If Nitric Oxide Is So Damaging, Please Explain This

[Javelina]

From the blog of Malcom Kendrick:

A few blogs ago I wrote of a study demonstrating that men with diabetes, who used Viagra, or other PDE5 inhibitors e.g. Cialis, were far less likely to die from CVD.

We know that Viagra/sildenafil has, as a primary mode of action, increasing nitric oxide synthesis in endothelial cells. This is how it maintains erections in erectile dysfunction. It also reduces blood pressure, particularly reducing blood pressure in the lungs. Nitric oxide is also the most powerful anti-coagulant agent known to man. Furthermore, it protects the endothelium from damage, and stimulates the production of endothelial progenitor cells in the bone marrow.

What effect does it have on LDL? None.

What effect does it have on cardiovascular and overall mortality? Well, very recently I was sent this paper: ‘Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction.’

This was a study on over forty-three thousand men over a six-year period, who had previously had a myocardial infarction (MI). Just over forty thousand did not have medication dispensed for erectile dysfunction (ED) (40,077), three thousand did (3,068). They were split into three groups: lowest number of ED scripts, medium and highest number.3

For the sake of brevity here I am just looking at the highest script group.

Well, well, well. Perhaps a couple of other well, wells for luck.

Yes, this study was observational. Yes, this means that other factors that may be at play. For example, those men requesting Viagra and other PDE5 inhibitors, may have been healthier than those who did not. But it is hard to believe they were over five times as healthy. The simple fact is that, when you see an effect as massive as this, it can generally be considered that you are looking at a causal relationship.

To put it another way, this is 81% relative risk reduction in overall mortality. Compare this with statins, in secondary prevention (using best figures possible), statins achieved a 15% relative risk reduction in overall mortality.

 

[mosaic01]

This is pretty interesting.

And then there's this study: Heart Beat: Play it safe, avoid L-arginine supplements - Harvard Health

L-Arginine Therapy in Acute Myocardial Infarction

Context The amino acid L-arginine is a substrate for nitric oxide synthase and is increasingly used as a health supplement. Prior studies suggest that L-arginine has the potential to reduce vascular stiffness.Objective To determine whether the addition of L-arginine to standard postinfarction...

jamanetwork.com

Intervention Patients were randomly assigned to receive L-arginine (goal dose of 3 g 3 times a day) or matching placebo for 6 months.

Results Baseline characteristics, vascular stiffness measurements, and left ventricular function were similar between participants randomized to receive placebo or L-arginine. The mean (SD) age was 60 (13.6) years; of the participants, 104 (68%) were men. There was no significant change from baseline to 6 months in the vascular stiffness measurements or left ventricular ejection fraction in either of the 2 groups, including those 60 years or older and the entire study group. However, 6 participants (8.6%) in the L-arginine group died during the 6-month study period vs none in the placebo group (P = .01). Because of the safety concerns, the data and safety monitoring committee closed enrollment.

Makes me actually wonder they simply confused the groups or actually switched them and then stopped the study. Maybe the entire study was already started with the goal of suppressing the healing potential of Arginine. The people behind these studies are sadly not there to promote the truth.

My suggestion may sound paranoid, but when you look up the average survival data from AMI survivors, you can find this:

Long-Term Survival and Recurrence After Acute Myocardial Infarction in England, 2004 to 2010

Background—There are limited population-based national data on prognosis in survivors of acute myocardial infarction (AMI), particularly on long-term survival and the risk of recurrence. Methods and

www.ahajournals.org

​

And in the age-group comparable to the age in the arginine study, we see that usually some people die in the first months after first AMI.

This study notes that the risk of dying within the first 4 months is 370% higher than in the general population. So it's a bit strange that the arginine study claims there were zero deaths in the control group. Instead of considering the non-deaths in the control group as remarkable, they focused on the deaths in the arginine group, even though some deaths are usually expected statistically after first AMI.

It actually seems the number of deaths in the arginine group fit perfectly to the expected number of deaths (5-10% in the first 6 months) in the group of first AMI men age 60 and older. Which could actually mean that after 6 months when they looked into the data, and saw that all patients on arginine were thriving, while the patients in the control group were dying as usual, they decided to reverse everything and cover it up.

