Cardiac Cell / Electrolyte Questions

[Sublime]

I am currently a paramedic student and was studying the basics of cardiology tonight, and have some questions my books just doesn't seem to be clear enough on.

I understand that potassium is intracellular while sodium is extracellular. I know that when the sodium channels open, it rushes in and pushes the potassium out, it causes the inside of the cell to be more positive than the outside, and it will cause depolarization of the cell. I understand that this causes the action potential to fire and this results in muscular contraction.

I do not understand some other things though.

1. I do not understand why the cell, while at resting potential, is negative on the inside relative to the outside of the cell. Potassium and sodium both have positive charges so why is the inside negative? Is it because there is more sodium and potassium outside the cell than inside?

I read this sentence in my book and it confused me, it said "During resting potential, the number of negative charges on the inside of the cell equals the number of positive on the outside". Once again why do they call the charges on the inside negative? And is there not more sodium / potassium ions outside than potassium ions inside?

2. When the cell is in resting potential, and no electrolytes are moving in or out, what exactly causes the cell to allow the sodium channels to open and let the sodium in? What causes this action to happen? I am just confused on what causes the cell to go from resting to depolarizing.

3. I read about slow and fast protein channels on the cell. It never went into much detail, other than the slow channels allow calcium into the cell. I am assuming the sodium channels are the fast channels. But I know there is also potassium channels on the cell also, is this the same as the calcium channels? If they are different, are the potassium channels slow channels also?

If anyone can help it would be greatly appreciated. I know I can ask in class but I do not have class for two days and just can't wait that long for an answer, its really bugging me I was stuck on this stuff for a while and can't seem to get it to click by reading my book.

 

[zmedic]

Here's the short answer. The inside is net negative because there is a 3 to 2 Na/K+ pump, so for every 2 K+ pumped in, 3 Na are pumped out. Since you are pumping out more positive than you are pumping in, it makes the inside negative. There actually are ions moving during "rest." There is a leak of sodium inward and potassium outward which makes the inside less negative. At a certain threshold there are sodium channels that detect this increasing (more positive) potential and the sodium channels open, depolarizing the cell. The fast channels are those that open suddenly in response to the voltage, as opposed to those that are just always open and leaking.

Same with potassium, there are fast ones that open right after depolarization to allow K to flood out of the cell and repolarize the cell. There are also slow ones that are leaking.

 

[jrm818]

Just for clarification (Zmedic I know you're a med student and probably simplified this a bit for didactic purposes, but I'd like to add a bit):

A semester in one post (let's see your paramedic instructor do that!):

The Na/K pump actually contributes very little to the voltage difference. It's primary purpose is simply to establish and maintain a high concentration of potassium inside the cell and a high concentration of sodium outside. The voltage difference is almost entirely a function of "leak" channels which are essentially always open and allow a small amount of Na and K movement.

If you think about the sodium channel independently(K cannot go through a Na channel): because there is much more sodium outside the cell than inside, sodium will flow into the cell through this open channel. However, as soon as any sodium (a positive ion) flows inside, an electrical gradient is established (now there is more positive inside than outside) which acts to force sodium outside (positives repel, so putting more positive inside results in "anti-positive" forces pushing Na+ out).

Thus there are two forces at work: the concentration gradient forcing sodium in, and the electrical gradient resisting the flow inward. The forces are stronger or weaker depending on the concentration differences.

Eventually these forces reach an equilibrium where there is some extra sodium inside the cell, but the net flow of sodium coming in (due to the concentration gradient) is balanced by the flow of sodium out (due to the electrical gradient) and no additional sodium accumulates inside the cell. (this point is around positive 55mV)

Potassium leak channels work exactly the same, but in reverse, and establish a very negative voltage with extra potassium outside the cell (thus depleting positive ions from inside the cell, and making the inside negative compared to the outside.)

