Net Deficiency Revisited

[ramakentesh]

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[ramakentesh]

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[ramakentesh]

And where NET deficiency is implicated in POTS:

http://content.nejm.org/cgi/content/full/342/8/541

http://www3.interscience.wiley.com/journal...=1&SRETRY=0

http://circep.ahajournals.org/cgi/content/full/1/2/103

[ramakentesh]

And studies where MIBG uptake was abnormally low in the heart - meaning that norepinephrine reuptake is reduced:

http://jnnp.bmj.com/content/early/2009/08/...168484.abstract

http://www.springerlink.com/content/62145t4047003q66/

[avidita]

Honestly that is a little over my level of understanding What does it mean in lamens terms *feels stupid*

[firewatcher]

Well, with the first article, they had no definitive conclusion because the sample (number of women) was too small and they could only follow it for one month. Basically, the researchers observed that if you use a drug to impair norepinephrine transport in young healthy women their autonomic and cardiovascular responses to the standard 4 ANS tests changes over the course of our month. Higher estrogen levels act as a protective mechanism and the sudden drop during menstruation causes a worsening POTS-like response. They don't know why yet. It was actually a good try at explaining why our symptoms are worse when we are right before our periods.

I haven't gotten to the rest yet.

Ramakentesh, what is your collective take on NET deficiency? Does the theory still hold water or are there pieces of that puzzle still missing?

[erik]

Maybe concerta rather than cocaine? Safer way to maintain steady chronic exposure clinically.

[ramakentesh]

post deleted.

[ramakentesh]

If the patient that was the 'phenotype' or whatever they called it in the Shannon et al study and compare symptoms.

[janiedelite]

Yes, I can relate to most everything in these articles. I was wondering, would an alpha1 blocker be the best treatment to try first? (starting with tiny doses, working up based on symptoms)

Right now, I'm on a beta 1 and 2 and alpha 1 blocker (carvedilol). For the first time I've found a drug that will stop my surges of flushing, chest pain, and hypertension in response to orthostatic or emotional stress. It also worsens my exercise intolerance, though. It feels like my heartrate just can't compensate for increased activityvery effectively. Maybe I need to drop the beta 1 blocking aspect? Basically, I'm more fatigued while upright on this drug, but I feel better overall if I'm lying down or sitting. It was worsening my Raynaud's initially, but not so much anymore.

[erik]

Before discovering POTS, and contemplating myself back to my childhood, I "self assess" to be SCT (sluggish cognitive tempo) which is now called ADD-PI or ADHD-PI. Vandy found that non-impulsive ADHD variant to be associated with NET:

Genetics may explain three types of ADHD

The researchers previously have found a link between a variant of the norepinephrine transporter gene and the predominantly "inattentive" type of ADHD, and a link between a variant in the dopamine transporter gene and the predominantly "hyperactive and impulsive" type.

BTW, some folks "characterize" depression in similar ways... and tailor treatments toward different monoamines. Hmm, what of the DT DAT (DopAmine Transport) & POTS... on top of NET... both genetically, managed by natural feedback loops (enzyme regulation loops), etc.

For POTS & ADHD, I am unclear if NET is determined to be a cause or a variant/exacerbater. For example, there is also a genetic variant that causes nerves to counter-regulate less/more against over-stimulation (it is associated with norepinephrine levels, essential hypertension and such). The combination of NET deficiency (which enhances "umph" of each nerve firing) with a diminished counter-regulation against that seems like a particularly potent circumstance.

Given that just the latter alone is associated with hypertension, it seems like one can argue that these things should produce a significantly different "presentation" of POTS... just as my ADHD looks nothing like ADHD, it looks like Sluggish Cognitive Tempo and Withdrawal... polar opposite of Hyperactivity and Acting-Out... yet internally, it is same. Fascinating stuff.

