Potassium and calcium effects on conduction

[ChessMaster3000]

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I went through a number of old threads about these issues, but there is a ton of conflicting information and rightfully so because its a very confusing topic. I was just wondering if someone could verify everything I have gathered from that, and if there is anything else high yield that we need to know:

1. Hypokalemia decreases resting membrane potential, and this increases excitability BECAUSE decrease extracellular potassium levels disallow potassium channel functioning during phase III of the AP. This is similar to hypercalcemia's affect on nerves (and possible cardiac pacemaker cells?) because calcium inhibits the action of Na channels in nerve, decreasing AP propagation. This prolonges the QT also.

2. Hypokalemia also increases contractility, in a mechanism similar to digoxin, whereby the na/k atpase cannot function as effectively causing calcium buildup in the cell.

3. Conversely, hyperkalemia increases RMP. This decreases excitability because more sodium channels are in an inactivated state.

4. Is any of this related to how hypercalcemia shortens QT and hypocalcemia prolongs QT? I feel like the concepts are connect but i just can't make the connection.

 

[Phloston]

For #1, it was always my impression that excitability is increased because more voltage-gated sodium channels are sensitized for subsequent myocardial contractions. Conversely, if the RMP is increased secondary to hyperkalaemia, fewer Na+ channels are available for excitation. It seems like you're referring more to why you'd see a flaccid t-wave, or even a q-wave, on an ECG in hypokalemia, reflective of attenuated repolarization.

For #2, I would be very circumspect making a statement like that. There's nothing wrong with how effective the Na+/K+-ATPase pump is in hypokalaemia, but it could be argued that lesser Na+ efflux from the cell decreases the proclivity for Na+/Ca2+ antiporter activity. In other words, I woudn't mention digoxin here, but just that less sodium would efflux in the hypokalaemic state.

#3: Yeah, as per #1.

#4: My impression regarding calcium has always been that because [Ca2+] is always higher outside the cell, the hypocalcaemia-induced weakened gradient would lead to a compensatory reduction in the sensitivity of some of the voltage-gated potassium channels, such that potassium efflux would take longer to occur, with subsequent elongation of the QT. Conversely, if extracellular Ca2+ is high, more K+ channels are activated and repolarization occurs more quickly. This used to confuse me too but the literature literally says that the mechanism hasn't been elucidated (http://onlinelibrary.wiley.com/doi/10.1002/clc.4960110205/pdf). I can say though that the non-dihydropyridine Ca2+ blockers function during phase-II and have no bearing on the QT, so drug delivery is a discrete mechanism from dyscalcaemia.

 

[ulikedaggers]

I went through a number of old threads about these issues, but there is a ton of conflicting information and rightfully so because its a very confusing topic. I was just wondering if someone could verify everything I have gathered from that, and if there is anything else high yield that we need to know:

1. Hypokalemia decreases resting membrane potential, and this increases excitability BECAUSE decrease extracellular potassium levels disallow potassium channel functioning during phase III of the AP. This is similar to hypercalcemia's affect on nerves (and possible cardiac pacemaker cells?) because calcium inhibits the action of Na channels in nerve, decreasing AP propagation. This prolonges the QT also.

2. Hypokalemia also increases contractility, in a mechanism similar to digoxin, whereby the na/k atpase cannot function as effectively causing calcium buildup in the cell.

3. Conversely, hyperkalemia increases RMP. This decreases excitability because more sodium channels are in an inactivated state.

4. Is any of this related to how hypercalcemia shortens QT and hypocalcemia prolongs QT? I feel like the concepts are connect but i just can't make the connection.

1. Hypokalemia hyperpolarizes the cell by shifting the concentration gradient such that potassium efflux increases. This should not increase excitability since the membrane potential will be more negative and further from threshold. Did you mean hyperkalemia?

2. I'm not sure that hypokalemia leads to calcium buildup in the cell...

3. Again, doesn't hyperkalemia increase excitability? Membrane is closer to threshold as a result of potassium buildup in the cell and also remains depolarized longer due to decreased efflux?

 

[sanj238]

1. Hypokalemia hyperpolarizes the cell by shifting the concentration gradient such that potassium efflux increases. This should not increase excitability since the membrane potential will be more negative and further from threshold. Did you mean hyperkalemia?

2. I'm not sure that hypokalemia leads to calcium buildup in the cell...

3. Again, doesn't hyperkalemia increase excitability? Membrane is closer to threshold as a result of potassium buildup in the cell and also remains depolarized longer due to decreased efflux?