Very complicated math can take the influence of sodium, potassium, and the relative "openness" of the sodium and potassium leak channels and come up with the "equilibrium voltage" where the contribution of sodium trying to get in and make the cell positive and the contribution of potassium trying to get out and make the cell negative are all accounted for. The math is way to complicated to bother with (http://en.wikipedia.org/wiki/Goldman_equation), but you can take it on faith that it is well derived and more or less accurate.

It turns out that this fancy math tells us that the potassium leak channels are a bit more leaky than the sodium leak channels, and so the negative potassium gradient dominates (potassium tries to get out, so depletes positivity from the inside of the cell) and the cell settles around -70mv (with only potassium leak channels and no sodium channels, which allow positive sodium to try to get inside, the resting voltage would be much lower). This is "polarized" because there is a voltage difference between the inside and outside of the cell.

Any influence to open more sodium channels (leak channels or other channels) will increase the amount of sodium getting into the cell and make the inside of the cell more positive (AKA less negative). More open channels means more sodium comes into the cell (sodium will keep coming in until the inside of the cell is as positive as +55mV, then the electrical force starts pushing it out faster than it comes in) and the cell becomes less negative (AKA less polarized AKA depolarized).

Embedded in the membrane of the cell are "voltage-gated" sodium channels. These channels open more and more as the voltage of the cell increases (becomes less negative). There is a "threathold" voltage where these channels are so open to sodium passage into the cell that they start a runaway reaction where more sodium comes in, makes the cell more positive which opens more channels which lets more sodium in which makes the cell even more positive etc. This results in a very rapid depolarization: the "action potential."

The voltage-gated potassium channels are sort of complicated, but basically they the same as the sodium channels but are a bit slower to open, so they aren't open until the sodium channels have been totally open for enough time for the inside of the cell to be a bit positive...once they open potassium flows out the cell down it's concentration gradient making the inside of the cell less positive (more negative AKA repolarized). Eventually all the voltage-gated channels close and only the "leak" channels are left open, which is the scenario we started with.


That may be more in depth than was needed, and is easier to explain with pictures, but hopefully it makes some sense. It really is a quite complex system (just looking at the goldman equation should convince you of that) but its possible to get a basic level of understanding without the math.

 

[zmedic]

I disagree with the beginning of the post. There is a total force on each ion, comprised of the concentration gradient and the electrical potential. But it is a total force. So the potassium ion either wants to diffuse into the cell or out of the cell, not both. If you have a channel that potassium can diffuse through it will only move (in a net fashion) in reaction to this total force. It is not diffusing one way through some channels and in another way through others.

To move a ion against this total gradient you need to either pump it or link that transport to another ion that is moving down it's gradient.

The Na/K+ pump is the MAIN source of maintaining this gradient.

Here is the first source I found: http://www.cvphysiology.com/Arrhythmias/A007.htm

there are plenty of others.

 

[jrm818]

I may have been unclear, here's my attempt to clear it up.

I disagree with the beginning of the post. There is a total force on each ion, comprised of the concentration gradient and the electrical potential. But it is a total force. So the potassium ion either wants to diffuse into the cell or out of the cell, not both. If you have a channel that potassium can diffuse through it will only move (in a net fashion) in reaction to this total force. It is not diffusing one way through some channels and in another way through others.

I agree with all of this, and I didn't mean to imply that potassium was acting differently at different channels, I was trying to explain how an equilibrium develops once a certain voltage is reached. In my experience it is not immediately obvious to people what "equilibrium" really means: the word net is important: while net movement will be in only one direction (or no direction at all at equilibrium), there are always individual ions moving in both directions across the channel.

To move a ion against this total gradient you need to either pump it or link that transport to another ion that is moving down it's gradient.

The Na/K+ pump is the MAIN source of maintaining this gradient.

