15 replies to this topic

[The_Dude]

[The following uses a simplified description of a complicated process, but that should not effect the main point.]

 

So we know that cGMP allows an erection to occur, and PDE5 is responsible for turning it off.

The fact that PDE5 inhibitors (Cialis,Viagra,Levitra) are a spectacular financial success has two big implications:

1 - everyone who finds that PDE5 inhibitors work - which is roughly two-thirds of those who try them - must have no problem producing nitric oxide and cGMP, otherwise it would not work.

2 - The fact that PDE5 inhibitors solve the problem for most older guys, indicates that PDE5 production increases as we age.

I've done a lot of web searching and amazingly, cannot find any discussion on the latter point, which seems to me a very big issue.

This is likely due to:

A - The current difficulty of searching for anything having to do with the issue. There seem to be thousands, maybe millions of bot-generated web pages that have a sentence or two of medical research on PDE5, followed by " Buy at best price at Joe's Safe Online Pharmacy dot com !! ".

B - The vast billions of dollars at stake seems to have the medical researchers tight lipped on anything having to do with PDE5, beyond the Wikipedia description.

So, I was curious if anyone on this board has read any discussions about why and how the PDE5 production increases as we age ?

Thanks !

[niner]

1771 hits on PDE5 in pubmed.  No Viagra ads...

[The_Dude]

1771 hits on PDE5 in pubmed.  No Viagra ads...

 

Searching pubmed directly is a good idea, thanks.

 

Just "PDE5" alone produces too many hits, so I am trying various combinations.
 

[The_Dude]

I tried every possible phrase "PDE5 accumulation" "PDE5 increase" "excessive PDE5" and nothing.

 

There are only papers about using PDE5 inhibitors for other purposes.  (Eventually we may find it is effective in cleaning dishes.)

 

All of the descriptions about ED in older people, emphasizes hypertension, diabetes, etc - i.e. they are assuming that there is some other underlying major condition.

 

The Elephant remains unnoticed.

Edited by The_Dude, 08 December 2014 - 04:00 AM.

[nowayout]

Increased PDE-5 production is not the only possible (or even probable) explanation.  There is a variety of other possible factors involved, from loss of elasticity of blood vessels to lowering of testosterone levels to mitochondrial changes to changes in brain pathways.  

 

Good news though: There is some research indicating that chronic use (every day, not just as-needed) of PDE-5 inhibitors can actually cure impotence in some men, to the extent that they eventually don't need the drug any more.  

Edited by nowayout, 08 December 2014 - 08:06 PM.

[The_Dude]

Increased PDE-5 production is not the only possible (or even probable) explanation.  There is a variety of other possible factors involved, from loss of elasticity of blood vessels to lowering of testosterone levels to mitochondrial changes to changes in brain pathways.  

 

Good news though: There is some research indicating that chronic use (every day, not just as-needed) of PDE-5 inhibitors can actually cure impotence in some men, to the extent that they eventually don't need the drug any more.  

 

Thanks for your reply.

 

However, if those were true, then inhibiting PDE5 would not work.  In fact, in something like 30-40% of those who try PDE5 inhibitors, they do not work, because there is some problem with Nitric Oxide creation, Nitric Oxide stimulation or cGMP activation.  Typically, that is due to clogged arteries and/or insufficient testosterone.

 

Interestingly, if you look at the Google search suggestions, you will find that many previous people have searched for things like "PDE5 accumulation" or "PDE5 excess".  But you won't find any results either there or in PubMed.

[Area-1255]

I tried every possible phrase "PDE5 accumulation" "PDE5 increase" "excessive PDE5" and nothing.

There are only papers about using PDE5 inhibitors for other purposes. (Eventually we may find it is effective in cleaning dishes.)

All of the descriptions about ED in older people, emphasizes hypertension, diabetes, etc - i.e. they are assuming that there is some other underlying major condition.

The Elephant remains unnoticed.

The answer is in the hormone pudding; research "T3 thyroid hormone inhibition of Phosphodiestearase".
As one ages , T3 drops, as does testosterone and Estrogen. Free T is responsible for sustaining dopamine receptors and nNOS protein expression.

[The_Dude]

 

I tried every possible phrase "PDE5 accumulation" "PDE5 increase" "excessive PDE5" and nothing.

There are only papers about using PDE5 inhibitors for other purposes. (Eventually we may find it is effective in cleaning dishes.)

All of the descriptions about ED in older people, emphasizes hypertension, diabetes, etc - i.e. they are assuming that there is some other underlying major condition.

The Elephant remains unnoticed.

The answer is in the hormone pudding; research "T3 thyroid hormone inhibition of Phosphodiestearase".
As one ages , T3 drops, as does testosterone and Estrogen. Free T is responsible for sustaining dopamine receptors and nNOS protein expression.

