Agmatine and Nitric Oxide.

[Ema]

I've been looking at the possibility of trying NOS inhibitors to help with mood, anxiety and hopefully pain.

I found several listed in this article, including agmatine.

But when I look up agmatine supplements, it seems like they are advertised to boost nitric oxide, not reduce it.

What have I got wrong here? Shouldn't something that inhibits NOS produce less NO, not more?

Any thoughts, @heapsreal, @Hip, @Mimi?

 

[deleder2k]

I am not sure if you're after a NOS inhibitor. Boosting nitric oxide could be a way to minimize ME symptoms according to research done at Haukeland University Hospital.

http://forums.phoenixrising.me/inde...ith-or-without-b-cell-depletion-in-cfs.36592/

 

[Ema]

I am not sure if you're after a NOS inhibitor. Boosting nitric oxide could be a way to minimize ME symptoms according to research done at Haukeland University Hospital.

http://forums.phoenixrising.me/inde...ith-or-without-b-cell-depletion-in-cfs.36592/

According to the article I linked, I'm after an NOS inhibitor...now whether or not that is a good idea remains to be seen!

But how can an NOS inhibitor increase NO, as per the supplement marketing? Shouldn't it decrease NO?

What am I missing?

 

[deleder2k]

Perhaps you can try something called Gaba2. My ME doc gave it to me a year ago. I didn't work me though. Didn't notice anything.


I think research points to the fact that NOS is greatly suppressed in ME. Treatment with nitrates which boost NOS has made a majority of patients significantly better in an open trial at Haukeland. It is Fluge and Mella's main hypothesis.

 

[minkeygirl]

@Ema if you try this and get cured, please let me know!

 

[Hip]

The Chinese herbal Saposhnikovia divaricata (Fang Feng) is an NOS inhibitor:
Inducible nitric oxide synthase inhibitor of the Chinese herb I. Saposhnikovia divaricata (Turcz.) Schischk

Apigenin and quercetin are NOS inhibitors:
Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1

More NOS inhibitors are to be found in these studies:
Arginine-Based Inhibitors of Nitric Oxide Synthase: Therapeutic Potential and Challenges
Nitric Oxide Synthase Inhibitors Attenuate Phencyclidine-Induced Disruption of Prepulse Inhibition

And of course there are lots listed in the study that you cited above:
Nitric Oxide Synthase Inhibitors as Antidepressants


B12 hydroxocobalamin inhibits NO, but not NOS itself.

 

[Ema]

Thanks @Hip! Lots to look through...

Can you explain why agamatine is advertised as a nitric oxide booster if it inhibits NOS?

 

[Ema]

Another study that says agmatine inhibits nitric oxide...

Ann N Y Acad Sci. 2003 Dec;1009:20-9.
Regulation of inducible nitric oxide synthase and agmatine synthesis in macrophages and astrocytes.
Regunathan S1, Piletz JE.
Author information

Abstract
Agmatine is a novel endogenous guanido amine synthesized from arginine by arginine decarboxylase.

Among several biologic effects, the ability of agmatine to protect against ischemic injury and chronic neuropathic pain is particularly interesting. Because inflammation is a common contributor to these conditions, we sought to determine if agmatine acts by decreasing the production of proinflammatory molecules such as nitric oxide and if agmatine synthesis is regulated by inflammatory stimuli.

We tested whether agmatine affects astroglial and macrophage (RAW 264.7 cell line) nitric oxide synthase-2 (NOS-2) expression. NOS-2 was induced in these cells by incubation with lipopolysaccharide (LPS) plus three cytokines for astrocytes and LPS alone for RAW 264.7 cells in the presence and absence of varying concentrations of agmatine. NOS-2 activity was assessed after 24 hours by nitrite accumulation in the culture media. Agmatine dose-dependently inhibited nitrite accumulation, and shorter incubation with agmatine (1 and 4 hours) also caused significant reduction. Agmatine decreased the expression of NOS-2 activity and NOS-2 protein as determined by immunoblot analysis. Incubation of astrocytes and RAW 264.7 cells with LPS/cytokines for 2 hours resulted in an increase in arginine decarboxylase (ADC) activity, whereas longer-term incubation (12-17 hours) lowered ADC activity. Agmatine levels in these cells are increased after 6-hour incubation with LPS/cytokines.

These results show that agmatine inhibits the production of nitric oxide by decreasing the activity of NOS-2 in macrophages and astroglial cells by decreasing the levels of NOS-2 protein. These findings provide a molecular basis for the neuroprotective and anti-inflammatory actions of agmatine.

 

[heapsreal]

Nitric oxide from what i understand is ok but by products of NO produce peroxinitrate which is what causes increased oxidization.

 

[Hip]

Thanks @Hip! Lots to look through...

Can you explain why agamatine is advertised as a nitric oxide booster if it inhibits NOS?

I did not see many compounds in those studies that looked like they could be obtained as a supplement, so they may not be that useful.


Possibly agmatine inhibits NOS but increases NO production overall via other mechanisms. As you know, nitric oxide metabolism is pretty complex. It does not say which type of NOS agmatine inhibits in the paper you cited; now iNOS is orders of magnitude more potent than eNOS and nNOS at creating NO, so if agmatine was only inhibiting say eNOS, then that would not reduce NOS levels very much; and if agmatine was also boosting some other aspect of nitric oxide production, then the overall result may well be an increase in NO.


By the way, does your study say which of the three types of NOS you need to inhibit?

 

[Ema]

now iNOS is orders of magnitude more potent than eNOS and nNOS at creating NO,

So the abstract I just posted says that agmatine inhibits NOS2...which I think is iNOS.

