wildstar9
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Please could someone answer my question below?

PGI2 (Prostacyclin, I'm guessing that's a prostaglandin) inhibits platelet aggregation. Low-dose aspirin prevents activation of the COX pathway in platelets but only to a degree that does not affect PGI2 synthesis.

My question is what's the point of inhibiting the COX pathway (by aspirin) if it's needed to prevent platelet aggregation by PGI2? Isn't this contradictory?
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macpatgh-Sheldon
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Hi,
It does depend what level of study you are in as to how complex or otherwise my answer should be. If you are doing an UG degree in e.g. biology, then stick to my simple explanation below; if you are, on the other hand, doing an MSc in e.g. clinical phamacology or physiology, then please give me an indication as to this in a reply to this post so I can provide more detail.

The fact is that there are several different eicosanoids (including prostaglandins) e.g. PGI2 [which you quote], PGF, PGE2, PGH, etc., and each might act on more than one of several different PG receptors. The actions of each of these receptors is mediated by a different subtype of the G protein e.g. Gs [subscript "s" for stimulatory] increases adenylyl cyclase activity, thus increasing levels of the second messenger cAMP, WHEREAS Gi [subscript "i" for inhibitory] does the opposite. So, you will appreciate the extreme complexity of this subject.

I AM TRYING, WITH GREAT DIFFICULTY , TO FOCUS IN ON YOUR SPECIFIC Q, BUT IS IS NOT EASY, GIVEN THE COMPLEXITY OF the biochemical pharmacology of THESE SUBSTANCES, sorry!

This is just the generic theory without details of individual PGs and separate receptors. Having said this, it is best to understand only the basics. As you correctly state prostacyclin [PGI2] inhibits platelet aggregation,so you might expect its inhibition by blockage of synthesis of PGI2 by aspirin to lead to an undesirable thrombotic action. However, the main action of aspirin (by ireversibly blocking the action of COX1 [cycloxygenase-1], which catalyses the conversion of arachidonic acid to the PGs in platelets by acetylation), is to reduce levels of PGE2 and of TxA2 [thromboxane], both of which would normally promote platelet aggregation. Hence, aspirin prolongs clotting time, and is useful [at low doses e.g. 75 mg/day] in preventing thromboembolic events in patients who have had clinical features of IHD [ischaemic heart disease] in their PMH [past medical history].

I hope this has makes things clearer and not more confusing!

Be safe!
M
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wildstar9
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(Original post by macpatgh-Sheldon)
Hi,
It does depend what level of study you are in as to how complex or otherwise my answer should be. If you are doing an UG degree in e.g. biology, then stick to my simple explanation below; if you are, on the other hand, doing an MSc in e.g. clinical phamacology or physiology, then please give me an indication as to this in a reply to this post so I can provide more detail.

The fact is that there are several different eicosanoids (including prostaglandins) e.g. PGI2 [which you quote], PGF, PGE2, PGH, etc., and each might act on more than one of several different PG receptors. The actions of each of these receptors is mediated by a different subtype of the G protein e.g. Gs [subscript "s" for stimulatory] increases adenylyl cyclase activity, thus increasing levels of the second messenger cAMP, WHEREAS Gi [subscript "i" for inhibitory] does the opposite. So, you will appreciate the extreme complexity of this subject.

I AM TRYING, WITH GREAT DIFFICULTY , TO FOCUS IN ON YOUR SPECIFIC Q, BUT IS IS NOT EASY, GIVEN THE COMPLEXITY OF the biochemical pharmacology of THESE SUBSTANCES, sorry!

This is just the generic theory without details of individual PGs and separate receptors. Having said this, it is best to understand only the basics. As you correctly state prostacyclin [PGI2] inhibits platelet aggregation,so you might expect its inhibition by blockage of synthesis of PGI2 by aspirin to lead to an undesirable thrombotic action. However, the main action of aspirin (by ireversibly blocking the action of COX1 [cycloxygenase-1], which catalyses the conversion of arachidonic acid to the PGs in platelets by acetylation), is to reduce levels of PGE2 and of TxA2 [thromboxane], both of which would normally promote platelet aggregation. Hence, aspirin prolongs clotting time, and is useful [at low doses e.g. 75 mg/day] in preventing thromboembolic events in patients who have had clinical features of IHD [ischaemic heart disease] in their PMH [past medical history].

I hope this has makes things clearer and not more confusing!

Be safe!
M
Thank for you the detailed answer. So please may I clarify this with you?

Does PGI2 synthesis not depend on the COX pathway? By giving someone Asprin aren't you just preventing the PGI2 to work? (sorry if you have already answered this; my English reading and writing skills aren't very good.
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macpatgh-Sheldon
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Hi dw about English being weak!

Ok yes, PGI2 synthesis also requires the cycloxygenase enzyme, but the effects of PGE2 and TxA2 on platelets are greatee than those of PGI2, so that the overall effect of aspirin [by blocking the action of COX-1] is presominantly [=mainly] that of inhibition of the thrombotic effects of PGE2 and TxA2 RATHER THAN the smaller effect of inhibition of the action of PGI2.

Since you are asking, and although I am trying my best NOT to make this rocket science (:flybye:), your inquisitive mind makes me go in that direction. PGE2 actually acts on two PG receptor types, including one at which PGI2 is the main binding ligand. So the matter is even more convoluted!

I copy part of my previous post here:-
"As you correctly state prostacyclin [PGI2] inhibits platelet aggregation,so you might expect its inhibition by blockage of synthesis of PGI2 by aspirin to lead to an undesirable thrombotic action. However, the main action of aspirin (by ireversibly blocking the action of COX1 [cycloxygenase-1], which catalyses the conversion of arachidonic acid to the PGs in platelets by acetylation), is to reduce levels of PGE2 and of TxA2 [thromboxane], both of which would normally promote platelet aggregation. Hence, aspirin prolongs clotting time,..."
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wildstar9
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(Original post by macpatgh-Sheldon)
Hi dw about English being weak!

Ok yes, PGI2 synthesis also requires the cycloxygenase enzyme, but the effects of PGE2 and TxA2 on platelets are greatee than those of PGI2, so that the overall effect of aspirin [by blocking the action of COX-1] is presominantly [=mainly] that of inhibition of the thrombotic effects of PGE2 and TxA2 RATHER THAN the smaller effect of inhibition of the action of PGI2.

Since you are asking, and although I am trying my best NOT to make this rocket science (:flybye:), your inquisitive mind makes me go in that direction. PGE2 actually acts on two PG receptor types, including one at which PGI2 is the main binding ligand. So the matter is even more convoluted!

I copy part of my previous post here:-
"As you correctly state prostacyclin [PGI2] inhibits platelet aggregation,so you might expect its inhibition by blockage of synthesis of PGI2 by aspirin to lead to an undesirable thrombotic action. However, the main action of aspirin (by ireversibly blocking the action of COX1 [cycloxygenase-1], which catalyses the conversion of arachidonic acid to the PGs in platelets by acetylation), is to reduce levels of PGE2 and of TxA2 [thromboxane], both of which would normally promote platelet aggregation. Hence, aspirin prolongs clotting time,..."
Thanks. That makes sense, now!
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