 

[Lancaster]

PDE5 inhibitors upregulate one downstream signalling cascade induced by nitric oxide - they don't significantly increase absolute NO production.
A lot of the issues with excessive nitric oxide synthesis come from the resulting competitive antagonism of O2 binding sites on cytochrome C oxidase, thereby inhibiting oxidative respiration.
This is independent of cGMP, the vasodilation-inducing effector molecule that nitric oxide increases via upregulation of guanylyl cyclase activity, and that viagra, cialis, etc., increase via inhibition of cGMP degrading PDE5.
i.e., the vasodilatory effects of PDE5 inhibitors come from potentiation of a single downstream cascade induced by NO, not by producing an excess of NO itself, with the latter (via inflammation-mediated induction of iNOS expression) generally being what's actually problematic.

 

[Lollipop2]

PDE5 inhibitors upregulate one downstream signalling cascade induced by nitric oxide - they don't significantly increase absolute NO production.
A lot of the issues with excessive nitric oxide synthesis come from the resulting competitive antagonism of O2 binding sites on cytochrome C oxidase, thereby inhibiting oxidative respiration.
This is independent of cGMP, the vasodilation-inducing effector molecule that nitric oxide increases via upregulation of guanylyl cyclase activity, and that viagra, cialis, etc., increase via inhibition of cGMP degrading PDE5.
i.e., the vasodilatory effects of PDE5 inhibitors come from potentiation of a single downstream cascade induced by NO, not by producing an excess of NO itself, with the latter (via inflammation-mediated induction of iNOS expression) generally being what's actually problematic.

Thanks for this explanation.

 

[UG Krishnamurti]

PDE5 inhibitors upregulate one downstream signalling cascade induced by nitric oxide - they don't significantly increase absolute NO production.
A lot of the issues with excessive nitric oxide synthesis come from the resulting competitive antagonism of O2 binding sites on cytochrome C oxidase, thereby inhibiting oxidative respiration.
This is independent of cGMP, the vasodilation-inducing effector molecule that nitric oxide increases via upregulation of guanylyl cyclase activity, and that viagra, cialis, etc., increase via inhibition of cGMP degrading PDE5.
i.e., the vasodilatory effects of PDE5 inhibitors come from potentiation of a single downstream cascade induced by NO, not by producing an excess of NO itself, with the latter (via inflammation-mediated induction of iNOS expression) generally being what's actually problematic.

Thanks for the explanation.
Do you then think that PDE5 inhibitors are something we can consider taking in a specific situation to improve blood vessels, blood flow or based on the shared study - to increase our lifespan?

 

[yerrag]

From the blog of Malcom Kendrick:

A few blogs ago I wrote of a study demonstrating that men with diabetes, who used Viagra, or other PDE5 inhibitors e.g. Cialis, were far less likely to die from CVD.

We know that Viagra/sildenafil has, as a primary mode of action, increasing nitric oxide synthesis in endothelial cells. This is how it maintains erections in erectile dysfunction. It also reduces blood pressure, particularly reducing blood pressure in the lungs. Nitric oxide is also the most powerful anti-coagulant agent known to man. Furthermore, it protects the endothelium from damage, and stimulates the production of endothelial progenitor cells in the bone marrow.

What effect does it have on LDL? None.

What effect does it have on cardiovascular and overall mortality? Well, very recently I was sent this paper: ‘Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction.’

This was a study on over forty-three thousand men over a six-year period, who had previously had a myocardial infarction (MI). Just over forty thousand did not have medication dispensed for erectile dysfunction (ED) (40,077), three thousand did (3,068). They were split into three groups: lowest number of ED scripts, medium and highest number.3

For the sake of brevity here I am just looking at the highest script group.

Well, well, well. Perhaps a couple of other well, wells for luck.

Yes, this study was observational. Yes, this means that other factors that may be at play. For example, those men requesting Viagra and other PDE5 inhibitors, may have been healthier than those who did not. But it is hard to believe they were over five times as healthy. The simple fact is that, when you see an effect as massive as this, it can generally be considered that you are looking at a causal relationship.

To put it another way, this is 81% relative risk reduction in overall mortality. Compare this with statins, in secondary prevention (using best figures possible), statins achieved a 15% relative risk reduction in overall mortality.

Do you have the link to the blog?

 

[Javelina]

Do you have the link to the blog?

This is a link to his blog: Dr. Malcolm Kendrick

 

[yerrag]

This is a link to his blog: Dr. Malcolm Kendrick

Thanks!

 

[proteome]

For example, those men requesting Viagra and other PDE5 inhibitors, may have been healthier than those who did not. But it is hard to believe they were over five times as healthy.

I can believe they were 5 times as healthy. To be getting laid enough at that age that you want help with it puts you in a smaller and smaller cohort of men.