Cardiac AP week 2 Flashcards Preview

CV M1 > Cardiac AP week 2 > Flashcards

Flashcards in Cardiac AP week 2 Deck (20):

What are the 4 phases of the AP and what are the membrane potential changes and times for each? What is the difference in the last phase btwn atrial and ventricular myocytes compared to myocytes with pacemaker activity?

Phase 0: very rapid upstroke reaching a peak overshot of about +20 to +40 mV (from -90mV) in about a msec

Phase 1: fairly rapid decline form the peak of the AP to about 0 to 10 mV and takes place over a period of a few tens of msec (roughly 50 msec)

Phase 2: prolonged plateau phase at a level of membrane potential around 0 to +10 mV lasts from 100-300 msec

Phase 3: membrane repolarization to resting level; fairly rapid process but not as rapid as the upstroke of the AP

Phase 4: in ventricular and atrial myocytes, this is the period where membranes are back at resting potentials. in myocytes that display pacemaker activity (SA node, AV node, some Purkinje fibers and a few cells in the atria and ventricles) phase 4 refers to the peroid of spontaneous depolarization that leads to the initiation of the next AP

It is important to note that the channels that are responsible for each of these phases in ventricular myocytes are the same in atrial myocytes and Purkinje fibers (with minor differences)

A image thumb

What channels are open (and closed) during phase 0 of the ventricular (and atrial, Purkinje fiber) AP?

The rapid upstroke of the AP of ventricular and atrial myocytes and Purkinje fibers is due to the activation of voltage gated Na+ channels allowing Na to flow into the cell (negative current), similarly to skeletal and nervous tissue. Must remember these channels behave essentially the same BUT ARE CODED BY DIFFERENT GENES. 

Additionally, the T-Ca2+ channel (T=transient) allows for Ca2+ influx. This channel is of greatest importance for pacemaker cells but may also occur in atrial and ventricular myoctyes. Its importance to the upstroke in ventricle and atria is limited due to it being overwhelmed by the voltage gated Na+ channels. 

Ik1 (inward rectifier K+ channels) are (mostly) closed. These channels are always open and have no gates. They hold the membrane near Ek at rest and close during depolarization. These channels prefer to conduct inward K+ current (rectifier 
channels prefer to conduct current in one direction). When at voltages less than -95, this channel conducts K+ current. at voltages less neg than -80 mV, current goes down. Bc physiologically, voltages do not 
go lower than -95 mV, it does not actually conduct inward current (even though it prefers to). Only conducts pos current (K+ leaving the cell). Note that current does not completely stop during AP but is very small. The properties of this channel are important. The fact that current decreases as the membrane potential becomes less negative means that the K+ current that is primarily responsible for establishing the cardiac myoctye resting potential is actually less during the action potential than when the cell is at rest. See slide 5 of notes

A image thumb

What channels are open (and closed) during phase 1 of the ventricular (and atrial, Purkinje fiber) AP?

Remember that this phase takes the membrane potential from +20-+40 to btwn 0 and +10 mv and lasts roughly 50 msec. 

During phase 1, voltage gated Na+ channels being to inactivate. This takes roughly 1-2 msec.

The transient outward K channels (ITo1) are activated (takes only a few msec). They are called transient bc they also inactivate over a relatively short period of time. both their activation and inactivation are due to membrane depolarization. 

L-type Ca2+ channels become activated. They oppose the tendency of the membrane to return towards resting and help to hold the membrane at its plateau lelve of 0 to +10 mV (although at this particular phase, repolarization outweighs depolarization). L-type Ca2+ channels activate at potentials more positive than about -30 mV (require several msec to activate) and inactivate very slowly, typically over a period of several hundred msec. They allow Ca2+ to enter the myoplasm to trigger contraction through calcium-induced calcium release. These channels are extremely important to the cardiac AP and to the contractile function of the heart but it is important to note that Ca2+ channels occur in densities that are very small (1/20 to 1/50) relative to density of voltage gated Na+ channels. 


A image thumb

What channels are open (and closed) during phase 2 of the ventricular (and atrial, Purkinje fiber) AP?

Remember that this phase of the AP is a prolonged period when the membrane potential is in the range of 0 to +10 mV for 100-300  msec (duration depends on cell type and location in the heart).

