Renin-Aldosterone Paradox Explained

[firewatcher]

If Hydrogen Sulfide inhibits plasma renin and is elevated in POTS patients, then this might explain the paradox. Now, WHY we have elevated H2S is still up for question.

Hydrogen Sulfide inhibits plasma renin activity

link to pdf

Hydrogen sulfide inhibits plasma renin activity.

Lu M, Liu YH, Goh HS, Wang JJ, Yong QC, Wang R, Bian JS.

J Am Soc Nephrol. 2010 Jun;21(6):993-1002. Epub 2010 Apr 1.

Source

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456.

Abstract

The development of renovascular hypertension depends on the release of renin from the juxtaglomerular (JG) cells, a process regulated by intracellular cAMP. Hydrogen sulfide (H2S) downregulates cAMP production in some cell types by inhibiting adenylyl cyclase, suggesting the possibility that it may modulate renin release. Here, we investigated the effect of H2S on plasma renin activity and BP in rat models of renovascular hypertension. In the two-kidney-one-clip (2K1C) model of renovascular hypertension, the H2S donor NaHS prevented and treated hypertension. Compared with vehicle, NaHS significantly attenuated the elevation in plasma renin activity and angiotensin II levels but did not affect plasma angiotensin-converting enzyme activity. Furthermore, NaHS inhibited the upregulation of renin mRNA and protein levels in the clipped kidneys of 2K1C rats. In primary cultures of renin-rich kidney cells, NaHS markedly suppressed forskolin-stimulated renin activity in the medium and the intracellular increase in cAMP. In contrast, NaHS did not affect BP or plasma renin activity in normal or one-kidney-one-clip (1K1C) rats, both of which had normal plasma renin activity. In conclusion, these results demonstrate that H2S may inhibit renin activity by decreasing the synthesis and release of renin, suggesting its potential therapeutic value for renovascular hypertension.

PMID:

20360313

Plasma Hydrogen Sulfide in Differential Diagnosis between Vasovagal Syncope and Postural Orthostatic Tachycardia Syndrome in Children.

Zhang F, Li X, Stella C, Chen L, Liao Y, Tang C, Jin H, Du J.

J Pediatr. 2011 Sep 13. [Epub ahead of print]

Source

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Abstract

OBJECTIVE:

To explore the predictive value of plasma hydrogen sulfide (H(2)S) in differentiating between vasovagal syncope (VVS) and postural orthostatic tachycardia syndrome (POTS) in children.

STUDY DESIGN:

Patients were divided between the POTS group (n=60) and VVS group (n=17) by using either the head-up test or head-up tilt test. Twenty-eight healthy children were selected for the control group. Plasma concentrations of H(2)S were determined for children in all groups (POTS, VVS, and control).

RESULTS:

Plasma levels of H(2)S were significantly higher in children with VVS (95.3±3.8 μmol/L) and POTS (100.9±2.1 μmol/L) than in children in the control group (82.6±6.5 μmol/L). Compared with the VVS group, the POTS group had plasma levels of H(2)S that were significantly increased. The receiver operating characteristic curve for the predictive value of H(2)S differentiation of VVS from POTS showed a H(2)S plasma level of 98 μmol/L as the cutoff value for high probability of distinction. Such a level produced both high sensitivity (90%) and specificity (80%) rates of correctly discriminating between patients with VVS and patients with POTS.

CONCLUSION:

H(2)S plasma level has both high sensitivity and specificity rates to predict the probability of correctly differentiating between patients with VVS and patients with POTS.

Copyright © 2011

[sue1234]

I'm going to look back through some old posts, but I know I have posted a thread a while back about gut bacteria. I know I remember something about gut bacteria producing hydrogen sulfide. I'll link it when I find it.

[Ernie]

Hi,

Thanks for sharing. Very interesting article.

[sue1234]

I didn't link it--I just reposted to it to bring it back up on the forum. It has alot of valuable information and research posted by a few of us, anyway.

These are interesting articles that show the children with POTS had the highest H2S, then vasovagal, and then normal. Once again, I'm sure there is no doctor out in my circle that will just run an H2S for me, much less even know what to do with the information. If you find any other info, please share.

[Guest maia]

Thank you for posting this, very interesting! I wonder if anyone has investigated POTS being in some way regulated/caused by a kidney malfunction in general. fludro works by retaining water/correctin water/salt imbalances... hypertension is or can be caused by kidney issues... Kidneys are filters, perhaps filtering the wrong things or the wrong ammounts?