Agree, and I said that. I may have misunderstood (and I apologize if so) but I took your first post to imply that the Na/K pump directly established the voltage difference since it pumps more positive ions out than it pumps in. That is not the case: there is a difference between establishing the concentration gradient for sodium and potassium and establishing an electrical gradient. If the Na/K pump was a 3 to 3 pump instead of 2 to 3, the electrophysiology of the cell would be almost unchanged, the concentration gradients would still be established (more K in, more Na out) and the voltage would be essentially the same. The voltage difference occurs almost totally because of the concentration gradients of Na and K: admittedly that gradient is established by the Na/K pump, but the pump contributes very little to the voltage directly.

The pump does technically contribute a small bit of voltage due to the current established by the 2/3 nature of the pump, but if you turn off the pump, you barely notice the difference and the cell works fine for many action potentials.

Here is the first source I found: http://www.cvphysiology.com/Arrhythmias/A007.htm

there are plenty of others.

 

[zmedic]

Please show me a source that the cell can fire multiple APs after you shut off the ATP pump. Without the pump the leak eliminates the gradient, and there is no potential difference.

 

[Sublime]

Thanks to both of you for those answers, after reading those it began to click.

However I am still somewhat confused on some things, I think. Exactly when does the sodium potassium pump come into play? I was under the impression that once the sodium rushed into the cell and it depolarized, the pump kicked in at that point to push the sodium out and potassium back in to repolarize, right? That would be Phase 4, correct?

Thank you for explaining the leak channels, their is a picture in my book that shows this but they never explained it well.

So basically, you have a cell at rest, and it is leaking sodium in, and potassium out, and once the sodium channels realize that due to these leaks, the cell is becoming more positive inside, it will open the sodium channels and allow the sodium to rush in, which causes it to depolarize. Then after it is done, the sodium potassium pump kick in to push the sodium out and potassium back in, to bring it back to a state of rest?

Do I have the basics of it down? I know there is other things that happen such as calcium release that allows muscle contraction, but I just want to know if I have the basics down.

Also, is this happening just in myocardial cells or is this the function of all muscle cells?

 

[zmedic]

There is a difference between myocardial cells and pacemaker cells.

Check these two pages out for a good picture of the electrical potential difference

http://www.cvphysiology.com/Arrhythmias/A004.htm

http://www.cvphysiology.com/Arrhythmias/A006.htm

The basics of an action potential are the same in all nerve and muscle cells in terms that sodium rushes in, k out and then they resent. Here is a good explanation of the muscle cell physiology:

http://people.eku.edu/ritchisong/301notes3.htm

 

[jrm818]

Please show me a source that the cell can fire multiple APs after you shut off the ATP pump. Without the pump the leak eliminates the gradient, and there is no potential difference.

Happily:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1365754/pdf/jphysiol01394-0054.pdf

Page 45 starts the discussion.

As a side note (nerd rant): I think this is really a cool article; this is really important scientific history with insanely clever experiments that gave us some of the knowledge we assume today has always been around. I think we tend to just accept on face that the sodium potassium pump exists, looks like the drawings with 5 slots we see in textbooks; if you really think about it it's not obvious at all how to discover this pump if you don't know it exists. Even knowing the pump exists, I'd be hard pressed to figure out how to prove there is such a pump, except that I already knew how these guys did it.

It took incredible genius and truly elegant experiments: These authors discovered the Na/K pump by radio-labeling Na in a giant squid axon and observing that sodium leaves the cells much more quickly than would be predicted using only the normal permeability of cells, that cyanide blocks this effect, and that the rapid removal of sodium only occurs when K+ is outside the cell. This is their discussion of those experiments, and the experiments that demonstrated the persistence of cellular excitability despite inhibition of the Na/K pump.

At any rate, you are correct that eventually the gradient will wear down, and the cell will loose excitability. That occurs over a surprisingly long period of time, however.

 

[jrm818]

Thanks to both of you for those answers, after reading those it began to click.

