltage sensing

A

o 6 transmembrane span forming a domain
 In each domain, one specific helical segment (S4) is responsible for voltage sensing (+ charged)
o 4 domains = 1 channel pore
 Make A1

56
Q

Steps of activation of gated channels

A

3 sequences, involving 2 gates
* Resting: negative membrane potential
o Activation gate m = closed
o Inactivation gate h = open
* Activated: early depolarization
o Both gates are open => allow current to flow
* Inactivated => incr depolarization
o Inactivation gate closes => current cease to flow
 Slowly recover during repol and reopen
o Activation gate close w repolarization

57
Q

Na+ channel activation

A
  • When membrane potential reach -70 to 60mV  trigger voltage sensor on S4
    o Outward mvt => molecular changes => open channel pore
    o Fast inward Na+ current flow
  • Depolarization triggers fast inactivation: 2 time constant
    o After <1ms: switch off Na+ current very rapidly
    o After 4ms: constant decr of Na+ inflow during later stages of AP
     Slow or late Na+ current (INa(s))
58
Q

Which anti arrhythmic inhibit Na+ channels

A

class I
o Lidocaine: prolongs inactivation state by interacting w S4 sensor
o Quinidine

59
Q

Other factors affecting Na+ channels function

A
  • Hyperkalemia: depolarizing hyperkalemic values => remove potential difference
    o Inhibition of cardiac contraction
  • Ionophores: compounds that incr flow of ions along [gradient] => act as pathways for ions
    o Monensin: pathway for Na+
     Promote release of ANP
60
Q

Ca2+ concentration gradient

A

Maintained because sarcolemma is not permeable to Ca2+
o Extra¢ [Ca2+] is high

61
Q

Ca2+ channel function

A

regulate entry of Ca2+ ions
o Need > depolarization to open
o Can also enter through reversal of Ca2+/Na+ exchanger

62
Q

Ca2+ channel molecular structure

A

o 4 subunits: alpha1, alpha2, beta, sigma
 B subunit interact w A1 to make more binding sites for Ca2+ antagonist drugs
o Major difference: presence of phosphorylation sites on C terminal tail
 Catecholamine stimulation => incr cAMP => channel phosphorylation
* incr probability of channel opening
o Enhanced inotropic response w B adrenergic stimulation
* prolong time of opening => allow more Ca2+ to enter

63
Q

types of Ca2+ channels

A

Transient (T) – channels

Long lasting (L) channels
* Open at > negative voltage
o Earlier phase of depolarization in SA node, AV node and Purkinje ¢
o Not present in ventricular or atrial myo¢
o Can develop as fetal growth program w LV hypertrophy
* Shorter burst of opening
* Not interact w antagonist drugs

64
Q

Features of T Ca2+ channels

A
  • Open at > negative voltage
    o Earlier phase of depolarization in SA node, AV node and Purkinje ¢
    o Not present in ventricular or atrial myo¢
    o Can develop as fetal growth program w LV hypertrophy
  • Shorter burst of opening
  • Not interact w antagonist drugs
65
Q

Features of L Ca2+ channels

A
  • Open at < negative (higher) voltage
    o Later phases of depolarization
  • 2 patterns of opening: short bursts or longer periods
    o Ca2+ blocking drugs change pattern to short bursts => decr amount of Ca2+ influx
     Dihydropyridines: amlodipine and Non-dihydropyridines: verapamil, diltiazem
     Shared properties: systemic vasodilation, coronary dilation
66
Q

Structure K+ channels

A
  • Functional k+ channel pore requires multiple subunits: 4 subunits of 2 or 6 spans
  • Simple structure: 2 transmembrane helices => Inward rectifier channel (Kir)
  • Another member: ATP-sensitive K+ channel (Katp) => stop K+ leak induced by hypoxic damage
67
Q

currents making major contribution to repolarization

A

K+ currents from channels Ks and Kr

Voltage operated/delayed rectifier K+ channels

68
Q

Features of delayed rectifier K+ channels

A
  • voltage operated
  • Slow activation after depolarization => delayed rectifier current
    o IK, IKv
69
Q

What channels are delayed rectifier K+ channels

A
  1. Slowly repolarizing K+ channel (Ks)
     Responds to B adrenergic stimulation
    * Allow adequate coronary flow when incr HR (shorter diastole)
     Diseases: long Q-T syndrome => B stimulation fail to abbreviate AP duration
    * Accelerate next depolarization => risk of serious arrhythmias
     Class III antiarrhythmic do not inhibit Ks channels
  2. Herg channel (Kr)
     Mutation of HERG genes  abnormalities in Kr current leading  congenital long Q-T syndrome
70
Q

Function of Inward rectifier superfamily

A

Kir

  • Set the resting membrane potential of cardiac myo¢
    o Outward current when membrane potential is above equilibrium
    o Contribute to repolarization phase of AP and help end AP  regain resting membrane potential
  • Hyperpolarization (<85mV): large inward K+ current
    o Help maintain high intra¢ K+ activity
    o Membrane polarity
71
Q