By the way, does your study say which of the three types of NOS you need to inhibit?

That study doesn't say...but another one says this about agmatine.

In addition to activity at these receptors, agmatine irreversibly inhibits neuronal nitric oxide synthase and downregulates inducible nitric oxide synthase.

 

[Hip]

So the abstract I just posted says that agmatine inhibits NOS2...which I think is iNOS.

I missed that post entirely. Must be going blind.


I have tried agmatine 750 mg daily in the past. It's an NMDA receptor antagonist, so I thought it might have similar anti-anxiety effect to high-dose transdermal magnesium, which is also an NMDA receptor antagonist. However, I did not notice any effects from agmatine, whereas transdermal magnesium always creates a noticeable calming effect when I apply it.


There are reports online of agmatine promoting the occurrence of out-of-body experiences / near-death experiences, a subject I had always been interested in. So I was kind of hoping the agmatine I took would trigger an OBE, but no such luck.

 

[Ema]

There are reports online of agmatine promoting the occurrence of out-of-body experiences / near-death experiences, a subject I had always been interested in. So I was kind of hoping the agmatine I took would trigger an OBE, but no such luck.

Oh, GREAT! Trust me, it'll happen to me. And NO THANK YOU!!

 

[Ema]

So it seems like all the bodybuilding sites are relying on this one article that says that agmatine activates eNOS. But I think it's disingenuous not to mention that it also strongly inhibits iNOS, which is much stronger.

Proc Assoc Am Physicians. 1997 Jan;109(1):51-7.
Agmatine activation of nitric oxide synthase in endothelial cells.
Morrissey JJ1, Klahr S.
Author information

Abstract
Agmatine is a product of arginine decarboxylation. Systemic infusion of agmatine into rats causes hypotension. This effect could be due either to a central action of agmatine (a clonidine displacing substance), or to a direct effect of agmatine on cells of blood vessel walls, which induces them to cause vasodilatation, or both. In this study, we examined the effects of agmatine on endothelial cell function by using cultured bovine pulmonary artery endothelial cells. Agmatine stimulated nitrite production three-fold above basal nitrite formation by endothelial cells. The increased nitrite production by agmatine was inhibited by idazoxan but not by yohimbine. Agmatine displaced [3H]-idazoxan from endothelial cell membranes and was found to induce transients in the cytosolic calcium of endothelial cells. The transients could be downregulated by repeated exposure to agmatine but were not affected by pretreatment with norepinephrine. These results suggest that agmatine can bind to a cell surface imidazoline receptor on endothelial cells and can stimulate nitric oxide production by increasing cytosolic calcium. Therefore, agmatine appears to act directly on endothelial cells to increase the synthesis of nitric oxide, a vasodilatory substance.

 

[South]

@Ema If you are trying to reduce Nitric Oxide, one of the studies in this thread (I think one that Hip linked to) is this one, which states "Apigenin and quercetin were the most potent inhibitors of NO production"
http://www.ncbi.nlm.nih.gov/pubmed/11213362

(don't confuse apigenin with agmatine)

Interesting because the apigenin and quercetin study seemed to actually focuse on changes in nitric oxide, not just on changes in the inos etc that then "might" change nitric oxide levels...at least that's the way I read it.

Quercetin is easy to get in most countries as a supplement. Apigenin is equally easy to get, I just found it on several big supplement websites.

But of course there are complications

Apigenin problem:
According to http://examine.com/supplements/apigenin/#summary6-1
Apigenin lowers cortisol, not good for those who have overly low cortisol already (I coudn't tell if that reference used some extremely high dose of apigenin to cause low cortisol, or if it was a realistic dose of apigenin)
At least though, apigenin is fairly well absorbed into real animals, so the nitric oxide study might really lower nitric oxide levels in actual humans, I think...
http://www.ncbi.nlm.nih.gov/pubmed/15466493

Quercetin problem:
studies on isolated cells for quercetin aren't that reliable, according to
http://examine.com/supplements/Quercetin/
because "cell studies [on quercetin] showing great results that are not that amazing in humans or animals. This is mostly due to quercetin having low oral bioavailability"

 

[South]

Another complication on apigenin:

Apigenin seems to lower blood pressure in a few scattered studies. (despite lowering nitric oxide, which I thought leads to somewhat higher blood pressure, not lower blood pressure)

And many people on this forum already have overly low blood pressure.

I didn't find one, neat clean study on apigenin and blood pressure, it's just a bunch of bass-akwards studies that seem to imply it.

There is this one that found apigenin to be a vasodilator:
http://www.ncbi.nlm.nih.gov/pubmed/1659912

 

[Ema]

Another complication on apigenin:

Apigenin seems to lower blood pressure in a few scattered studies. (despite lowering nitric oxide, which I thought leads to somewhat higher blood pressure, not lower blood pressure)

And many people on this forum already have overly low blood pressure.

I didn't find one, neat clean study on apigenin and blood pressure, it's just a bunch of bass-akwards studies that seem to imply it.

There is this one that found apigenin to be a vasodilator:
http://www.ncbi.nlm.nih.gov/pubmed/1659912

I actually have a bottle of apigenin here. I try not to read too too much about supplements because I don't want to influence myself.

I bought it because it's supposed to be good at calming down an overactive immune system and reducing systemic inflammation.

The cortisol connection is definitely interesting though. I guess it doesn't matter for me though since I replace cortisol.

The vasodilation worries me a bit because of migraine though.

Very interesting! Thanks!