blocked acetylcholinesterase activity

[thebillsfan]

would cause an increase in acetyl choline in the synapse. now, would this cause increased muscle contractions (ie, spams) OR would it cause the postsynaptic neuron to be "insensitive" to future depolarizations since it will be continuously depolarized? sort of a catch-22

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[Charles_Carmichael]

Blocking acetylcholinesterase doesn't really cause an increase in the amount of ACh in the synapse; it just causes the ACh to remain in the synapse for a longer period of time (ie. delayed degradation).

It would cause increased muscle contraction since the receptors are exposed to ACh for a longer period of time. There cannot be a continuous depolarization. Think of how the voltage gated ion channels work. The Na+ channel closes a short instant after it is opened (the slow acting gate), which causes the refractory period and the gate remains closed until repolarization. So you cannot have a cell continuously depolarized; there will be refractory periods, repolarizations, and then, another depolarization if enough ACh binds the receptor again to depolarize the cell enough to fire an AP. Hope this helps.

 

[lord_jeebus]

http://en.wikipedia.org/wiki/Sarin#Biological_effects

Kaushik, continuous depolarization is possible and is best illustrated by the mechanism of the drug succinylcholine. Acetylcholinesterase inhibitors (eg. neostigmine) can potentiate this effect, and at high enough doses can induce it on their own.

 

[Charles_Carmichael]

http://en.wikipedia.org/wiki/Sarin#Biological_effects

Kaushik, continuous depolarization is possible and is best illustrated by the mechanism of the drug succinylcholine. Acetylcholinesterase inhibitors (eg. neostigmine) can potentiate this effect, and at high enough doses can induce it on their own.

Nevermind OP, I stand corrected! Thanks for the info lord_jeebus.

Edit: Wait, no, I just realized the mistake I made in my first post. I should've written that continuous AP firing (without refraction) is not possible. I don't know why I ended up writing that continuous depolarization is not possible. I know it's possible, because I even used hyperkalemia as an example (in previous threads) of being in a state of continuous depolarization and how it could cause paralysis due to Na+ channel closing.

So, disregard my original post about continuous depolarization not being possible. I must've had a huge brain fart! I blame it on the after-tennis high!

 

[thebillsfan]

Nevermind OP, I stand corrected! Thanks for the info lord_jeebus.

Edit: Wait, no, I just realized the mistake I made in my first post. I should've written that continuous AP firing (without refraction) is not possible. I don't know why I ended up writing that continuous depolarization is not possible. I know it's possible, because I even used hyperkalemia as an example (in previous threads) of being in a state of continuous depolarization and how it could cause paralysis due to Na+ channel closing.

So, disregard my original post about continuous depolarization not being possible. I must've had a huge brain fart! I blame it on the after-tennis high!

so, because it is continuously depolarized, subsequent action potentials cannot be induced?

 

[Charles_Carmichael]

so, because it is continuously depolarized, subsequent action potentials cannot be induced?

If the cell is depolarized enough to activate the Na+ channels, their slow activating gate will close after a short instant. This gate will remain closed to Na+ influx until repolarization occurs. Whether or not an AP can be induced depends on the percentage of the Na+ channels that are closed, which depends on the membrane potential; the more depolarized the membrane potential is, the higher the percentage of Na+ channels that are likely to be closed.

 

[stockraider]

increased acetylcholine will stay on the receptors, keep the Na channels open and keep the sarcolemma depolorized, meaning Ca2+ will stay on the troponin which will keep the actin bound to myosin that will keep the muscle contracted

 

[lord_jeebus]

increased acetylcholine will stay on the receptors, keep the Na channels open and keep the sarcolemma depolorized, meaning Ca2+ will stay on the troponin which will keep the actin bound to myosin that will keep the muscle contracted

This is incorrect. Clinically, when you administer a depolarizing neuromuscular block (continuous depolarization), initial muscle fasciculation is followed by flaccid relaxation of the muscle - this effect is why succinylcholine is used medically. Basically, the reason is that the sarcoplasmic reticulum and calcium will return to their resting state despite the continued depolarization.

 

[stockraider]

This is incorrect. Clinically, when you administer a depolarizing neuromuscular block (continuous depolarization), initial muscle fasciculation is followed by flaccid relaxation of the muscle - this effect is why succinylcholine is used medically. Basically, the reason is that the sarcoplasmic reticulum and calcium will return to their resting state despite the continued depolarization.

wait, so the muscle will contract when depolorization occurs, and then go flaccid even while wthe acetylcholine and depolorization continue? so is the only effect of inhibited acetylcholinestrase that the muscle CANT contract again?

i know you explained this, but I just want to make sure I got all the angles here.

 

[Charles_Carmichael]

wait, so the muscle will contract when depolorization occurs, and then go flaccid even while wthe acetylcholine and depolorization continue? so is the only effect of inhibited acetylcholinestrase that the muscle CANT contract again?

i know you explained this, but I just want to make sure I got all the angles here.

As I mentioned in my previous post, after a certain amount of depolarization, the Na+ channels open. This is followed quickly by the closing of the slow acting inactivation gate on the Na+ channels so they close; this means that there can be no influx of Na+ and no AP can be fired. This is what happens during the refractory period of a normal AP.

What lord_jeebus is saying, I think, is that initially, when you administer these drugs there will be contraction. But if the cell is kept at a continuously depolarized state, which these drugs can do, no action potentials can be fired after the first one because the Na+ channels are likely to be closed (due to the slow acting inactivation gate); remember, the slow acting gates remain closed until repolarization occurs. Without action potentials, the increase in intracellular calcium cannot be triggered to initiate a muscular contraction (the rise in intracellular calcium follows an action potential).

 

[lord_jeebus]

wait, so the muscle will contract when depolorization occurs, and then go flaccid even while wthe acetylcholine and depolorization continue? so is the only effect of inhibited acetylcholinestrase that the muscle CANT contract again?

exactly