However I am still somewhat confused on some things, I think. Exactly when does the sodium potassium pump come into play? Always. The pump is always pumping, though the speed depends on the concentrations of ions. I was under the impression that once the sodium rushed into the cell and it depolarized, the pump kicked in at that point to push the sodium out and potassium back in to repolarize, right?
not quite: the pump does NOT directly repolarize the neuron, and the neuron WILL reploarize, even if you turn off the ATP pumps (like with cyanide, as in the article I posted). The neuron repolarizes for two reasons.

1) a quick repolarization occurs because slow opening voltage gated ions open a bit after the voltage gated ion channels open. This allows a flood of positive potassium out of the cell, which counteracts the flood of positive sodium that just came into the cell (the sodium channels are now closing, ending the flood, so the flood of potassium out takes over and drives the inside of the cell negative.

2) eventually both Na and K channels close. This occurs when the cell is pretty negative (below resting potential of -70 actually). Now the only open channels are the leak channels, and the cell re-establishes its resting potential all on its own: entirely due to the concentration gradient as I described in the first post.

It's important to realize that though we talk about the movement of ions across the channels as if there is a huge flood, the actual number of ions needed to change the voltage from -70mv to +20mV is quite tiny: much much smaller than the numbers of ions inside and outside the cell. Thus, though some sodium came in and some potassium flowed out during the action potential, the number of ions was too small to make a measurable difference in the concentration gradients (literally: so small it cannot be measured). Thus, the concentration gradients are unchanged after the action potential, and the cell polarizes to -70mv for the same reason it was polarized before the action potential: the leak channels. Making any sense?

That would be Phase 4, correct?

Thank you for explaining the leak channels, their is a picture in my book that shows this but they never explained it well.

So basically, you have a cell at rest, and it is leaking sodium in, and potassium out, and once the sodium channels realize that due to these leaks, the cell is becoming more positive inside, it will open the sodium channels and allow the sodium to rush in, which causes it to depolarize. I hate anthropormorphizing things like ion channels. It's a common thing to do, and lots of teachers use it to explain, but I find it really just obscures reality.

Sodium channels don't "realize" anything, they simply open in response to a decrease in voltage difference. As Zmedic mentioned, there are some pacemaker cells that will slowly leak sodium and depolarize periodically all on their own as you describe(like in the SA node: that's why the heart has automaticity and will beat on it's own, the SA node cells will depolarize periodically without stimulus).

Most cells aren't like this. Most cells will only open more sodium channels in response to a stimulus: for instance an electrical impulse from another neuron or muscle cell that causes the cells to open more sodium channels. This isn't an all or nothing phenomenon: the impulses can summate, so it may take many excitatory impulses to open enough sodium channels that the cell reaches its "threathold" and fires an action potential.

Then after it is done, the sodium potassium pump kick in to push the sodium out and potassium back in, to bring it back to a state of rest? see above, the pump is normally always "on" but is not responsible for repolarization. I know it seems logical that it would be, but if you read the bit of the article that I posted, there is some explanation there that is pretty understandable that may allow you to convince yourself that the pump has nothing to do with repolarization (other than establishing the needed concentration gradients). The Na/K pump is acutally too slow to keep up with rapid action potential firings. I mentioned that the number of ions moving during an action potential is small, but the pump moves even smaller numbers of ions.

Turning off the pump doesn't stop repolarization, and even with the pump on, the action potentials outrun the pump. However, since the pump had lots and lots of time to slowly build up a huge concentration gradient, this "outrunning" can happen for a long time before the cell stops working. It is the gradient that is responsible for repolarization: it drives potassium out to make the cell negative quickly (it would happen slowly with only leak channels and without potassium voltage channels, but speed allows for quick repeated firing) and then the gradient forces sodium and potassium through leak channels to establish resting potential at -70. If no voltage channels are open, the cell will always return to its resting potential for all the reasons in the first post.

Do I have the basics of it down? I know there is other things that happen such as calcium release that allows muscle contraction, but I just want to know if I have the basics down.

Also, is this happening just in myocardial cells or is this the function of all muscle cells?

