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Exercise Intolerance


ramakentesh
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Here is an interesting article and link to another article talking about neuronal nitric oxide being specifically decreased in CFS and other conditions and how it causes exercise intolerance:

http://chronicfatigue.about.com/b/2008/12/...ue-syndrome.htm

http://www.hhmi.org/news/campbell20081127.html

and this mechanism in POTS:

http://www.nymc.edu/fhp/centers/syncope/nN...flow%20POTS.htm

http://ajpheart.physiology.org/cgi/reprint/00600.2007v1.pdf

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Fascinating for sure. N.O. is pretty ubiquitous in the body as signaler, secondary messenger, etc. As with any enzyme (such as NOS, NET, DAT) one has to ask what is regulating it. Is there a signal somewhere that is altering the production, transport, catabolism, etc. of that enzyme that is observed to be deficient or increased? Is it just a permanent genetic factor? It is interesting/surprising that this looks specifically neuronal in POTS... endothelial would have been a likely suspect too.

Some interesting research tidbits:

Effect of estrogen on endothelial dysfunction in postmenopausal women with diabetes.

Treatment with estrogen causes increased release of nitric oxide and this appears to be an important mechanism involved in the cardioprotective effect of estrogen.

Impaired flow-mediated vasodilation in type 2 diabetes: lack of relation to microvascular dysfunction.

A reduced availability of nitric oxide (NO) is an important feature of endothelial dysfunction occurring early in the course of type 2 diabetes. The measurement of flow-mediated dilation (FMD) of the brachial artery after forearm ischemia is supposed to be a non-invasive method to assess endothelial production and release of NO. The impairment of reactive hyperemia due to microvascular dysfunction in diabetes might cause an insufficient increase in shear stress stimulating the endothelial NO release, thus leading to an underestimation of FMD.
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Treatment with estrogen causes increased release of nitric oxide and this appears to be an important mechanism involved in the cardioprotective effect of estrogen

Well that's interesting too, because I posted this summer about how great I felt while I was taking high dose estrogen (for infertility treatments). I also notice that during the second half of my monthly cycle my POTS symptoms worsen.

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Treatment with estrogen causes increased release of nitric oxide and this appears to be an important mechanism involved in the cardioprotective effect of estrogen

Well that's interesting too, because I posted this summer about how great I felt while I was taking high dose estrogen (for infertility treatments). I also notice that during the second half of my monthly cycle my POTS symptoms worsen.

That IS interesting. Maybe it's time I hop back on the pill.

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There is also this study on phases of BC pills and relation to baroreflex (which is potentially key to POTS). There are probably other subsequent investigations:

Sympathetic Activity and Baroreflex Sensitivity in Young Women Taking Oral Contraceptives

It is hard to keep all the vocabulary straight, so I wouldn't know if the study supports the notion of a beneficial baroreflex mediated change or if other hormonal effects are more likely.

I don't know if NO/NOS stuff is being adjusted specifically in neurons via a hormonal activity... endothelial NO stuff is mentioned more often but who knows.

Perhaps this study gives quick insight as to regulation of nNOS:

Nitric Oxide Limits Pressor Responses to Sympathetic Activation in Rat Spinal Cord

Because NOS is activated by an increase in intracellular calcium, such as that caused by stimulation of N-methyl D-aspartate (NMDA) receptors, we tested the possibility that NO synthesis modulates the pressor response elicited by NMDA in the spinal cord.
This is not the calcium ion effect happening later via cAMP (which NO triggers, and which the PDE inhibitors amplify)... this is more of a neuroregulatory calcium activity via NMDA-receptor influence. This Nitric Oxide page gives a great many more details on how NO is regulated:

http://www.whatislife.com/reader2/Metabolism/pathway/no.html

Some key things it mentions are NMDA & non-NMDA glutamate receptors (the NMDA regulating calcium, the non-NMDA regulating arginine uptake) and also calmodulin. It is unclear to me which of these things apply to which neurons... but the first "pressor response via NMDA" article seems to indicate involvement in the nNOS deficit implicated in the NYMC study. Perhaps something can be done other than just amplifying the cAMP to make up for NO deficiency?

