Action potential and currents Flashcards
Define resting membrane potential + normal value
Difference in electrical charges btwn extra and intra¢ = -80-90mV
What are the most important ion gradients for RMP
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-
Relation of AP phases to ECG
- Phase 0 = QRS
- Phase 1 = J point
- Phase 2 = ST segment
- Phase 3 = T wave
- Phase 4 = electrical diastole
Phase 0 key events
RAPID DEPOL
* Opening of voltage gated Na+ channels
* Influx of Na+ =>membrane potential to +20-30mV = inward current (INa)
* Rapid upstroke = fully depolarize the ¢
Describe Na+ channel gates
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
Phase 1 key events
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
More prominent phase 1
Better defined in atrial and Purkinje ¢ AP
Stronger in epicardium vs endocardium
Can cause J wave on ECG in R wave downslope
Phase 2 key events
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+
Phase 3 key events
- 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
Phase 4 key events
- Membrane potential back to resting values
o During diastole, activity of exchange systems maintain ionic balance
Which current maintain resting phase
Atrial, ventricular, His Purkinje ¢: value is mainly determined by conductance of K+ through IK1 channels
Atrial myocytes AP features
- 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
Ventricular myocytes AP features
- 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
Purkinje AP features
- 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
Pacemaker cells AP features
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
Steps of PM cells AP
- When membrane potential reach -60mV = opening of Na+ channel = slow influx of Na+
* Membrane potential ¬from -60mV to -40mV - When membrane potential reach -40mV
* Opening of fast Ca2+ channels (T type) = rapid influx
* Sharp rise in potential to around +10mV - Closing of Ca2+ channels and opening of K+ channels = efflux of K+
* Bring potential membrane back to -60mV
SA node automatic activity: which cells
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
Rate of spontaneous depolarization in SA node: 3 main factors
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
5 proposed PM currents to explain spontaneous depolarization in SA node
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)
Normal spontaneous depol rates
- SA node: 60-180bpm
- AV node: 40-60bpm
- Purkinje fibers: 20-40bpm
Delayed rectifier K+ current (Ik)
- Major K+ current in PM ¢
- Alteration of its rate => important governor of AP pattern
- Activated when depolarization reach apex => contribute to repolarization
- Time dependent
Background inward current (IP or IB)
- Spontaneous inward Na+ current along [gradient]
- Remains when all other are blocked
- Role is controversial
Slow inward nodal Ca2+ current (ICa)
- 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
Inward current (If)
- 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
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
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
Pattern of atrial activation
Isochrone: equal travel time
- Internodal tracts: ¢ histologically similar to Purkinje fibers
o Insensitive to incr in extra¢ [K+]
AV node electrophysio properties
- Spontaneous slow diastolic depolarization: can serve as subsidiary PM
- 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 - Decremental conduction: progressive delay of impulse propagation with incr HR
- Concealed conduction: alteration of AV node conduction by previous event not visualized on ECG
- Conduction can occur anterograde or retrograde
Decremental conduction mechanism
o Affect slope of subsequent AP
o Cumulative effect can lead to block impulse
o Control # and order of SV impulses
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
3 AV node functional regions and AP features
- Atrionodal region
* Shortest AP duration (close to atrial myocytes) - 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) - Nodal-His bundle
* Longest AP duration
* Fastest spontaneous PM activity
Effect of adenosine
- Inhibit L type Ca2+ current
- Hyperpolarization by adenosine-sensitive K+ channel
- Occurs w adenosine A1 R
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
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
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
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
AV node: B stim (catecholamines)
↑ conduction velocity
o incr Ca2+ current by phosphorylation of Ca2+ channels
incr rate of diastolic depolarization
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
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
Electrical properties of myocardium
Excitability
Automaticity
Refractoriness
Conduction
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
Def excitability
- Ability to generate an AP from a stimulus = or > the membrane potential threshold
- Depends on availability of Na+ channels
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
Def refractoriness
- Period of time where myocytes are not excitable
o From phase 0 to 3: inactivation of Na channels
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
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
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
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
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
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]
Ions determining RMP
Na+, K+, Cl-
o Ca2+ not considered = low permeability
o Membrane is permeable to Na+, K+
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+
Driving force of current flow through channels
o Potential across membrane
o Concentration gradient for that ion
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
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
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
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))
Which anti arrhythmic inhibit Na+ channels
class I
o Lidocaine: prolongs inactivation state by interacting w S4 sensor
o Quinidine
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
Ca2+ concentration gradient
Maintained because sarcolemma is not permeable to Ca2+
o Extra¢ [Ca2+] is high
Ca2+ channel function
regulate entry of Ca2+ ions
o Need > depolarization to open
o Can also enter through reversal of Ca2+/Na+ exchanger
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
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
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
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
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
currents making major contribution to repolarization
K+ currents from channels Ks and Kr
Voltage operated/delayed rectifier K+ channels
Features of delayed rectifier K+ channels
- voltage operated
- Slow activation after depolarization => delayed rectifier current
o IK, IKv
What channels are delayed rectifier K+ channels
- 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 - Herg channel (Kr)
Mutation of HERG genes abnormalities in Kr current leading congenital long Q-T syndrome
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
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
Which cells have prominent Ito
Prominent in atrial, Purkinje and subepicardial ventricular ¢
Where are found Ligand operated members of the Kir superfamily
Ikach & Ikado
nodal tissue + atrium
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
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
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
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
What activates ischemia-induced K+ current flow
- Na+ activated K+ current: respond to incr intra¢ [Na+]
o Important in ischemia
Role of Cl channels
- Role in heart remain unclear
- Existence of Cl- current not confirmed
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
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+
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
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+
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
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
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
Catecholamines induced arrhythmias
- Stimulate Na+/K+ pump → hyperpolarization → ↑ conduction velocity
- Shorten repol and effective RP → dispersion of refractoriness
- ↑ slope of phase 4 (↑ L-type Ca2+ current) → ↑ rate of diastolic depol
- Stim Ca2+ currents → delayed afterdepol
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
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
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
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
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 ¢
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
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
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
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
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
Ca2+ channel blocking drugs
Dihydropyridines: amlodipine (long acting), nifepidine (short acting)
Non dihydropyridines: diltiazem, verapamil
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
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
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
- Hemodynamic and neurohumoral effects of CCB
o B blockers inhibit RAAS (decr renin release) + oppose symp adrenergic state in CHF
- Carotid vascular protection CCB
o Endothelial protection, promotes NO formation
o Coronary vasodilation
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
