hypokalemia, repolarization, QT prolongation

[beastmaster]

Katzung Pharm writes that decreased extracellular K+ decrease K+ conductance (and vice versa). The significance of this is that in phase 2 plateau of the cardiac cycle slows the opening of the slow delayed rectifier channels, prolonging repolarization, and hence prolonging the QT. Katzung's statement in the book is unexplained and unreferenced but is supported by other sources and real life observed effects.

But it's completely counterintuitive. If extracellular K+ is low, I would expect the gradient to favor a more rapid K+ transfer out of the cell, and a quicker repolarization, but no. So clearly the electrochemical gradient is not involved -- then what is causing this effect ???? How does extracellular K+ convince the intracellular K+ to act against its will.

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[Idiopathic]

Correct me if Im wrong, but to effectively repolarize, doesnt potassium have to reenter the cell (not the other way around)? This is made more difficult when extracellular K is low, right? Havent looked this up in a while, but it seems like this is what I recall.

 

[Krazykritter]

Correct...To repolarize the ventricles (T wave) K+ must ENTER the cell making it more positive. If gradient is low, K will not move in as quickly thus stretching out the T wave. This prolongs QT interval b/c QT measure the time ventricle begins depolarizing until it is repolarized (end of T wave).

This phase is affected by your Class III anti-dyrhtymics & somewhat by the Class Ia drugs. So you can use these to treat tachycardias (both supra & ventricular, I believe).

 

[FotoFusion]

Correct me if Im wrong, but to effectively repolarize, doesnt potassium have to reenter the cell (not the other way around)? This is made more difficult when extracellular K is low, right? Havent looked this up in a while, but it seems like this is what I recall.

It's the other way around. Repolarizing means the potential becomes more negative than it was before. If K+ enters the cell, the cell would DEpolarize and become more positive. As K+ leaves the cell, it leaves behind negatively charged proteins and makes the cell more negative..thus repolarizing the cell. So K+ leaving = repolarizing and a more negative cell. K+ entering = depolarizing and a more positive cell.

To the original poster, changes in potassium don't just alter the electrochemical gradient. An increase in serum potassium also increases potassium conductance and vice-versa. So with decreased serum potassium, K+ conductance decreases and phase 3 is extended because of fewer open K+ channels to allow K+ to leave the cell, which in turn prolongs QT. Hope that helps!

edit: That's from big Katzung, box titled effects of hypokalemia.

 

[beastmaster]

To the original poster, changes in potassium don't just alter the electrochemical gradient. An increase in serum potassium also increases potassium conductance and vice-versa. So with decreased serum potassium, K+ conductance decreases and phase 3 is extended because of fewer open K+ channels to allow K+ to leave the cell, which in turn prolongs QT. Hope that helps!

edit: That's from big Katzung, box titled effects of hypokalemia.

Actually, you just restated what I wrote in my original post, right down to my source. I know what happens. I'm interested in WHY this happens, specifically what I put in bold, because to me its counterintuitive.

So to summarize my original question, why would an increase in extracellular K+ further increase the conductance of K+ out of the cell ?? Electrochemical logic contradicts this from happening.

 

[FotoFusion]

Actually, you just restated what I wrote in my original post, right down to my source. I know what happens. I'm interested in WHY this happens, specifically what I put in bold, because to me its counterintuitive.

So to summarize my original question, why would an increase in extracellular K+ further increase the conductance of K+ out of the cell ?? Electrochemical logic contradicts this from happening.

so i did, oops.

Serum K+ only increases to ~5 or 6mM in hyperkalemia and to 3ish mM in hypokalemia. intra K+ concentration is much higher than that so even with K+ higher or lower than normal extracellularly, the chemical gradient forces K+ to leave the interior. So even if the outside K conc. goes up or down a little, the Ik (potassium current) will still be going outward, but will vary a little in magnitude.

What does change significantly is that the number of membrance K+ channels open and permeable to K+ varies with the outside concentration of K.

so with hyhperkalemia: More outside K+ -> more K+ channels open -> increased conductance. The echem gradient is less than it used to be, but the direction of K flow is still to the outside but since the membrane is more permeable to K, the cell repolarizes faster and thus a shorter QT.

With hypokalemia, fewer K+ channels are open and the conductance decreases, so even though the echem gradient is stronger than normal, K can't leave the cell as quickly and QT increases.

Does that seem acceptable?

 

[beastmaster]

Serum K+ only increases to ~5 or 6mM in hyperkalemia and to 3ish mM in hypokalemia. intra K+ concentration is much higher than that so even with K+ higher or lower than normal extracellularly, the chemical gradient forces K+ to leave the interior. So even if the outside K conc. goes up or down a little, the Ik (potassium current) will still be going outward, but will vary a little in magnitude.

Ah, this clears up alot, thanks.

so with hyperkalemia: More outside K+ -> more K+ channels open -> increased conductance.

why? why? why? why?

What is the method and reason for extracellular K+ to open MORE K+ outflow channels?? Am I wrong in perceiving this as a paradoxical positive feedback type effect or have I gone nuts here.

 

[FotoFusion]

Ah, this clears up alot, thanks.


why? why? why? why?

What is the method and reason for extracellular K+ to open MORE K+ outflow channels?? Am I wrong in perceiving this as a paradoxical positive feedback type effect or have I gone nuts here.

Hm, I figured if Katzung says it's so, then it's good enough for me. But I did some digging. You're right though, it is the opposite of what you'd expect. Best answer I found so far:

"For reasons that are not well understood, these Ikr currents are sensitive to extracellular potassium levels, and as the potassium levels increase in the extracellular space, potassium conductance through these currents is increased so that more potassium leaves the myocyte in any given time period."
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1413606

sorry dude, that's the best I got.

 

[beastmaster]

For reasons that are not well understood, ...

This sort of hedging needs to be outlawed in the scientific journals.

It's all good, thanks for your efforts