Note that the current during this phase is small relative to the currents in phases 1 and 3 and is in balance (therefore resulting in a plateau). The currents (conductances) that occur during this phase are comparable to (but different and somewhat larger than) those occurring at rest. Due to this, relatively small changes in ionic currents (number of channels open and various types) can have profound effects on the amplitude, shape, and duration of the plateau phase of the AP.

The Na+/Ca2+ exchanger is electrogenic in nature bc it moves 3 Na+ into the cell for 1 Ca2+ out of the cell. Due to this, it usually moves positive charge into the cell therefore depolarizing the membrane. The magnitude of this inward current depends on myoplasmic Ca2+ concentrations-increases as Ca2+ increases which occurs during the AP. Therefore it contributes to maintaining the plateau at a depolarized potential. 

The L-type Ca2+ channel that was activated in phase 1 is still open (remember it activates slowly and inactivates slowly) and is essential for maintaining the depolarized plateau phase as well as the influx of Ca2+ required for contraction. 

Three voltage gated delayed rectifier K+ channels are activated at this point (IKs, IKr, and IKur). s=slow, r=rapid, and ur=ultra rapid which indicates how fast they activate in response to membrane depolarization. These channels gradually open during the plateau phase and eventually lead to membrane repolarization. Note that their speeds are in comparison to each other and even the ultra rapid K+ channel is still much slower than Na+ and Ca2+ channels. In atrial myocytes, IKur channels are are frequent whereas they are infrequent in ventricular myocytes. This likely partly accounts for the shorter duration of atrial myocyte APs.

The IK1 channel is conducting a small amount of current due to depolarization of the membrane. 


A image thumb

What channels are open (and closed) during phase 3 of the ventricular (and atrial, Purkinje fiber) AP?

During this phase, the membrane repolarizes relatively rapidly. Note that this process is much more graudal than the rapid (phase 0) of the upstroke of the AP. This phase usually requires tens of msec to complete. 

L-type Ca2+ channels are inactivated and deactivated. By the end of the AP, many of these channels have inactivated. Additionally, as the potential during the plateau and the repolarizing phase of the AP gradually moves back toward resting AP, L-type Ca2+ channles that have not inactivated will deactivate. The activation gates of these channels begin to open at -30 mV and have a 50% probability of being open near 0 mV. This reduces Ca2+ influx and tendency for membrane to be depolarized. 

Current through the voltage gated delayed rectifier channels increases. The most important of these in ventricular myocytes is IKs

The inward rectifier K channel (IK1) is also important to this phase. Remember that the current flowing through this channel increases with membrane repolarization. As the membrane repolarizes, more and more current flows through these channels which serves as a positive feedback loop. 

The cAMP activated chloride channel (ICl,cAMP) is also involved in membrane repolarization. Even though this channel is generally thought to be active with sympathetic NS stimulation, its imporant to note that there is some tonic level of SNS activity even under resting conditions. 

A image thumb

What channels are open (and closed) during phase 4 of the ventricular (and atrial, Purkinje fiber) AP?

This phase refers to the resting potential which is near -90 mV. When the membrane is at rest, the permeability is highest to K+, mostly due to the inward rectifier K channel, IK1. There are smaller permeabilities to other ions (mostly Na+ and Cl-.

A image thumb

What are the differences btwn the atrial and ventricle myocyte APs and what accounts for them?

The atrial AP is shorter in duration and has a more pronounced phase 1. The presence of more IKur channels in atria vs ventricles is likely responsible for the shorter duration. 

A image thumb

What are the major differences that can be noted btwn the APs and the channels involved of atrial and ventricular myocytes as compared to those of the SA and AV nodes?

The rising phase (phase 0) is much more gradual than in ventricles and atria. Teh peak amplitude of the AP is also smaller and there is no well-defined plateau. Also, there is no real resting potential for cells of the SA and AV nodes. Phase 4 is a gradual depolarization phase that leads to periodic APs. 