 

Very interesting stuff - but the references all refer to cAMP rather than cGMP, so it is not specifically PDE5.

 

But I did come across one reference that hypertension produces elevated levels of PDE5 - the first such specific reference (although not related to aging).

 

I expect that is why many people do not experience low blood pressure vasodilation side effects - because the resultant blood pressure is still elevated, even though lower.

[Area-1255]

I tried every possible phrase "PDE5 accumulation" "PDE5 increase" "excessive PDE5" and nothing.

There are only papers about using PDE5 inhibitors for other purposes. (Eventually we may find it is effective in cleaning dishes.)

All of the descriptions about ED in older people, emphasizes hypertension, diabetes, etc - i.e. they are assuming that there is some other underlying major condition.

The Elephant remains unnoticed.

The answer is in the hormone pudding; research "T3 thyroid hormone inhibition of Phosphodiestearase".
As one ages , T3 drops, as does testosterone and Estrogen. Free T is responsible for sustaining dopamine receptors and nNOS protein expression.

Very interesting stuff - but the references all refer to cAMP rather than cGMP, so it is not specifically PDE5.

But I did come across one reference that hypertension produces elevated levels of PDE5 - the first such specific reference (although not related to aging).

I expect that is why many people do not experience low blood pressure vasodilation side effects - because the resultant blood pressure is still elevated, even though lower.

Exactly, but we also have to remember that cAMP often recruites other PDE's or that selective inhibition of one isoform may inhibit or increase another. Hence why Tadalafil also inhibits other PDE's yet too on a crusader alike its parent pathway, all riding on the same horse my brotha!

[The_Dude]

Aha!  I had to go to the legal documents for the lawsuit over Viagra by Pfizer against Teva from 2011.  There I found statements of fact that are carefully checked for accuracy, because Pfizer do not want their decision thrown out over a technicality.  Here are the quotes:

 

To initially relax the smooth muscle tissue, which in turn sets off the chain reaction, the nervous system reacts to sexual stimuli by producing nitric oxide.
This nitric oxide reacts with guanylate cyclase, an enzyme, producing cyclic guanosine monophosphate ("cGMP").
cGMP can be inhibited, however, by another enzyme, PDE5. Thus, if there is too much PDE5, cGMP can be inhibited and the whole process of smooth
muscle tissue relaxation can be thwarted.
This is where Viagra comes in, when an individual's ED is caused by this imbalance in PDE5 and cGMP.
The way Viagra works, then, is to inhibit excess PDE5 so that cGMP can work the way that it is supposed to.

There was a footnote to this:

ED has many causes, both psychological and physical. In regard to physical causes, when ED is not the result of by any particular physical injury to the body, such as paralysis or certain lower back injuries, then it is often caused by an imbalance at the cellular level between PDE5 and cGMP.
In this type of case, Viagra is effective.

Yes, it is true that clogged arteries (and other conditions) can cause insufficient nitric oxide in the system, and those people with those conditions would see benefit from nitric oxide generating supplements.

However, it is clear that Pfizer's research indicates that most ED is due to excess PDE5 - not a lack of nitric oxide.

In fact, those who have a lack of nitric oxide do not benefit from PDE5 inhibitors, because they are not producing cGMP, so it does not matter whether PDE5 is inhibited or not.

And, in fact, a significant minority (something like 30-40% IIRC) do not benefit from Viagra or Cialis, precisely because they are not generating enough nitric oxide.

But - for those who do respond to Viagra and Cialis, then it seems clear that their problem is excess PDE5 - we see this confirmed by Pfizer themselves.

So, why has there been so little mention of the problem of excess PDE5 - including its origin and prevention ?

I think there are two possible reasons:

1 - Viagra and Cialis are big business world-wide.  They are sold for $20 and wholesale for $0.30.  There is a big motivation to just sell people pills, rather than do anything to prevent the condition (this is also true of many other conditions).

2 - If there is research into the origin of the condition of excess PDE5, then it is undoubtedly being done very quietly, so that whoever comes up with a treatment can patent it.

[Area-1255]

Aha!  I had to go to the legal documents for the lawsuit over Viagra by Pfizer against Teva from 2011.  There I found statements of fact that are carefully checked for accuracy, because Pfizer do not want their decision thrown out over a technicality.  Here are the quotes:

 

To initially relax the smooth muscle tissue, which in turn sets off the chain reaction, the nervous system reacts to sexual stimuli by producing nitric oxide.
This nitric oxide reacts with guanylate cyclase, an enzyme, producing cyclic guanosine monophosphate ("cGMP").
cGMP can be inhibited, however, by another enzyme, PDE5. Thus, if there is too much PDE5, cGMP can be inhibited and the whole process of smooth
muscle tissue relaxation can be thwarted.
This is where Viagra comes in, when an individual's ED is caused by this imbalance in PDE5 and cGMP.
The way Viagra works, then, is to inhibit excess PDE5 so that cGMP can work the way that it is supposed to.