10 characters

 

[phillybadboy]

sodium ions leak into cells, and potassium ions leak out of cells, sodium is pumped out and potasium is pumped in. but does sodium leak out though leak channels and does potassium leak in through leak channels?

 

[phillybadboy]

are you guys still here? how do i start a thead?

 

[systemet]

are you guys still here? how do i start a thead?

There should be a "New Thread" button above the thread list in the parent forum.

 

[8jimi8]

What a refreshing discussion.

I'm looking for a resource, I'm sure someone has put this together before:

I want a side by side comparison of : stages of depolarization, electrolyte in/outflux, and the ECG wave.

Anyone seen anything like that?

 

[systemet]

Well, not side-by-side, but here's a go:

This shows an ECG recording and a series of action potentials (both cardiac and pacemaker) on the same axes. It gives you the general idea that the SA node and AV nodal activity is intrinsically different from the other cardiac tissue. [They could do a better job of showing that that the phase 4 in the AV node has a gentler slope than the AV node, i.e. that it paces more slowly].

It also shows nicely that the cardiac action potential is actually different in different regions of the heart, e.g. the plateau phase is less prolonged in the atria versus the ventricles. It does fail to show that an action potential in towards the base of the ventricle (the top) will be a little longer than one towards the bottom. Or that there's a difference in the action potentials as you move from the endocardium (longer) towards the epicardium (shorter). But it's not a bad representation.

* Obviously the timing of the action potential relative to the ECG depends on which cardiomyocyte you choose to record a potential from, as, even in the ventricle, they're activated at different times in the QRS. The QRS itself is, of course, the aggregate of million of cardiac action potentials added together -- and it going to vary dependent on the lead, etc. etc.

[The webpage this comes from is interesting, but gets a little technical http://www.bem.fi/book/06/06.htm]

I also found this image, that's pretty nice:

This shows a typical ventricular cardiac AP on top, and changes in the conductance (inverse of resistance) of the membrane to different ionic species.

Here you see the classic steep upstroke of phase 0, as the sodium channels open, and Na enters the cell, depolarising it. We can see the increased conductance of the cell to Na (gNa) in the bottom tracing. This sodium influx causes depolarisation -- we see the cell now has a positive resting membrane potential.

This sodium current is short-lived, as the channels rapidly inactivate -- this is reflected in the bottom tracing by the sudden decrease in gNa. However, it's enough to trigger a rapid opening of a subgroup of potassium channels, producing a slight outward K+ current (not really shown in the bottom tracing), that lowers the membrane potential a little. This gives us phase 1 (early repolarisation).

Calcium channels also open in response to depolarisation, but do so a little more slowly, as seen by the ramp in the gCa conductance. Movement of Ca2+ into the cell (depolarising) is balanced by moving of potassium out (hyperpolarising) during the plateau phase (phase 2). As these calcium channels begin to deactivate, and gCa decreases, the potassium conductance also increases (gK), and our membrane potential begins to return to resting values (repolarisation, phase 3).

This particular cell isn't exhibiting any pacemaker activity, so the phase 4 slope stays steady and level, as the membrane potential sits at rest until the cell is subsequently activated by the next stimulus.

[The webpage here explains this quite clearly: http://www.cvpharmacology.com/antiarrhy/cardiac_action_potentials.htm

And here, a little more crudely drawn, are representative ion currents. We see a very short lived sodium current for phase 0 (INa), a longer-duration calcium current (ICa), and several different potassium currents that contribute to repolarisation (IKs and IKr), and then serve to help restore potassium (and ultimately sodium) equilibria (IK1). The annotation on the side identifies varies ion channel subunits. Mutations in some affect action potential duration and are responsible for hereditary long QT syndrome. Many drugs that cause acquired long QT syndrome bind and act at HERG.

* Hopefully these images reproduce nicely for everyone.