SA and AV nodal cells do not have any significant number of voltage gated Na+ channels. Additionally, SA and AV nodal cells contain pacemaker channels (these also occur in some Purkinje fibers but are absent in atria and venticles). The variety of the K+ channles involved is not as large as in atria in ventricles and is not as well understood. T-type Ca2+ channels play a more important role in the upstroke of the SA and AV nodal APs.  Note that there are less Ca2+ channels in SA and AV nodes and that Ca2+ channels conduct current more slowly leading to a more gradual depolarization observed in phase 0. 

A image thumb

What channels are open (and closed) during phase 4 of the SA and AV nodal APs?

Remember that this phase is not a resting potential but is a continuously depolarizing phase. 

During this phase, pacemaker channels, or Ichannels are activated. The f stands for funny bc unlike most other voltage gated channels, these channels are activated when the membrane hyperpolarizes. These channels are closed when Vm is less negative than about -35 mV. So, during most of the AP these channels are closed. AS the AP ends and the membrane becomes more negative than -35 mV, these channels begin to gradually open. Opening is a slow process and requires several hundred msec to complete. However, as soon as they begin to open they tend to depolarize the membrane. These are non-selective cation channels that conduct Na+ and K+ which drives the membrane potential toward 0 mV. Since these channels open and close so slowly, even though Vm is becoming less negative, pacemaker channels remain open until well into the rising phase of the next AP. These channels do not allow the membrane to become more negative than about -60 mV.

Inward rectifier channels, IK1, begin to pass less current during this phase as the membrane depolarizes. This is an example of positive feedback bc the more the membrane depolarizes, the less current these channels conduct and this allows for more depolarization.

T-type Ca2+ channels are involved in the end of phase 4 and the beginning of phase 0. They activate at more negative potentials than L-type Ca2+ channels (activation beings when membrane potential less negative than about -50 mV as compared to -30 mV for L-type Ca2+ channels). They are transient though bc they inactivate faster than L-type. They give a rapid boost to membrane depolarization once the membrane has depolarized to -50 to -45 mV. The faster this depolarization occurs, the faster threshold is hit and the faster the heart rate. 

A image thumb

What channels are open (and closed) during phase 0 of the SA and AV nodal APs?

T-type Ca2+ channels activate first and give the boost to depolarization (the beginning of phase 0). After these channels inactivate, L-type Ca2+ channels activate. (there are also fewer T-type than L-type). L-type Ca2+ channels drive the membrane toward ECa. The lower density of these channels as compared to Na+ channels in ventricles and atria as well as their slow activation accounts for the much more gradual upstroke of the AP in the SA and AV nodal cells as compared to ventricles and atria (and Purkinje fibers).

The AP ends due to the inactivation of L-type Ca2+ channels and the increased current through IK1 due to the decrease in membrane potential. K+ current through this channel further repolarizes the membrane. Repolarization is also achieved thorugh delayed rectifier K+ channels. 


A image thumb

What 3 factors account for the AV nodal delay?

Although the AV node is a very small structure, it takes about 0.1 sec for an AP to propagate through it. Reasons are:

1. absence of Na+ channels

2. relatively low density of Ca2+ channels

3. relatively fewer gap junctions btwn cells (increases longitudinal resistance and therefore increasing conduction velocity)


When a pt has a myocardial infarction, what happens to ATP in the infarcted area?

What happens to Vm in the infarcted area?

What happens to Na+ channels?

What happens to AP conduction?

What happens to the ordered depolarization and repolarization of the heart?

1. ATP stores decrease due to lack of oxygen.

2. Vm goes up. With no ATP, Na and K gradients are not maintained and drives the membrane potential toward 0.

3. Resting inactivation of Na+ channels begins to occur. Recall that these channels need a rapid depolarization of the membrane to activate and with the slow rise of membrane potential, resting inactivation occurs. 

4. AP conduction does not occur through the infarcted cells bc cells are dead. Get fibrous tissue which is an insulator and does not conduct APs.

5. Ordered depolarization and repolarization no longer occurs. End up with portions that depolarize later than normal bc AP had to go around infarcted area. Get depolarized tissue next to repolarized tissue and makes heart more likely to generate an arrythmia. 


In addition to channel types that are implicated in APs, there are also several regulatory (or modulatory) channels that can modify the AP and serve other vital fxns. What are the 3 modulatory channels we are responsible for?

Note that modulatory channels may either be classified as K+ or Cl- channels.