I did a little googling after reading this and hydrogen sulfide levels can be used as a marker for lower respiratory infections, proteus mirabilis can cause kidney stones, and reinfect due to being harbored in the stones, salmonella causes hydrogen sulfide, as well as candida infectins... just looking around a bit it looked like there were many bacterial overegrowths that cause hydrogen sulfide increases... very interesting for me particularly because i have been on antibiotics a few times this year for no apparent reason other than i felt awful and the pots was out of control and the only thing that helped was a course of flagyl. interesting indeed.

Also found this:

http://www.emaxhealth.com/83/17089.html

So, hydrogen sulfide relaxes smooth muscles and arteries... ?! I guess ill be staying away from garlic

[Guest maia]

here is another with an interesting bit about hydrogen sulfide: http://www.innovationmagazine.com/innovation/volumes/v4n2/coverstory4.shtml

The second paragraph talks about hydrogen sulfide causing problems by inhibiting a mitochondrial enzyme. Dont some people with POTS get worked up for mitochondial issues? I wonder if there is a cytochrome oxidase supplement. Id be willing to try it.

I also found the first paragraph rather interesting. If Viagra was created because they found out that nitric oxide dilated blood vessels in the penis, I think they should find out how tighten up our smooth muscles and arteries in our legs by countering the h2so4. Perhaps that could be a good marketing ploy.... new to the forum so ill leave out my marketing idea,it might offend...

[Guest maia]

i cant post a link to the article but if you google 'cytochrome oxidase supplement' the first 2 below the scholarly aricles links are to a medical study which showed that copper supplementation in rats increased the cytochrome oxidase.

So, if hydrogen sulfide relaxes our arteries and smooth muscles, and it does this by decreases in cytochrome oxidase, im going to go suck on some pennies!

... also interesting to google 'cytochrome oxidase+vascular tone' there is an article in there which discusses mitochondrial function/free radicals, ATP, and cytochrome.. I know there are creatine supplements that increase ATP...

Also in that first article i mentioned it states that hydrogen sulfide can play a role in memory formation and when i googled the cytochrome i came across somethign about decreased nitric oxide playing a role in improving alzheimers by taking nsaids... a little off from the pots but interesting in reference to memory issues/foginess of pots...

ill post when i find some copper and atp supplements and give then some time to see if they help. thank you for the article!

[issie]

We have discussed nitric oxide and it seems there are some studies suggesting that it depends on what type of POTS you have - some may need more nitric oxide - others less. Us with HyperPOTS seem to need more - those with higher bp's. Those with more orthostatic issues and lower bp's may need less. (At least that's what I remember from our conversations and the articles Rama posted.) You can do a search in the forum and pull up allot of info on this.

Also, do a search on renin-aldosterone and you will find lots of conversation on this too. Interesting subjects and none of my doctors seem to interested to do any type of research on these things. I do feel they are a very important piece of our puzzle.

Issie

[firewatcher]

"We have discussed nitric oxide and it seems there are some studies suggesting that it depends on what type of POTS you have..."

I haven't read the full text, but since the study is on children with POTS, I am guessing that this would be the genetic subgroup (usually Hyper-POTS, or ends up being that in adulthood.) I know that I have always had this and did not have a viral trigger. NO and H2S are both "gasotransmitters," and like NO, occur in varying levels depending on the disorder. I don't think any of the researchers know what to do with this yet, the studies are just too new.

[firewatcher]

This might explain why NO levels are low in hyper-POTS as well.

Unfortunately, there is not enough known about gasotransmitters and disease to determine any effective treatments that manipulate them. We also have no idea whether this is a chicken or egg scenario: H2S is elevated in hypoxic conditions, so is it high in POTS patients due to postural hypoxia or is it contributing to/causing POTS because it is elevated?

Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide.

Oh GS, Pae HO, Lee BS, Kim BN, Kim JM, Kim HR, Jeon SB, Jeon WK, Chae HJ, Chung HT.

Free Radic Biol Med. 2006 Jul 1;41(1):106-19. Epub 2006 Apr 25.

Source

Department of Microbiology and Immunology and Medicinal Resources Research Institute, Wonkwang University School of Medicine, Iksan, Chonbuk 570-749, Republic of Korea.