Edited December 15, 2009 by Erik

[ramakentesh]

Deleted post

[erik]

Do you know details of the "genetic neuro counter-reaction to overstimulation" thingy I'm thinking of... was it Gly16 perhaps? I'm going to have to read up and figure out. It could be devastating when combined with NET deficiency (and perhaps a partial DBH deficiency & some side cardio factors too boot)! It seems it could also affect whether "reuptake inhibitor" therapies backfire or help. Did someone have a post about beta-receptor genetic variations lately? Some very profound "confluences" seem possible.

[janiedelite]

I think Blair Grubb advocates alpha/beta blockers. Mayo suggest phentobarbotil and vandy suggest clonidine. Ive spoken to a person with NET deficiency that was doing ok on beta blockers and midodrine. My old doctor suggested midodrine to stop the NET deficiency causing the excessive vasoconstrictive response to normal blood pooling.

Thanks! I tried midodrine once and seemed to develop a tolerance to the doses very quickly. I had to keep increasing. Then it made my Raynaud's flare pretty badly so I quit. I'll just keep on with the carvedilol.

[ramakentesh]

And more interesting reading:

The paradoxical findings in our study are probably explained by the complex effect of NET inhibition on the sympathetic nervous system. With an exclusively peripheral site of action one would expect NET inhibitors to increase synaptic norepinephrine concentrations, which in turn should increase sympathetic responses. Systemic NET inhibition elicits a more complicated response, presumably through interaction of peripheral and central nervous responses. When NET inhibitors are applied directly to the brain, sympathetic activity decreases substantially.16 The sympatholytic response is likely to be mediated through central nervous system 2 adrenoreceptors.16,17 Also with systemic administration, NET inhibition elicits a central sympatholytic response in rabbits16,17 and humans.7,8 The overall response to NET inhibition in each organ depends on the balance between peripheral stimulatory and central nervous inhibitory mechanisms. NET inhibition with desipramine reduces renal and forearm norepinephrine spillover, but increases cardiac norepinephrine spillover in healthy subjects.8

One possible explanation for the discrepant sympathetic response between organs is an anatomic difference in adrenergic synapses. In the heart, pre- and postsynaptic membranes are located particularly close to each other.18 This anatomic feature makes the heart more dependent on NET for removal of norepinephrine from the synaptic cleft. Indeed, a larger proportion of the released norepinephrine is taken up through NET in the heart compared with other organs.19 Another possible explanation for the discordant effect of NET inhibition on the heart, vasculature, and kidney is an organ-specific alteration in baroreflex regulation. In an earlier study, NET inhibition with reboxetine was associated with a shift in the baroreflex heart rate curves such that at a given blood pressure heart rate was increased. In contrast, baroreflex regulation of sympathetic vasomotor tone was attenuated.7 Redistribution of baroreflex outflow from the vasculature toward the heart has also been described in patients with POTS;20 NET inhibition could have a similar effect on baroreflex regulation of renal sympathetic nerve activity.

If the organ-specific changes in norepinephrine turnover with NET inhibition were physiologically relevant, one would expect to see corresponding changes in sympathetic responses in each affected organ, particularly during sympathetic stimulation. Cardiac sympathetic activity regulates heart rate and cardiac contractility. Given the increase in cardiac norepinephrine spillover with NET inhibition,8 heart rate and cardiac output are expected to increase. In any event, heart rate and cardiac output increased with NET inhibition in our study. Similarly, selective and nonselective NET inhibition increased heart rate in the supine position and even more so in the upright position.9,21 Similar abnormalities in heart rate regulation have been described in patients with familial NET deficiency.22 The pressor response to nonselective NET inhibition can be prevented with ?-adrenoreceptor blockade.21 Clearly, changes in cardiac norepinephrine turnover with NET inhibition are functionally relevant.

Considering the norepinephrine spillover data, vascular and renal sympathetic responses should be decreased during NET inhibition. Vascular sympathetic efferents control vascular tone. In the present study, systemic vascular resistance decreased during NET inhibition. Furthermore, selective and nonselective NET inhibition attenuated the response to cold pressor testing in several previous studies.7,9,21 Thus, the reductions in sympathetic vasomotor tone and norepinephrine spillover are indeed associated with attenuated vascular sympathetic responses.