Function of transient outward K+ current

A

Ito

  • Voltage gated K+ current
    o Early repolarization after the peak of upstroke
    o Also contribute to phase 2
72
Q

Which cells have prominent Ito

A

Prominent in atrial, Purkinje and subepicardial ventricular ¢

73
Q

Where are found Ligand operated members of the Kir superfamily

A

Ikach & Ikado
nodal tissue + atrium

74
Q

Channels part of Ligand operated members of the Kir superfamily

A
  • Muscarinic operated channels: operated by M2 R
    o Inhibitory G protein Gi
    o Sensitive to Ach => current = IkAch
  • Adenosine operated channels: respond to A1 R
    o Inhibitory G protein Gi
    o Sensitive to adenosine => current Ikado
75
Q

Effect of Ligand operated members of the Kir superfamily

A

Both current incr outward K+ flow => hyperpolarization
o Spontaneous firing rate of nodal tissue slows => incr HR

76
Q

What activates the largest conductance K+ channel? Where is it important

A

BkCa

  • Ca2+ activated K+ channel (part of delayed rectifier family)

vascular SM¢
o incr intra¢ [Ca2+] after opening of Ca2+ channels => open BkCa
o Large efflux of K+ => hyperpolarization => Ca2+ channel closure

  • Largest conductance for K+ = much more K+ can flow through vs other K+ channels
77
Q

Role ATP-sensitive K+ channel

A
  • Controlled by internal binding of ATP
  • No obvious physiologic role in cardiac myo¢
    o May be metabolic sensor that link cytosolic energy metabolism to membrane electrical activity
    o Alarm systems => ischemia => decr ATP => open channel => outward K+ flux => accumulation outside the ¢ => loss of normal membrane polarization => state of inactivity of the ¢
  • In SM ¢: adenosine => open channel => coronary vasodilation
78
Q

What activates ischemia-induced K+ current flow

A
  • Na+ activated K+ current: respond to incr intra¢ [Na+]
    o Important in ischemia
79
Q

Role of Cl channels

A
  • Role in heart remain unclear
  • Existence of Cl- current not confirmed
80
Q

Role of Ca2+/Na+ exchanger

A
  • Exchange of 3Na+ for 1ca2+
    o No energy required
    o Responsive to (direction of flux determined by):
     Membrane potential
     [Ca2+] and [Na+] each side of membrane
  • Electrogenic in the direction of Na+ flux
81
Q

Direction of Ca2+ flux with the Ca2+/Na+ exchanger will affect:

A

o Early depolarization: inward Ca2+
o Accumulation of Ca2+ in subsarcolemmal space => tend to
 Outward ca2+
 Inward Na+

82
Q

Where does intracell Ca2+ comes from during systole

A

75% of Ca2+ liberated in systole comes from SR

25% comes from T-Tubules by L-channels or Ca2+/Na+ exchanger

83
Q

Role of Na+/H+ exchanger, what drives it

A
  • Role is efflux of H+ created energy metabolism
    o Driven by [Na+] gradient
  • Electroneutral exchange of 1Na+ for 1 H+
84
Q

Role of Na+/K+ pump

A
  • Role is to correct the massive influx of Na+ during early depolarization
    o Use ATP to extrude Na+ from the ¢ against [gradient]
    o 3Na+ out for 2K+ in
85
Q

Activation sites of Na+/K+ pump

A

o Na+: internal surface of membrane
o K+: internal surface of membrane
o Binding change molecular configuration => transmit to other subunits => active form

86
Q

Effect of digitalis

A

Inhibit Na+/K+ pump
o incr intra¢ [Na+]
o Reverse mode of Na+/Ca2+ exchanger => promote incr intra¢ [Ca2+]
 Positive inotropic effect

87
Q

Catecholamines induced arrhythmias

A
  1. Stimulate Na+/K+ pump → hyperpolarization → ↑ conduction velocity
  2. Shorten repol and effective RP → dispersion of refractoriness
  3. ↑ slope of phase 4 (↑ L-type Ca2+ current) → ↑ rate of diastolic depol
  4. Stim Ca2+ currents → delayed afterdepol
88
Q

Major function of Ca2+ channels

A

Concentration gradient maintained because sarcolemma is not permeable to Ca2+
o Extra¢ [Ca2+] is high

Fct: regulate entry of Ca2+ ions
o Threshold to open Ca2+ > vs Na+ channels → phase 2
o Can also enter through reversal of Ca2+/Na+ exchanger

89
Q

Molecular structure of Ca2+ channels

A

similar to Na+ channel
o 4 subunits (transmembrane domain): A1, A2, B, sig
 Each have 6 helices
* S4 helical segment: + charged => act as voltage sensor
 B subunit interact w A1 to make more binding sites for Ca2+ antagonist drugs