Abstract

Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO.

PMID:16781459

[Lenna]

Just to quickly address the nitric oxide piece -- my son has been taking Losarten (brand name Cozaar) since last spring to boost his body's production of NO. While this has not been a miracle drug for him, it HAS helped quite a bit.

[sue1234]

I put the "Gut bacteria as a possible cause..." post back up, but don't know if anyone is reading it. From page 2, post number 17, I had posted the Wikipedia version of H2S. It was interesting and relevant to what we are discussing here:

I wanted to add, from Wikipedia, what happens in the body with hydrogen sulfide:

Function in the body

Hydrogen sulfide is produced in small amounts by some cells of the mammalian body and has a number of biological signaling functions. (Only two other such gases are currently known: nitric oxide (NO) and carbon monoxide (CO).)

The gas is produced from cysteine by the enzymes cystathionine beta-synthase and cystathionine gamma-lyase. It acts as a relaxant of smooth muscle and as a vasodilator[21] and is also active in the brain, where it increases the response of the NMDA receptor and facilitates long term potentiation,[22] which is involved in the formation of memory.

Eventually the gas is converted to sulfite in the mitochondria by thiosulfate reductase, and the sulfite is further oxidized to thiosulfate and sulfate by sulfite oxidase. The sulfates are excreted in the urine.[23]

Due to its effects similar to nitric oxide (without its potential to form peroxides by interacting with superoxide), hydrogen sulfide is now recognized as potentially protecting against cardiovascular disease.[21] The cardioprotective role effect of garlic is caused by catabolism of the polysulfide group in allicin to H2S, a reaction that could depend on reduction mediated by glutathione.[24]

Though both nitric oxide and hydrogen sulfide have been shown to relax blood vessels, their mechanisms of action are different: while NO activates the enzyme guanylyl cyclase, H2S activates ATP-sensitive potassium channel in smooth muscle cells. Researchers are not clear how the vessel-relaxing responsibilities are shared between nitric oxide and hydrogen sulfide. However there exists some evidence to suggest that nitric oxide does most of the vessel-relaxing work in large vessels and hydrogen sulfide is responsible for similar action in smaller blood vessels.[25]

Like nitric oxide, hydrogen sulfide is involved in the relaxation of smooth muscle that causes erection of the penis, presenting possible new therapy opportunities for erectile dysfunction.[26][27]

In Alzheimer's disease the brain's hydrogen sulfide concentration is severely decreased.[28] In trisomy 21 (the most common form of Down syndrome) the body produces an excess of hydrogen sulfide.[23] Hydrogen sulfide is also involved in the disease process of type 1 diabetes. The beta cells of the pancreas in type 1 diabetes produce an excess of the gas, leading to the death of beta cells and to a reduced production of insulin by those that remain.[25

[issie]

A quick search on hydrogen sulfite rendered a supplement that can inactivate it - Beta Alanine. It is an amino acid and is the precussor to carnosine. Most body builders recommend taking it over carnosine or even creatine. It is supposed to help to balance out the ph acidity of the muscles and help increase muscle strength, energy and decrease lactic acid build-up. It sounds like it might help with mitrocondrial issues, because it increases energy there. I read that it will also increase nitric oxide. The one warning given is that it can cause a pins and needles effect and also hot flashes. This is supposed to subside with time. They recommend at least a 12 week trial and then give a break and then take again. Creatine is supposed to get and keep fluid in the muscle - but I read one report that a person felt like it increased their blood pressure - this might be good for those with low bp's. Although, one person said that there was a study saying that it would not increase your bp. So, guess everyone may react differently. It's recommended to spread it out over the day and it is supposed to help exercise endurance.

Just found this interesting. Wonder if it would help us.

Issie

[juliegee]

One cause for excessive levels of hydrogen sulfide could be... a chronic systemic mycosis (fungal) infection- something I've been thinking about for a while. Apparently, as fungus dies off, it emits high levels of H2S.

It's hard to find good legitimate medical information on mycoses. Most physicians don't acknowledge it beyond very peripheral concerns- affecting skin & nails YET most articles go on to say it can ultimately cause death if unchecked Something tells me that there is something in between minor cosmetic concerns...and death . There must be a type of chronic systemic fungal infection.

