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18 Cards in this Set
- Front
- Back
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Ion channels
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Ion channels are selective, but passive.
Selective – only sodium can cross a sodium channel Passive – movement and direction are determined by net influence of concentration gradient vs. voltage gradient. The channel does not “push” the ion across in any way Although ion channels are passive, they can open or close depending on cellular conditions This ability to open and close causes most cardiac ion channels to be essentially unidirectional |
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Ion exchangers
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Ion exchangers are selective (for at least two ions) and passive.
Ions are exchanged based on differences in concentration gradients. Exchange is not necessarily one-to-one, and can reverse direction depending on relative concentration gradients. |
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Ion pumps
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Ion pumps are selective, and actively transport ions across membranes against concentration or voltage gradients.
ATP is the usual energy source for this. Note that cell’s active mechanisms work to increase intracellular potassium, and decrease intracellular sodium and calcium. |
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Concentration vs. Electrical gradients
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Negatively charged intracellular proteins generate electrical gradient which
opposes concentration gradient – establishes steady state equilibrium. In the myocyte, intracellular voltage is – 90 mV at equilibrium. Negatively charged cell is polarized relative to the neutral extracellular environment The difference in voltage is the membrane potential |
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K+ channels
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There are three main groups:
-One group is open at rest. -The other two groups are closed at rest, and open up at different points during the cardiac action potential. |
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Cardiac myocyte at rest
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Na+ channels are closed
Ca++ channels are closed Some K+ channels are closed Some K+ channels are open Cell is actively pumping out Na+ and Ca++ K+ is leaking out passively, leaving behind a negative intracellular charge (– 90 mV) |
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Ventricular action potential vs surface EKG
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QRS = rapid depolarization (Phase 0)
ST segment = plateau (Phase 2) T wave = repolarization (Phase 3) - alterations in the action potentials of enough ventricular myocytes will alter the surface EKG |
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Sodium channels
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Are the primary channels responsible for myocyte depolarization
Activate rapidly, and inactivate rapidly Activation occurs when threshold is reached – (voltage-gated Three states -closed (Resting) -open (active) -inactive (cell membrane repolarization induces change to closed (resting) state |
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Gap junctions
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Gap junctions allow transmission of depolarizing current from cell to cell
Cells in resting state – fully polarized; sodium channels all closed First cell depolarizes to threshold – causes all sodium channels in that cell to open Sodium influx causes full depolarization of cell First cell is now fully depolarized by rapid sodium influx Depolarizing current will now be transmitted to second cell across gap junction Gap junctions allow transmission of depolarizing current to next cell This will depolarize the next cell enough to reach its threshold Second cell reaches threshold, all sodium channels open, fully depolarizes Depolarizing current now delivered to third cell – sodium channels open… First cell is still depolarized – no other ion channels activated yet Sodium channels in first cell begin to inactivate: no more sodium influx All this is very rapid – other ion channels haven’t even responded yet. |
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Cardiac action potential
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Phase 4 resting
-K is being brought into cell by Na-K pump, but then leaks back out, leaving cell negatively charged. Notice that some K channels are open at rest, while others are closed. The closed channels are voltage-gated, will open once cell voltage reaches a specific threshold. - All Na+ channels are in resting (closed) state Phase 0 - rapid depolarization - Depolarizing current pushes cell to threshold - Na+ channels open, rapidly depolarize cell Phase 1 - transient partial repolarization -Sodium channels inactivate while cell is still depolarized. Transient outward current reverses a little bit of depolarization “overshoot”. Transient outward current is mostly a potassium current, but there may also be an inward chloride current as well. Phase 2 - plateau -Depolarization of cell triggers Ca++ channels to open - Slower and sustained Ca++ influx prolongs depolarization, and triggers release of Ca++ from Sarcoplasmic Reticulum: contraction -- “calcium-activated calcium release”: excitation-contraction coupling Phase 3 - rapid repolarization -Ca++ channels close - Voltage-gated K+ channels remain open, repolarize cell - Na+ channels begin to revert to resting (closed) state Phase 4 is diastole, everything else is systole |
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Cardiac action potential vs Surface EKG: Na+ and K+ channel blocking drugs
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Na+ channel blocking drug will:
- slows upstroke of phase 0 - prolong QRS K+ channel blocking drug will: - prolong AP phase 3 - prolong QT |
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Refractory periods
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Absolute Refractory Period