There was a footnote to this:

ED has many causes, both psychological and physical. In regard to physical causes, when ED is not the result of by any particular physical injury to the body, such as paralysis or certain lower back injuries, then it is often caused by an imbalance at the cellular level between PDE5 and cGMP.
In this type of case, Viagra is effective.

Yes, it is true that clogged arteries (and other conditions) can cause insufficient nitric oxide in the system, and those people with those conditions would see benefit from nitric oxide generating supplements.

However, it is clear that Pfizer's research indicates that most ED is due to excess PDE5 - not a lack of nitric oxide.

In fact, those who have a lack of nitric oxide do not benefit from PDE5 inhibitors, because they are not producing cGMP, so it does not matter whether PDE5 is inhibited or not.

And, in fact, a significant minority (something like 30-40% IIRC) do not benefit from Viagra or Cialis, precisely because they are not generating enough nitric oxide.

But - for those who do respond to Viagra and Cialis, then it seems clear that their problem is excess PDE5 - we see this confirmed by Pfizer themselves.

So, why has there been so little mention of the problem of excess PDE5 - including its origin and prevention ?

I think there are two possible reasons:

1 - Viagra and Cialis are big business world-wide.  They are sold for $20 and wholesale for $0.30.  There is a big motivation to just sell people pills, rather than do anything to prevent the condition (this is also true of many other conditions).

2 - If there is research into the origin of the condition of excess PDE5, then it is undoubtedly being done very quietly, so that whoever comes up with a treatment can patent it.

Pfizer is the one marketing the drugs, you think their "research" is credible? 

Also wouldn't explain the men who can't perform even on high doses of these drugs, you NEED nitric oxide for these drugs to work.

 

Assuming libido isn't an issue - there are over 100 biochemical pathways interacting with nitric oxide itself.

15 of the main ones.

 

-Testosterone

-Estrogen

-Progesterone-Sigma2

-Opioids

-Alpha-1-adrenergic receptors

-Serotonin 5-ht1A,1B,2A,2C,3A,4A

-Dopamine D1-D4

-NMDA-glutamate pathway.

-Oxytocin

-Vasopressin

-Endothelin A

-Protein Kinase A/C

-Muscarinic receptors.

-GABA-A and GABA-B

-Calmodulin/Calcitonin

[The_Dude]

I think you are still missing the basic point (perhaps due to skimming):

 

About 30-40% do not respond to Viagra/Cialis.  These are the ones who have insufficient nitric oxide, due to arterial blockages or other reasons.  (These are the ones who respond to Citrulline, Pycnogenol, Pomegranate, Beets, Kale, etc.)

 

About 60-70% do respond (which is why they sell so well).  So, what is happening in those cases, is that PDE5 is inhibited, and at that point, there is no problem with cGMP being created by nitric oxide mechanism.  This shows that there is not a nitric oxide problem for those men, otherwise it would not work.

Edited by The_Dude, 10 December 2014 - 11:59 PM.

[Area-1255]

I think you are still missing the basic point (perhaps due to skimming):

 

About 30-40% do not respond to Viagra/Cialis.  These are the ones who have insufficient nitric oxide, due to arterial blockages or other reasons.  (These are the ones who respond to Citrulline, Pycnogenol, Pomegranate, Beets, Kale, etc.)

 

About 60-70% do respond (which is why they sell so well).  So, what is happening in those cases, is that PDE5 is inhibited, and at that point, there is no problem with cGMP being created by nitric oxide mechanism.  This shows that there is not a nitric oxide problem for those men, otherwise it would not work.

Right, I'm not missing any point - but just know that let's say you are dopamine deficient, then cirtulline, pycnogenol etc will do very very little, because there are CENTRAL regulating factors of NOS; nitric oxide synthase....besides the libido thing...if you have too much serotonin, a complete glutamate deficiency, or dopamine deficiency, etc....then those above sups will do practically nothing.

 

The neurotransmitter networks responsible for the synthesis enzymes NEED to be in tact.

[mjp108]

This has all been informative but I seem to have lost what you really wanted to get at.  May I suggest that if the issue is ED that you investigate PRP injections.

[SearchingForAnswers]

So for some people, excess PDE5 could be at least partially responsible for hypertension. I believe I read somewhere on this side that one of the members was crushing up viagra, or one of the PDE5 inhibitors, and taking small amounts daily to effectively control his blood pressure.

[Ark]

Would it be of negative benefit to take cialis with Parkinson's disease? Would it help or hurt if taken at night?