Yeah honestly I dont know where they get this from. I think its all unnecessary...just understand the commonsense stuff and you would understand that decreased K would lead to decreased activity..... on the other hand increased K actually leads to refractory behavior since while you are correct, the Na channels close when they reach threshold.

most of this is beyond the USMLE...relax, take a breather.

 

[sanj238]

For #1, it was always my impression that excitability is increased because more voltage-gated sodium channels are sensitized for subsequent myocardial contractions. Conversely, if the RMP is increased secondary to hyperkalaemia, fewer Na+ channels are available for excitation. It seems like you're referring more to why you'd see a flaccid t-wave, or even a q-wave, on an ECG in hypokalemia, reflective of attenuated repolarization.

For #2, I would be very circumspect making a statement like that. There's nothing wrong with how effective the Na+/K+-ATPase pump is in hypokalaemia, but it could be argued that lesser Na+ efflux from the cell decreases the proclivity for Na+/Ca2+ antiporter activity. In other words, I woudn't mention digoxin here, but just that less sodium would efflux in the hypokalaemic state.

#3: Yeah, as per #1.

#4: My impression regarding calcium has always been that because [Ca2+] is always higher outside the cell, the hypocalcaemia-induced weakened gradient would lead to a compensatory reduction in the sensitivity of some of the voltage-gated potassium channels, such that potassium efflux would take longer to occur, with subsequent elongation of the QT. Conversely, if extracellular Ca2+ is high, more K+ channels are activated and repolarization occurs more quickly. This used to confuse me too but the literature literally says that the mechanism hasn't been elucidated (http://onlinelibrary.wiley.com/doi/10.1002/clc.4960110205/pdf). I can say though that the non-dihydropyridine Ca2+ blockers function during phase-II and have no bearing on the QT, so drug delivery is a discrete mechanism from dyscalcaemia.

so much man. so much. not even testable stuff...just know basics...thats what you should tell everyone at least

 

[ChessMaster3000]

For #1, it was always my impression that excitability is increased because more voltage-gated sodium channels are sensitized for subsequent myocardial contractions. Conversely, if the RMP is increased secondary to hyperkalaemia, fewer Na+ channels are available for excitation. It seems like you're referring more to why you'd see a flaccid t-wave, or even a q-wave, on an ECG in hypokalemia, reflective of attenuated repolarization.

For #2, I would be very circumspect making a statement like that. There's nothing wrong with how effective the Na+/K+-ATPase pump is in hypokalaemia, but it could be argued that lesser Na+ efflux from the cell decreases the proclivity for Na+/Ca2+ antiporter activity. In other words, I woudn't mention digoxin here, but just that less sodium would efflux in the hypokalaemic state.

#3: Yeah, as per #1.

#4: My impression regarding calcium has always been that because [Ca2+] is always higher outside the cell, the hypocalcaemia-induced weakened gradient would lead to a compensatory reduction in the sensitivity of some of the voltage-gated potassium channels, such that potassium efflux would take longer to occur, with subsequent elongation of the QT. Conversely, if extracellular Ca2+ is high, more K+ channels are activated and repolarization occurs more quickly. This used to confuse me too but the literature literally says that the mechanism hasn't been elucidated (http://onlinelibrary.wiley.com/doi/10.1002/clc.4960110205/pdf). I can say though that the non-dihydropyridine Ca2+ blockers function during phase-II and have no bearing on the QT, so drug delivery is a discrete mechanism from dyscalcaemia.

Ok, that all makes sense. You are probably right about #1, and that also doesnt preclude my reasoning for a flaccid t-wave/u wave. And I think the details of #4 are well beyond the scope, but thanks for explaining. I think it sounds like the effect of Ca on K channels is the opposite of Ca effect on Na channel (Ca inhibits sodium channels).

Sanj/Ulikedaggers--this probably wouldnt be tested directly, but I think understanding this is useful if you want to go that route. Definitely not required knowledge but it is an important concept nonetheless.

 

[Renaissance Man]

3. Again, doesn't hyperkalemia increase excitability? Membrane is closer to threshold as a result of potassium buildup in the cell and also remains depolarized longer due to decreased efflux?

No, hyperkalemia decreases excitability and stops the heart, hence why lethal injections involve a huge injection of potassium.

