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
Overdrive suppression: mechanism and pathophys
* 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
26
Propagation of impulse from SA node
* 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
27
Pattern of atrial activation
Isochrone: equal travel time * Internodal tracts: ¢ histologically similar to Purkinje fibers o Insensitive to incr in extra¢ [K+]
28
AV node electrophysio properties
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
29
Decremental conduction mechanism
o Affect slope of subsequent AP o Cumulative effect can lead to block impulse o Control # and order of SV impulses
30
AV node slow impulse conduction by 2 mechanism
 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
31
3 AV node functional regions and AP features
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
32
Effect of adenosine
* Inhibit L type Ca2+ current * Hyperpolarization by adenosine-sensitive K+ channel * Occurs w adenosine A1 R
33
His bundle AP
* ¢ 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
34
Autonomic nervous system control: intracell effects
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
35
SA node: B stim (catecholamines)
* 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
36
SA node: vagal stim (Ach)
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
37
AV node: B stim (catecholamines)
↑ conduction velocity o incr Ca2+ current by phosphorylation of Ca2+ channels  incr rate of diastolic depolarization
38
AV node: vagal stim (Ach)
↓ conduction velocity o Same mechanisms as SA node  AV node sensitive to p∑ inhibition (physio AVB) o Inhibit Ca2+ channel opening
39
Atrial myocytes: vagal stim
↓ AP duration and refractory period o Activation of outward K+ currents → shorter plateau phase o ↓ duration of Ca2+ channel opening → ↓ inotropy
40
Electrical properties of myocardium
Excitability Automaticity Refractoriness Conduction
41
Factors influencing cardiac activity
* 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
42
Def excitability
* Ability to generate an AP from a stimulus = or > the membrane potential threshold * Depends on availability of Na+ channels
43
Def automaticity
* 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
Def refractoriness
* Period of time where myocytes are not excitable o From phase 0 to 3: inactivation of Na channels
45
Def total RP
* 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
Def supernormal excitability
* 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
How changes in cardiac cycle length alter RP
o Fast HR  shorter cycle  shorter AP duration and refractory period o Currents responsible for this mechanism: IKS & ITO
48
Polarization of sarcolemma
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
Voltage gated channels role
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
Which pumps are responsible for restoration of ion balance
Ca2+ ions are pumped out by Na+/Ca2+ exchanger Na+/K+ pump Na+ out to restore [gradient]
51
Ions determining RMP
Na+, K+, Cl- o Ca2+ not considered = low permeability o Membrane is permeable to Na+, K+
52
Role of Na+/K+ pump
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
Driving force of current flow through channels
o Potential across membrane o Concentration gradient for that ion
54
Structure of channels
* 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
Molecule structure of channels: which segment responsible for voltage sensing
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
Steps of activation of gated channels
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
Na+ channel activation
* 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
Which anti arrhythmic inhibit Na+ channels
class I o Lidocaine: prolongs inactivation state by interacting w S4 sensor o Quinidine
59
Other factors affecting Na+ channels function
* 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
Ca2+ concentration gradient
Maintained because sarcolemma is not permeable to Ca2+ o Extra¢ [Ca2+] is high
61
Ca2+ channel function
regulate entry of Ca2+ ions o Need > depolarization to open o Can also enter through reversal of Ca2+/Na+ exchanger
62
Ca2+ channel molecular structure
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
types of Ca2+ channels
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
Features of T Ca2+ 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
65
Features of L Ca2+ channels
* 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
Structure K+ channels
* 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
currents making major contribution to repolarization
K+ currents from channels Ks and Kr Voltage operated/delayed rectifier K+ channels
68
Features of delayed rectifier K+ channels
- voltage operated * Slow activation after depolarization => delayed rectifier current o IK, IKv
69
What channels are delayed rectifier K+ channels
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
Function of Inward rectifier superfamily
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
Function of transient outward K+ current
Ito * Voltage gated K+ current o Early repolarization after the peak of upstroke o Also contribute to phase 2
72
Which cells have prominent Ito
Prominent in atrial, Purkinje and subepicardial ventricular ¢
73
Where are found Ligand operated members of the Kir superfamily
Ikach & Ikado nodal tissue + atrium
74
Channels part of Ligand operated members of the Kir superfamily
* 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
Effect of Ligand operated members of the Kir superfamily
Both current incr outward K+ flow => hyperpolarization o Spontaneous firing rate of nodal tissue slows => incr HR
76
What activates the largest conductance K+ channel? Where is it important
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
Role ATP-sensitive K+ channel
* 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
What activates ischemia-induced K+ current flow
* Na+ activated K+ current: respond to incr intra¢ [Na+] o Important in ischemia
79
Role of Cl channels
* Role in heart remain unclear * Existence of Cl- current not confirmed
80
Role of Ca2+/Na+ exchanger
* 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
Direction of Ca2+ flux with the Ca2+/Na+ exchanger will affect:
o Early depolarization: inward Ca2+ o Accumulation of Ca2+ in subsarcolemmal space => tend to  Outward ca2+  Inward Na+
82
Where does intracell Ca2+ comes from during systole
75% of Ca2+ liberated in systole comes from SR 25% comes from T-Tubules by L-channels or Ca2+/Na+ exchanger
83
Role of Na+/H+ exchanger, what drives it
* Role is efflux of H+ created energy metabolism o Driven by [Na+] gradient * Electroneutral exchange of 1Na+ for 1 H+
84
Role of Na+/K+ pump
* 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
Activation sites of Na+/K+ pump
o Na+: internal surface of membrane o K+: internal surface of membrane o Binding change molecular configuration => transmit to other subunits => active form
86
Effect of digitalis
Inhibit Na+/K+ pump o incr intra¢ [Na+] o Reverse mode of Na+/Ca2+ exchanger => promote incr intra¢ [Ca2+]  Positive inotropic effect
87
Catecholamines induced arrhythmias
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
Major function of Ca2+ channels
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
Molecular structure of Ca2+ channels
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
3 states of Ca2+ channel activation
 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
Major difference Ca2+ channels vs Na+
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
Types of Ca2+ channels
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
Transient T channels: opening, location
* 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
Long lasting L channels: opening, location
* 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
Ca2+ channels in heart muscle
* 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
Ca2+ channels in SA and AV node
* L-type Ca2+ channels: o Affected by β stim * T-type Ca2+ channels: o No ability to block
97
Ca2+ channels in vasculature
* 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
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Ca2+ channel blocking drugs
Dihydropyridines: amlodipine (long acting), nifepidine (short acting) Non dihydropyridines: diltiazem, verapamil
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Non dihydropyridines: site of action, negative effects
* 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
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Dihydropyridines: site of action, side effect
* Vascular selectivity: vessels > myocardium > nodes (no clinical effects) * Bind N site on 1-subunit *  BP can induce reflex adrenergic activation with tachycardia
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MOA Ca2+ channel blockers
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
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* Hemodynamic and neurohumoral effects of CCB
o B blockers inhibit RAAS (decr renin release) + oppose symp adrenergic state in CHF
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* Carotid vascular protection CCB
o Endothelial protection, promotes NO formation o Coronary vasodilation
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Clinical use of CCB
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