Renal sympathetic responses are more diverse and therefore are particularly difficult to assess and to interpret in humans. The kidney is densely innervated by autonomic, predominantly adrenergic, efferent neurons.23 In animals, electrical stimulation of renal nerves leads to a graded increase in renin?angiotensin system activity, sodium reabsorption, and renal vascular resistance, depending on stimulation frequency.23,24 For each response, sympathetic activity must exceed a certain threshold. Moderate increases in renal sympathetic nerve activity can directly reduce sodium excretion and activate the renin?angiotensin system without major changes in renal blood flow and glomerular filtration.24 Sympathetically mediated sodium reabsorption is explained in part by direct activation of renal tubular -adrenoreceptors.25 The response is attenuated with phenoxybenzamine and mimicked by norepinephrine.26 The threshold for renal hemodynamic changes during sympathetic stimulation is higher than the threshold for hormonal responses or for tubular sodium reabsorption. In dogs, a 5-fold increase in renal nerve activity was required to decrease RBF by 40%.24 In our study, we assessed renin?angiotensin system activity as a low threshold sympathetic response and renal vascular resistance as a higher threshold response. In the supine position, sympathetic activity is relatively low. Thus, a further reduction in renal nerve activity is likely to exert an effect on sodium excretion and the renin?angiotensin system only, whereas renal perfusion or GFR are unlikely to change to a significant degree.23 Indeed, in the supine position, we observed changes in renin?angiotensin system activity but no change in renal hemodynamics. In the upright position, sympathetic activity may be sufficient to elicit renal vasoconstriction. Thus, inhibition of renal sympathetic activity with NET inhibition could only elicit a hemodynamic response during orthostatic stress.

Our study has several potential limitations. We used only one reboxetine dose in our study. The distribution of sympathetic activity between organs may be related to the degree of NET inhibition. The degree of NET inhibition may also influence the balance between central sympathetic inhibition and peripheral sympathetic stimulation. In contrast to previous studies, upright norepinephrine concentrations were not increased in this study. Higher reboxetine plasma concentrations and higher tilt angles in previous studies may account for this discrepancy.9,27 We only studied men. However, NET inhibition has a gender-specific effect on the cardiovascular system.27 Thus, our findings cannot be simply extrapolated to women. Finally, we cannot exclude completely that reboxetine directly interfered with some of our laboratory measurements. Despite these issues, our study strongly suggests an important effect of NET on the distribution of sympathetic activity between the heart, the vasculature, and the kidney.

Perspectives

Our study supports the idea that NET function profoundly influences the distribution of sympathetic activity between the heart, vasculature, and kidney. All of these changes are physiologically relevant because they lead to corresponding changes in organ function. Thus far, no other target has been shown to have a stronger effect on sympathetic distribution than NET. Our findings may be clinically relevant given the widespread clinical use of NET inhibitors. Furthermore, genetic variability in NET function may not only occur in the rare patient with NET deficiency,22 but also in the general population. Several single nucleotide polymorphisms in the NET gene are associated with substantial alterations in NET function.28 Moreover, abnormalities in the distribution of sympathetic activity between the heart, vasculature, and kidney have been described with aging,29 as in different pathophysiological conditions, such as heart failure,30 POTS,20 and obesity.31 NET abnormalities may possibly be important in this regard.