- All Na+ channels are inactivated – cannot reopen in any circumstance; must first get to resting (closed) state - All Ca++ channels are open - Cell is completely inexcitable - No stimulus of any strength is able to generate a new action potential - Phase 2 Effective Refractory Period - Na+ channels are still inactivated - Some Ca++ channels are now closed -- which means they can reopen - A very strong stimulus can provoke a weak, localized action potential - Any induced action potential will be too weak to propagate to other cells - Effectively, the cell is inexcitable - The Effective Refractory Period is important clinically. The Absolute Refractory Period is clinically irrelevant. -End Phase 2, beginning Phase 3 Relative Refractory Period - Cell is beginning to repolarize (phase 3) - Cell has not yet returned to resting state - Most Na+ channels are still inactivated -- some are moving to resting (closed) - Ca++ channels are mostly closed -- which means they can reopen - A strong stimulus can induce an action potential that will be lower amplitude and slower velocity than “normal” - But the action potential will be strong enough to propagate normally to adjacent cells |
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Premature beats and refractory periods
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If premature beat or pacing stimulus arrives during the Effective Refractory Period, there is effectively no response
If premature beat or pacing stimulus arrives after the Relative Refractory Period, it produces a completely normal action potential If a sufficiently strong premature beat or pacing stimulus arrives after the ERP but during the Relative Refractory Period, it produces a slower-onset action potential within the cells directly activated, but propagation to adjacent cells is normal – clinically the same as a normal beat |
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Automaticity: Average vs pacemaker current
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Average cell
- In “average” atrial and ventricular myocytes, phase 4 is nearly quiescent - One group of K+ channels is open, maintaining resting – 90 mV - Na+ and Ca++ channels are closed - Cell will not generate a new action potential unless depolarizing current arrives via gap junction from a neighboring cell (an external stimulus) Pacemaker current -Some cells have a slow inward leak of positive ions across membrane during phase 4. This leak is the “pacemaker current”. - For some specialized cells this is normal function: -- Sinus Node, AV Node, His bundle and Purkinje fibers - For some cells this is result of disease, usually ischemia or metabolic -Once threshold (– 70 mV) is reached, action potential is generated - An automatic rhythm is being generated by this cell -- can be propagated to other cells |
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Automaticity: Sinus + AV Node
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Sinus and AV node are very “leaky” during phase 4
Phase 4 current flow is so much that the cell never repolarizes to – 90 mV - Doesn’t even make it to – 70 mV Maximum negative repolarization is – 60 mV - – 60 mV is the “resting” potential for Sinus and AV nodal cells Recall that Na+ channels don’t return to resting (closed) state until cell is fully repolarized ( – 90 mV ), and these cells never reach that level Result: Na+ channels are not active in Sinus or AV nodal cells - the cell membranes are never polarized enough to use them - Also, Sinus and AV nodal cells have much smaller concentration of Na+ channels than all other cardiac cells – effectively absent No Na+ channel activity: phase 0 is driven by Ca++ channels instead - Ca++ channels are slower than Na+ channels - Phase 0 has a slower, more gradual rise - Phase 1 does not occur – it is a response to rapid Na+ “overshoot” - Phase 2 also doesn’t occur – Ca++ channels drive phase 0 instead - Phase 3 still occurs normally -- Still driven by voltage-gated K+ channels Again, the Sinus and AV nodes have less negative resting and threshold potentials vs. other cardiac cells – they are less polarized at rest -resting potential is the most negative; threshold is less negative |
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Autonomic effects on automaticity
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Sinus and AV nodes are heavily influenced by autonomic nervous system
Sympathetic nervous system causes increase in heart rate Parasympathetic nervous system causes decrease in heart rate This is accomplished primarily by changing the slope of phase 4 depolarization -Sympathetic stimulation increases slope of phase 4 depolarization (Epinephrine/NE at alpha and beta receptors) -Parasympathetic stimulation decreases slope of phase 4 depolarization and hyperpolarizes at end of phase 3 (ACh at nicotinic and muscarinic receptors) |
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Pacemaker current
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Phase 4 depolarization is caused by “slow, inward leak” of positive ions
The positive ion is almost exclusively Na+ -But the leak is not through the “Na+ channels” I described before -Remember I said that Na+ channels are “effectively absent” in SA and AV nodal cells If (funny current) NOT ON TEST If – flows mainly through HCN channels HCN = “Hyperpolarization-activated,Cyclic Nucleotide-gated” -Hyperpolarization-activated means that these channels open when the cell is more polarized -So they are voltage-gated like the Na+ and Ca++ channels we already discussed, but are activated on the opposite end of the membrane potential |
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HCN channels
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NOT ON TEST
Hyperpolarization activated HCN channels open in phase 4, cause slow inward leak of mostly Na+ -HCN Channels are also permeable to K+, but this is probably not clinically important Eventually depolarizes cell toward threshold of the Ca++ channels, which activates phase 0 In SA and AV nodal cells, there are effectively no Na+ channels (other than the HCN channels) -Phase 0 is produced by Ca++ channels only -T-type Ca++ channels are activated first --Probably have a slightly lower threshold for activation --Give the L-type Ca++ channels an extra “push” to open --T-type = “transient”, L-type = “long-acting” HCN channels are cyclic nucleotide-gated -Second messenger -Sympathetic stimulation increases cAMP, increases HCN, increases heart rate -Parasympathetic stimulation decreases cAMP, decreases HCN, decreases heart rate -Beta blockers decreases sympathetic stimulation -Calcium channel blockers indirectly decrease HCN channel responsiveness to cAMP |