 

[Renaissance Man]

To the OP,

Serum potassium levels and the heart have always messed me up, but I read in Basic and Clinical Pharmacology: "In the heart, however, changes in serum potassium concentration have the additional effect of altering potassium conductance (increased extracellular potassium increases potassium conductance) independent of simple changes in electrochemical driving force, and this effect often predominates. As a result, the actual observed effects of hyperkalemia include reduced action potential duration, slowed conduction, decreased pacemaker rate, and decreased pacemaker arrhythmogenesis.”

I asked my pharm professor about this and he said this basically means that there are potassium channels in pacemaker cells that are affected by plasma levels of [K+]. During times of hypokalemia, these potassium channels close up and essentially trap K+ inside of cells. Therefore cells stay closer to their threshold potential and get positive faster. Hence tachycardia, and also longer action potentials.

 

[ChessMaster3000]

To the OP,

Serum potassium levels and the heart have always messed me up, but I read in Basic and Clinical Pharmacology: "In the heart, however, changes in serum potassium concentration have the additional effect of altering potassium conductance (increased extracellular potassium increases potassium conductance) independent of simple changes in electrochemical driving force, and this effect often predominates. As a result, the actual observed effects of hyperkalemia include reduced action potential duration, slowed conduction, decreased pacemaker rate, and decreased pacemaker arrhythmogenesis.”

I asked my pharm professor about this and he said this basically means that there are potassium channels in pacemaker cells that are affected by plasma levels of [K+]. During times of hypokalemia, these potassium channels close up and essentially trap K+ inside of cells. Therefore cells stay closer to their threshold potential and get positive faster. Hence tachycardia, and also longer action potentials.

Hmm, so you are arguing that in hypokalemia the RMP becomes less negative? I thought, as @Phloston suggested, that the increase potassium conductance only relates to the prolongation of the QT interval. Many places Ive read postulate that RMP becomes more negative in hypokalemia.

 

[Renaissance Man]

Hmm, so you are arguing that in hypokalemia the RMP becomes less negative? I thought, as @Phloston suggested, that the increase potassium conductance only relates to the prolongation of the QT interval. Many places Ive read postulate that RMP becomes more negative in hypokalemia.

Hypokalemia actually causes decreased potassium conductance (the slope of Ik is slowed down in phase 3), hence the prolonged QT interval. I know that for the pacemaker cells hypokalemia causes a faster rate of depolarization, probably due to the fact that potassium channels are closed and the cells reach their threshold quicker. There are quite a few papers on the paradoxical nature of this. I'm sure the RMP is decreased but as my pharmacy book said the conductance effect "predominates."

 

[ulikedaggers]

RMP certainly becomes more negative in hypokalemia.

 

[Renaissance Man]

RMP certainly becomes more negative in hypokalemia.

"Certainly" just like hyperkalemia causes hyper-excitability? My professor sent me two of these papers, and it looks like things are far from clear, especially in hypokalemia. Anyways it doesn't matter for Step 1, but again it looks like the change in potassium conductance can cause these "paradoxes". You will probably need to be at your institution to read more than abstracts, unfortunately.

http://www.ncbi.nlm.nih.gov/pubmed/21653227
http://www.pnas.org/content/106/10/4036.full.pdf+html
http://stke.sciencemag.org/cgi/content/abstract/sigtrans;4/184/pe35

 

[ulikedaggers]

"Certainly" just like hyperkalemia causes hyper-excitability? My professor sent me two of these papers, and it looks like things are far from clear, especially in hypokalemia. Anyways it doesn't matter for Step 1, but again it looks like the change in potassium conductance can cause these "paradoxes". You will probably need to be at your institution to read more than abstracts, unfortunately.

http://www.ncbi.nlm.nih.gov/pubmed/21653227
http://www.pnas.org/content/106/10/4036.full.pdf html
http://stke.sciencemag.org/cgi/content/abstract/sigtrans;4/184/pe35

Yes, I was wrong about the path/physio related to hyperkalemia. However, I was correct about the molecular bio.. The cell does get depolarized in hyperkalemia. Likewise, hypokalemia hyperpolarizes the cell - the Nernst potential demands it. Whatever happens as a result is beyond my level of education at this point.

 

[Renaissance Man]

I agree its easier to understand that way, but under levels of pathological hypo/hyperkalemia it looks like the Nernst equation doesn't exactly hold true as shown in those papers. Obviously this has no bearing on us if we don't go into cardiology, but it interesting nonetheless.