The most common mycosis is candida albicans, but there are MANY different types of mycoses: http://www.ncbi.nlm.nih.gov/books/NBK7902/ And the array of symptoms they cause is staggering, including tachycardia, low BP, severe allergy symptoms, fatigue, cognitive deficits, chronic sinusitis, severe GI symptoms, even joint issues etc. Many alternative health sites, (that espouse the chronic systemic theory) strongly link system-wide fungal infections to Chronic Fatigue Syndrome. Anybody seeing the overlap? I find it compelling. Apparently, the fungus can become off-balanced especially when the host is immunodeficient (as many of us are.)

Here's a list of weird (fungal or fungal-related)) things that I have going on. Forgive me for oversharing , I just wondered if anyone else had similar issues:

-recent severe outbreak of tinea versicolor. This is identified by a loss of patchy pigment especially apparent with sun exposure.

-thickened yellow pinky toenails

-roseca (thought to be related to a fungal condition)

-jock itch type rash where my sports bra hits following any long exercise session

-chronic vaginal redness, pain, intermittent discharge (NOT what one would expect with a typical yeast infection BUT this presentation is typical of many mycoses)

-chronic sinusitis

-chronic ear pain

-allergy symptoms with NO allergies

-intermittent breathing problems

-POTS/hypotension

-fatigue

-cognitive fog

-chronic constipation

-GERD

-chronic low IgG and intermittently low IgA

Could this be a part of what is causing our symptoms??? Somewhere I read that Dr. Oz does believe in the chronic systemic theory. He puts his patients on Diflucan, a strict diet, and encourages probiotics. Since I've been reading about this, I've added yogurt (with live cultures) to my daily diet Yuck. But, I swear it's helping...

[sue1234]

Before my POTS, I went to a holistic physician and did a few rounds of Nystatin and Diflucan for "systemic" yeast. Of course, I felt lightheaded taking all of that. I did a couple of rounds over a few years, but that was all before my POTS began. I did not really notice any difference in how I felt. At that time, I was seeing the doctor because I had no energy.

I do have a fungusy toenail. I do have itchy dandruff. And I have bloating. The couple of times I had to do the antifungals for a vaginal yeast infection, I got really lightheaded. I sat down and read all about the medication, and found it could lower cortisol levels. I assumed it was lowering mine, so hope I don't have to take it again. But, who knows?

[juliegee]

Apparently the medication causes a severe "die-off" and symptoms initially GREATLY worsen. After reading all that I have, I think I'd be better off severely adjusting my diet, upping probiotics and eating the yucky yogurt. At the point I'm at, I'll probably have anaphylaxis to the diflucan

Did your practitioner do any TESTING before putting you on the meds?

Thanks for your input, Sue-

Juie

[issie]

Julie,

Yes to allot of your symptoms. I wonder if anyone has taken allot of antibiotics. This can cause a severe overgrowth of the bad types of bacteria. I had to take a massive amount with a ruptured appendix that didn't get operated on because I didn't have insurance. That's what gave me the ulcerative colitis that I nearly died from (not to mention that I could have died from an unoperated on ruptured appendix). But, to get my gut ecology back into better shape not only did I have to do chemo (two times) to kill off the bad bacteria (along with the good) but had to do allot of diflucan and other yeast/bacterial type meds. Then LOTS and I mean LLLOOOOTTTSSSS of probiotics and kefir to get the good back in. I still have some sort of bacterial thing - but am much better. I've found a super good probiotic from NOW brand called "Probiotic 10 - 50 Billion" - it is really expensive. But, it's the best one I've EVER used and I've used allot of them. NOW has one that is a probiotic 8 - but I haven't tried that. If anyone is interested, I found a place in NJ that mail orders supplements and everything is always 30% off and NOW is usually 50% off of retail. I order all my supplements from there - PM if you want to know their phone number. I do believe there is probably a bacterial connection, but don't think this is all and everything - just a part of it.

[bensman]

I have taken Nystatin twice for extended periods of time. I also did the candida diet last winter for 3 months, while on Nystatin and also taking probiotics. At first we thought I was experiencing the die off (herxheimer reaction), but as time went on I kept getting worse and worse. It was intense. I'm not sure if I didn't do it long enough (3 months seemed like toture on the limited diet) or if there was something I was eating that I might have been reacting to. I felt better after I stopped the diet and Nystatin. Maybe I should have stuck it out longer.