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

[erik]

Here's some more NET info from a prior post that you may have read. I bumped in to this not long ago when searching for CGRP... a totally different topic although it invites another nexus (migraine, sympathetic activity, blood flow stuff, etc.):

Norepinephrine Transporter, Looking for Research

[erik]

Another study indicating systemic changes resultant from NET:

Influences of Norepinephrine Transporter Function on the Distribution of Sympathetic Activity in Humans

They get in to some great topics in their "discussion" section, especially how complicated things get with paradoxical effects. This closing paragraph is catchy:

Our study supports the idea that NET function profoundly influences the distribution of sympathetic activity between the heart, vasculature, and kidney. All of these changes are physiologically relevant because they lead to corresponding changes in organ function. Thus far, no other target has been shown to have a stronger effect on sympathetic distribution than NET. Our findings may be clinically relevant given the widespread clinical use of NET inhibitors. Furthermore, genetic variability in NET function may not only occur in the rare patient with NET deficiency, but also in the general population. Several single nucleotide polymorphisms in the NET gene are associated with substantial alterations in NET function. Moreover, abnormalities in the distribution of sympathetic activity between the heart, vasculature, and kidney have been described with aging, as in different pathophysiological conditions, such as heart failure, POTS, and obesity. NET abnormalities may possibly be important in this regard.

[firewatcher]

Alrighty, I'm confused now. I think many here are. Can you two put this into a short synopsis of how this works in a POTS patient. I know there are differing types/etiologies, but as far as NET, NO and Ang II, what do you think is the series of events that leads us to where we are?

What does each do in or is implicated/theorized to do in POTS of whichever type?

Neuronal Norephinephrine transporter deficiency (NET):

Nitric Oxide:

Angiotensin II:

[ramakentesh]

post deleted

[issie]

Another bump - possibilities of NET deficincy or norepiphrine transporter problems. Another suggestion as to Hyper POTS or Low Flow POTS.

[issie]

My link

I just found an article from Vandy dated 2011 that suggest a genetic link for NET. I don't know if I did this right, so hope it comes up.

Well, it works, but not quite what I wanted. If you click on it - it takes you there. Here's it typed in in case this doesn't work for you.

http://www.mc.vanderbilt.edu/reporter/index.html?ID=1039

[arizona girl]

My link

I just found an article from Vandy dated 2011 that suggest a genetic link for NET. I don't know if I did this right, so hope it comes up.

Well, it works, but not quite what I wanted. If you click on it - it takes you there. Here's it typed in in case this doesn't work for you.

http://www.mc.vander...ex.html?ID=1039

good article issie, I know I almost triple on standing. It will be interesting to see where this goes.

[ramakentesh]

While that article sas that it is coyright 2011 its actually a republishing of an article from 2000.

There are several unresolved problems with the original study. Why, if many of her family also had the gene mutation, does she orthostatic intolerance and POTS much worse than any one else in her family? Why is it that the majority of POTS patients have suggested reduced norepinephrine reuptake yet only one patient has ever been identified with a functional mutation of the NET gene?

There was an unpublished study in Australia that suggested that there might be epigenetic silencing of the NET gene in POTS. Its yet to be published however.

[HopeSprings]

I had seen Dr. Stewart several years ago and he tested my laying and standing norepi, dopamine and epi. Norepi was very elevated standing and dopamine was a bit elevated. These results were of interest to Vanderbilt (i think they were researching NET at the time- maybe they still are) so they sent me a DNA kit and had me send them saliva. They tested it for NET -- it was negative. I think this is a very rare cause of POTS.

[issie]

While that article sas that it is coyright 2011 its actually a republishing of an article from 2000.

There are several unresolved problems with the original study. Why, if many of her family also had the gene mutation, does she orthostatic intolerance and POTS much worse than any one else in her family? Why is it that the majority of POTS patients have suggested reduced norepinephrine reuptake yet only one patient has ever been identified with a functional mutation of the NET gene?

There was an unpublished study in Australia that suggested that there might be epigenetic silencing of the NET gene in POTS. Its yet to be published however.

So, Rama, if you've seen this report - can you give us an overview? Do you know the results? What can be done if there is a genetic component to this noriepi transporter deficiency. How can we get our bodies to efficiently use the norepi and it not just swirl around in our bodies and cause other problems? I think there is a possibility of genetic components in my case - everyone in my family has some sort of orthostatic issue.