How is the IKACh channel stimulated? What parts of the heart is it located in? What are its effects?

This is a K+ channel that is stimulated by ACh release from the parasympathetic NS (vagal) nerve terminals that innervate the atria and nodal tissue of the heart (SA and AV nodes). Do not innervate ventricles!

This channel is a critical modulator of the excitability of the SA node, AV node, and atrial myocytes. When opened, they cause a hyperpolarization of membranes (most importantly in SA and AV nodes) which slows the rate of spontaneous depolarization (phase 4) and therefore slows heart rate. 


How/when are ATP-sensitve K+ channels (IK,ATP) channels open? What are the beneficial and harmful aspects of the activation of this channel?

With normal ATP levels, these channels are closed. They open in reponse to low levels of ATP which occurs most commonly during periods of ischemia. They are the most abundant K+ channels in the heart despite having no significant role in most normal physiological situations. When these channels are activated, they allow K+ efflux and this shortens the AP pacemaker activity to reduce further depletion of ATP reserves. When these channels are open for a lengthy amount of time, K+ accumulates in the extracellular space and is particularly severe in ischemic regions bc there is not enough blood flow to removed extra K+. This can lead to hyperkalemia which leads to Na+ and eventually Ca2+ channel inactivation. These changes affect the shape and duration of APs as well as slow AP conduction, cause complete failure of conduction in localized regions, and can predispose the heart to arrythmias. 


What is Ecl and how is this determined? How/when are ICl,cAMP channels open? Where in the heart are they located? What are their effects?

The equilibrium potential for Cl- is around -55 mV which is roughly halfway btwn the resting and depolarized membrane potentials. Bc of this, Cl- channels are wel suited to fine-tune the cardiac AP. Cl- is not actively transported and so may travel across the membrane both ways depending on Vm (whereas Na+ is always moved into the cell, K+ is always moved out). AT membrane potentials more negative than Ecl, it leaves the cell and causes membrane depolarization. At potentials more positive than Ecl, it enters the cell and causes membrane hyperpolarization. 

ICl,cAMP channels are activated by the sympathetic NS (as was discussed in the heart lectures but this channel was not show in pic). This channels are in atria and ventricles but are more common in ventricles. When activated, this channel leads to shortening of the cardiac AP. Membrane depolarization is required to fully activate these channels. Note that even at rest there is always some sympathetic tone so this channel contributes somewhat to the cardiac AP under resting conditions. 


Where in the body may smooth muscle be found?

walls of most blood vessels, GI tract, reproductive and urinary tracts, airways of lungs, iris of eye, skin surrounding hair follicles


What innervates smooth and cardiac muscle? How is their contractile behavior modulated in comparison to skeletal muscle? 

Both smooth muscle and cardiac muscle are innervated by the ANS. The contractile behavior of smooth muscle is modulated by ANS inputs, circulating hormones, and numerous local chemical factors (changes in O2, CO2, pH, osmolarity).The electrical and contractrile behavior of smooth and cardiac muscle is modulated by many external influences while the behavior of skeletal muscle is very sterotyped. Additionally, cardiac and most types of smooth muscle do not require NS inputs to produce APs (and hence contraction). Have pacemaker ability whereas skeletal muscle only produces and AP and contraction if stimulated by a motorneuron. The ANS modulates the behavior of smooth and cardiac muscle rather than initiating and AP. 


What are the differences btwn synapses observed in nervous and skeletal muscle tissue vs smooth and cardiac muscle? What effect does this have on the innervated tissues, particularly in smooth and cardiac muscle?

Synapses in nervous tissue and skeletal muscle are very small spaces with the receptors for NTs in the postsynaptic membrane localized to the synapse. ANS nerve terminals generally travel across the surface of cardiac and smooth muscle cells forming periodic varicosities that are the sites of NT release (NE, ACh). The varicosities are a larger distance (up to a micron) and ANS receptors (alpha and beta adrenergic receptors, muscarinic receptors) are generally dispersed over the entire surface of the post-synaptic cell. The overall affect is a slower and graded but more global response (as opposed to more local response in skeletal muscle and nervous tissue)


True or false: Smooth muscle is usually designed to provide a very finely graded (higly modulated) contractile responses.