90
Q

3 states of Ca2+ channel activation

A

 Resting state: negative membrane potential => closed activation gate (m), opened inactivation gate (h)
 Active state: depolarization => both gates are open, allow ion flow
 Inactive state: increase depol => inactivation gate close (h)
 Repolarization: close activation gate and inactivation gate reopens
 Also inactivated by [subsarcolemmal] as it incr from SR release

91
Q

Major difference Ca2+ channels vs Na+

A

presence of phosphorylation sites on C terminal tail
 Catecholamine stimulation => incr cAMP => channel phosphorylation
* incr probability of channel opening
o Enhanced inotropic response w B adrenergic stimulation
* incr time of opening => allow more Ca2+ to enter

92
Q

Types of Ca2+ channels

A

Transient (T) – channels
Long-lasting (L) - channels

  • Stretch mediated Ca2+ channels: mechanoR + LIM proteins
  • Na+/Ca2+ channel exchanger: remove Ca2+ from ¢
  • Ca2+ ATPase pump: remove Ca2+ from ¢
93
Q

Transient T channels: opening, location

A
  • Open at > negative voltage
    o Earlier phase of depolarization in SA node, AV node and Purkinje ¢
    o Not present in ventricular or atrial myo¢
    o Can develop as fetal growth program w LV hypertrophy
    o No role in excitation contraction coupling → mediate PM activity
  • Shorter burst of opening
  • Not interact w antagonist drugs
    o Mibefradil: adverse hepatic interactions
94
Q

Long lasting L channels: opening, location

A
  • Open at < negative (higher) voltage
    o Later phases of depolarization
    o Ca2+ current contributes to AP plateau
    o Lead to Ca2+ triggered Ca2+ release
  • 2 patterns of opening: short bursts or longer periods
    o Ca2+ blocking drugs change pattern to short bursts => decr amount of Ca2+ influx
     Dihydropyridines: amlodipine and Non-dihydropyridines: verapamil, diltiazem
     Shared properties: systemic vasodilation, coronary dilation
95
Q

Ca2+ channels in heart muscle

A
  • L-type Ca2+ channels:
    o Stimulated by depol → provide Ca2+ required for contraction by Ca2+ induced Ca2+ release
    o Autonomic control: β adrenergic stim → Pi of channel → ↑ Ca2+ entry
  • Stretch mediated Ca2+ channels
  • Na+/Ca2+ exchanger and Ca2+ ATPase: remove Ca2+ from cell
96
Q

Ca2+ channels in SA and AV node

A
  • L-type Ca2+ channels:
    o Affected by β stim
  • T-type Ca2+ channels:
    o No ability to block
97
Q

Ca2+ channels in vasculature

A
  • L-type Ca2+ channels:
    o Stimulate Ca2+-Calmodulin → MLCK → actin and myosin → contraction
     Gs: IP3 and DAG → SR → Ca2+ release → sustained vasoconstriction
    o Control: stimulated by
     NE: α1 and symp
     Ang II: symp and RAAS
     ET-1: Ang II, shear stress
    o Blocked by dihydropyridine
98
Q

Ca2+ channel blocking drugs

A

Dihydropyridines: amlodipine (long acting), nifepidine (short acting)

Non dihydropyridines: diltiazem, verapamil

99
Q

Non dihydropyridines: site of action, negative effects

A
  • SA/AV node > myocardium = vessels
    o Nodal inhibition (decr HR) + vasodilation => decr myocardial O2 demand
  • Bind respectively D and V sites on A1-subunit
  • Reflex tachycardia is uncommon because of SA node effects
  • Contraindicated in CHF => inotrope negative
100
Q

Dihydropyridines: site of action, side effect

A
  • Vascular selectivity: vessels > myocardium > nodes (no clinical effects)
  • Bind N site on 1-subunit
  •  BP can induce reflex adrenergic activation with tachycardia
101
Q

MOA Ca2+ channel blockers

A

Inhibition of L-type channel opening in vascular SM ¢ and myocardium => decr inward Ca2+ flow
* Ca2+ entry blockade => decr Ca2+ available for contractile proteins
o Vascular SM ¢: vasodilation
 Ca2+ regulate contractile mechanism: Ca2+ binds calmodulin => stimulation of myosin light chain kinase (MLCK) => Pi of myosin light chains => actin-myosin interaction => contraction
 cAMP inhibits MLCK
 Ca2+ channel blockers will block this pathway = VASODILATION
 B blockers will decr cAMP formation => decr MLCK inhibition => VASOCONSTRICTION
o Myo¢: negative inotrope

102
Q
  • Hemodynamic and neurohumoral effects of CCB
A

o B blockers inhibit RAAS (decr renin release) + oppose symp adrenergic state in CHF

103
Q
  • Carotid vascular protection CCB
A

o Endothelial protection, promotes NO formation
o Coronary vasodilation

104
Q

Clinical use of CCB

A

o Similar to B blocker therapy except:
 Contraindicated in CHF => inotrope negative
 Lack of effect on ventricular arrhythmias

SVT: decr sinus rate, inhibit myocardial contraction

4. Physiology and pathophysiology (18 decks)

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