What are the currents and channels that act in the different phases of the cardiac AP?
Phaase 0 = Rapid Depolarization mediated by Fast Na current
Phase 1 = early partial repolarization by K channel (I-ito)
Phase 2 = broader balance between Ca influx and K efflux (I-K1) for stable potential
Phase 3 = Repolarization and K efflux
Phase 4 = Hyperpolzarization and K efflux
What are the equilibrium potentials of the ions and Vm (resting membrane potential)?
Ena = 61 mv
Ek = -91
Ecl = -85
Eca = 140
Vrest = -80--90
What is the inward rectifier current?
Channel that pass current best when the membrane is negative near Vm (-91) and pass better at negative potentials
Pass K+ current
Modulating these currents can affect the AP duration - inhibiting can prolong AP (and therefore QT interval!)
What is Effective and Relative Refractory Period and what's happening then?
ERP = too many Na channels are inactivated and so inward current is too small to cause excitation or too slow to excite neighboring cells (Phase 2 and 3)
RRP = some Na channel inactivation goes away and have elevated threshold for AP (Phase 3 end)
How does automaticity work in pacemaker cells? What causes regeneration of AP?
Maximum diastolic membrane potential is -60 mV (vs -90 in other fibers) becuase have little inward rectifier currents (less Ik1)
Fibers also have little I-NA (fast Na channels), Phase 0 rapid depolarization due to I-f channel and inward calcium currents
Gradual depolarization from -60 to -40 in Phase 4 due to slow depolarizaiton through the I-f channels
What are strategies for interrupting arrhythmias?
Increasing threshold by either Decreasing Na current OR by decreasing Ca current for nodal fibers
Extending Refractory period by increasing AP duration by Decreasing delayed K current and so takes longer to repolarize
What are the I-f currents/channels? How do they work and where are they found?
I-f in nodal cells and PKJ, activated by hyperpolarization potentials more negative then -50 mV and permit BOTH Na+ influx and K+ efflux but Na+ Influx predominates
Therefore, as cell repolarizes these start to open again and allow slow uptstroke of AP to threshold and then Phase 0 by Ca channels
Modulated directly by cAMP - shifts activation curve to more positive potentials (Right)
What are the 2 effects of Sympathetic (NE) modulation on sinus rate? (Hint: via cAMP)
NE stimulates Adenylyl cyclase to increase cAMP levels which acts to:
1) Direct activation of I-f channels shifted to more positive voltages (earlier activation) and allowing more Na influx earlier
2) activating PKA to phosphorylate L-Type Ca channel and keep it open for more Ca current
What are the effects of inhibiting adenylate cyclase with Adenosine and Ach? What is the additional modulation mechanism to HR used with Adenosine/Ach?
Adenosine / Ach block Adenylyl cyclase via either Purinergic Receptors (Adenosine) or M2 Receptors (Ach) to:
1) decrease cAMP and shift I-f voltages to more negative potentials = Later activation to slow rate
2) reduce PKA and phosphorylation of L-type Ca channels = less Ca current
3) Activating K channels by Gk to turn on Ik-Ado or Ik-Ach channels and having hyperpolarizing effect on nodal fibers
How does Impulse propagation depend on currents? Why are PKJ cells so fast at conduction? Why are AV node cells so slow?
Conduction velocity depends on spread of depolarization which is increased with incrased amplitude of Na current
also depends on the rate of rise of the AP which depends on Na current amount as well
PKJ are SO fast bc have SOOOO many Na-channels so Na current in Phase 0 of AP is huge
AV node cells have little Na-current and depend on Ca current which is slower and there's less of it
What is enhanced automaticity? Characteristics of it?
Either when latent pacemaker develop faster rhythm then Sa node (in high catecholamine, hypoxia, ischemia etc) or increased automaticity at ectopic site
Impulses do NOT look normal bc not using I-f currents bc fibers depolarized and so I-f currents not contributing and usually APs are slower because have a lot of Na channels still inactivated at depolarized potentials so less Na current
What are the 2 types of AP trigggered acitivity causing arrhythmia?
Early After Depolarizations and Delayed After Depolarizations
What's happening in EAD?
depolarizing after-potentials that are arising during normal repolarization phase - *SEEN MOST COMMONLY WHEN AP IS PROLONGED!!
Mediated in Phase 2 by Ca currents and in Phase 3 by both Ca and Na currents
Contributes to Torsade De Pointes
Eliminated by increasing frequency of pacemaker or decreasing AP duration
What is happening in DAD?
Depolarizing after potential that begins after max diastolic hyperpolarization and occurs when there is high intracellular calcium
ex. Digitalis/Digoxin or Strong sympathetic input
Increased Ca in cell triggers Ca-Induced-Ca release from SR and activates Na-Ca exchanger (3 Na in for 1 Ca out) to depolarize cell - thereofre upstroke by fast Na current and so Look more normal!!!
seen in PKJ and Ventricular fibers
What is Torsade de Pointes? How does it happen?
Polymorphic Ventricular Tachycardia with continuously changing, abnormal QRS complex that is preceded by long QT interval
Dangerous bc can deteriorate into Ventricular Fibrillation
Mechanism: Prolonged QT more likely to get EAD which initiates it and then reentry loop sustains the arrhythmia
How can drugs lead to Torsade?
Prolong QT by blocking K channels (Quinidine Class 1a, Sotalol Class 3, Erythromycin etc) and then get EAD and reentry loop - Torsade!!
Hypokalemia worsens drug effects and likelihood!
Frequently drugs that block the HERG channel (Ikr) trigger long QT