 

[8jimi8]

Well, not side-by-side, but here's a go:

This shows an ECG recording and a series of action potentials (both cardiac and pacemaker) on the same axes. It gives you the general idea that the SA node and AV nodal activity is intrinsically different from the other cardiac tissue. [They could do a better job of showing that that the phase 4 in the AV node has a gentler slope than the AV node, i.e. that it paces more slowly].

It also shows nicely that the cardiac action potential is actually different in different regions of the heart, e.g. the plateau phase is less prolonged in the atria versus the ventricles. It does fail to show that an action potential in towards the base of the ventricle (the top) will be a little longer than one towards the bottom. Or that there's a difference in the action potentials as you move from the endocardium (longer) towards the epicardium (shorter). But it's not a bad representation.

* Obviously the timing of the action potential relative to the ECG depends on which cardiomyocyte you choose to record a potential from, as, even in the ventricle, they're activated at different times in the QRS. The QRS itself is, of course, the aggregate of million of cardiac action potentials added together -- and it going to vary dependent on the lead, etc. etc.

[The webpage this comes from is interesting, but gets a little technical http://www.bem.fi/book/06/06.htm]

I also found this image, that's pretty nice:

This shows a typical ventricular cardiac AP on top, and changes in the conductance (inverse of resistance) of the membrane to different ionic species.

Here you see the classic steep upstroke of phase 0, as the sodium channels open, and Na enters the cell, depolarising it. We can see the increased conductance of the cell to Na (gNa) in the bottom tracing. This sodium influx causes depolarisation -- we see the cell now has a positive resting membrane potential.

This sodium current is short-lived, as the channels rapidly inactivate -- this is reflected in the bottom tracing by the sudden decrease in gNa. However, it's enough to trigger a rapid opening of a subgroup of potassium channels, producing a slight outward K+ current (not really shown in the bottom tracing), that lowers the membrane potential a little. This gives us phase 1 (early repolarisation).

Calcium channels also open in response to depolarisation, but do so a little more slowly, as seen by the ramp in the gCa conductance. Movement of Ca2+ into the cell (depolarising) is balanced by moving of potassium out (hyperpolarising) during the plateau phase (phase 2). As these calcium channels begin to deactivate, and gCa decreases, the potassium conductance also increases (gK), and our membrane potential begins to return to resting values (repolarisation, phase 3). a
q
This particular cell isn't exhibiting any pacemaker activity, so the phase 4 slope stays steady and level, as the membrane potential sits at rest until the cell is subsequently activated by the next stimulus.

[The webpage here explains this quite clearly: http://www.cvpharmacology.com/antiarrhy/cardiac_action_potentials.htm

And here, a little more crudely drawn, are representative ion currents. We see a very short lived sodium current for phase 0 (INa), a longer-duration calcium current (ICa), and several different potassium currents that contribute to repolarisation (IKs and IKr), and then serve to help restore potassium (and ultimately sodium) equilibria (IK1). The annotation on the side identifies varies ion channel subunits. Mutations in some affect action potential duration and are responsible for hereditary long QT syndrome. Many drugs that cause acquired long QT syndrome bind and act at HERG.

* Hopefully these images reproduce nicely for everyone.

Never thought I'd receive what I was looking for at 6am thanks!!

 

[systemet]

Never thought I'd receive what I was looking for at 6am thanks!!

No problem man, it's 1530 here, and this served as a good excuse to procrastinate. I've got a bunch of other things I should be doing instead

 

[phillybadboy]

thanks for help

 

[phillybadboy]

after depolarization does the cell become more positive inside than outside? and i guess potassium would out because of this, but would more sodium ions leak out through leak channels also than normal because the cell is more positive at this time? or is the leaking of potassium enough to repolarize cell? also the sodium potassium exchange is not needed to repolarize cell? its needed to maintain concentation gradient?

 

[phillybadboy]

does each skeletal muscle cell have its own neuron or motor neuron, what is the size of skeletal muscle cell to neurons in muscle? what is the size of neurons in the body compared to neurons in brain or spinal cord?