Of course, one can consider all the NO "sports" products & research too. Maybe some of that would come in handy?

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On angiotensin II

http://cat.inist.fr/?aModele=afficheN&cpsidt=17425253

On reduced nitrix oxide induced dilation in the same form of POTS:

http://www.circ.ahajournals.org/cgi/conten...HA.104.526764v1

On cutaneous neuronal nitric oxide being low in the same form of POTS:

http://ajpheart.physiology.org/cgi/content...act/293/4/H2161

And probably what your after - defect in ACE2 reduces angiotensin II catabolism in Low Flow POTS and contributes to reduced neuronal NO:

http://hyper.ahajournals.org/cgi/content/f...urcetype=HWFIG:

Aim 4 reinforces the importance of Ang-(1-7) and ACE2 because Ang-(1-7) is able to improve the blunted heating response in POTS. The data support previous observations of cutaneous NO deficiency in POTS10 caused by excessive Ang II.20
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From the last article:

Perspectives

POTS is associated with a hyperadrenergic state of sympathoexcitation and widespread vasoconstriction. Our previous work showed that cutaneous and systemic Ang II is increased in low-flow POTS, in which NO bioavailability is reduced. We have now shown that there is blunted activity of ACE2, which is the central pathway for Ang II degradation. This may be the first human illness in which this deficit has been detected. The findings transcend the tachycardia syndrome and point to mechanisms for Ang II excess and sympathetic activation that are potentially present in diverse systemic illnesses of vascular regulation.

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I'm trying to digest the details as best I can and will continue to re-read stuff but I am having trouble connecting some dots so far.

#1 seems to indicate that only low-flow POTSies have low blood volume (normal & high don't). Just an interesting thing if I am reading it right. Renin activity was reduced & AngII increased in low-flow, and whereas others had Renin & AngII correlated, they were inversely correlated in low-flow (like a flipped relationship). I think this looks like the study about AngII in POTS on NYMC site, especially since the "Angiotensin II concentrations seem to follow a bimodal distribution" as they say. I may be recalling this very study, but I remember that

#2 is consistent with #3, though I believe L-NAME is non-specific NOS inhibitor so presuming conclusion from #3 to hold we don't get added info from #2.

#3 seems to match the study summary from the first post:

The data suggest that nNO activity but not NO of endothelial NOS origin is reduced in low-flow POTS.
It specifically implicates neuronal NOS (nNOS) as opposed to endothelial (eNOS). It seems to state that endothelial function is intact in terms of NO & NOS activity, but I might be misinterpreting it??? The nNOS vs eNOS inhibition via AngII thing is what I'm trying to understand causally.

#4 is complicated & I'll need to re-review a few more times! The NOS inhibitor used was nitro-L-arginine (NLA) same as the non-specific inhibitor used in #3 but no nNOS-specific inhibitor was used. That might not have been necessary, I don't know... would it have been informative to use the same nNOS specific inhibitor as in #3? I think this study was subsequent to #3 but not sure. I'll have to see if I can wrap my head around the study with further examination.

Is there a description of how AngII ends up inhibiting nNOS specifically? I have had easier time finding descriptions of endothelial & renal interactions but #3 study says it's nNOS and not eNOS. Am I mis-interpreting that or otherwise missing an obvious chain of events? I'll re-read but if you can describe the causal link for me that would be a cool shortcut! Are there AT receptors modulating the neuronal function... is it that simple? Where are AT receptors known to be located?

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yeah pretty much - both endothelial and neuronal nitric oxide are involved in vascular dilation - because there was global vasoconstriction the assumption made was that it was endothelial but this wasnt the case. Reduced neuronal nitric oxide also effects the vasomotor nerves causing orthostatic intolerance.

Angiotensin II increases free radicals which some how reduces neuronal nitric oxide - im not sure of this precise mechanism but perhaps the formation of the super oxide free radical has some role. Angiotensin II is a vasoconstrictor itself that stimulates the release of norepinephrine, nNOS effects overall sympathetic outflow and potentiates the effects of norepinephrine.

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