Julie - My integrative doctor did testing on me. It was called a Comprehensive Stool Analysis/Parasitology Test.

[juliegee]

Interesting stuff. Thanks for your input, guys. Has anyone ever heard of anyone IMPROVING after taking the anti-fungals?

I guess I'm surmising it's beyond my gut- more systemic than that. I have to use an almost daily neti-pot with antibiotics to keep my sinus stuff at bay... Maybe because it's fungal- NOT bacterial??? The skin & vaginitis stuff this summer blew me away....very intense. THAT'S what got me thinking along this route.

It IS interesting how the symptoms between systemic mycoses & what most of us experience overlap AND that the fungus causes high levels of hydrogen sulfide that could in turn explain the renin-aldosterone paradox. Just saying ...

[issie]

I just read the text of the first listed article about Hydrogen Sulfite deactivating renin and lowering bp. For us with HyperPOTS wouldn't this be a good thing, to have higher hydrogen levels? That may explain why my body's renin is so very low - it's trying to lower my bp - since my bp stays in the high range. Am I understanding this text correctly? Someone help my brain to grasp this study. It seems very technical tonight. It appears that they are thinking that it would be wise to use hydrogen sulfite to lower bp even over ACE inhibitors. So, if that's the case - us with the high bp's wouldn't want to lower our hydrogen sulfite levels - we'd want to increase them. But, those with low bp's might want to lower hydrogen sulfite levels to raise their renin levels and thus raise their bp's. (Am I understanding this correctly?)

[lieze]

This somehow in my brain is all linking in to my sulfite sensitivity.

Sulfite is a poison in the body.

The body requires a process to break it down to a harmless state.

Most people have a sulfite limit where beyond that they start experiencing allergic responses which vary in severity.

If there is something missing in that loop of breaking down the sulfite you get symptoms.

Yes on suspected yeast issues.

Also the vaginal crap that comes and goes and sinus almost constant.

And I have the one funky toenail but guess what ?

It's growing out and looking more normal. There is only the top 1/8 maybe of the nail now that looks fungusy. I think that seems highly irregular for it to improve on it's own.

I don't know if getting out of the mold my body is able to detox better?

Severely sensitive to garlic and onion-react to just the odor in the air.

I could be way off but I think this is related.

[lieze]

To the member interested in increasing copper you'll find it in chocolate Nesquik. I consume an average of 10 tablespoons per day.

It also contains theobromine that works similar to theophyline which will make your breathing a bit better.

I guess I am self medicating.

[firewatcher]

"For us with HyperPOTS wouldn't this be a good thing, to have higher hydrogen levels? That may explain why my body's renin is so very low - it's trying to lower my bp - since my bp stays in the high range."

Since this is a study on children with POTS, I am presuming that they are more likely to be the genetic variant, instead of post-viral. I could be completely wrong. BUT...I had POTS as a child and always had incredibly LOW blood pressure whenever it was taken. Who knows what happens to the body after a lifetime of crazy autonomic stuff?! I know that my BP swings higher now than it ever has. I also don't know if this is the "chicken" or the "egg." Having high H2S could be the cause or the result.

Pure oxygen also seems to help break down H2S in the system, could that be why my Hb and Hct are so high...a compensatory mechanism? But then our H2S may be high due to chronic hypoxia in the brain....

this all goes in circles.

Edited September 20, 2011 by firewatcher

[targs66]

Funny coincidence - I've recently become interested in the fungus connection. I just went to my GP for problems relating to a fungus-y toenail which has become infected. My GP gave me an Rx for antibiotics (flucloxacillin) and when those are done, I'm supposed to take an Rx for Terbinafine (which is generic Lamisil, I think).

I read about side effects of the terbinafine/lamisil, and I am really scared of taking it -- it sounds like otherwise healthy people ended up very very ill! The site I found allowed people to post their own experiences taking various drugs. Even if their liver enzymes were normal, the symptoms they describe sound like mine on a bad day - dizziness, chronic fatigue, shakiness, terrible brain fog, weakness, etc. Plus there were all sorts of other weird things they experienced like hair loss and skin sores.

I hate to not take it if it could possibly help me -- but am so afraid of making myself worse. Has anyone ever taken an antifungal medication?

thanks!

[issie]

Maybe because it's fungal- NOT bacterial???

Mine started out as fungal and then because of the antibiotics took a really bad turn into bacterial. Then you have a combination of issues.