Aldosterone and MS

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Re: Aldosterone and MS

Postby Anonymoose » Sat Dec 22, 2012 9:58 am

These aren't the best papers/articles to support this argument, but they'll have to do for now. :P

Lack of noreinephrine activity (due to block or shortage) causes MS symptoms. Aldosterone blocks NE. Also, aldosterone causes release of bnp (link in first thread post under how complicated can this get). Bnp decreases the release of NE. So, aldosterone both blocks and indirectly reduces secretion of NE.

Other interesting leads regarding NO, etc but no time to chase them right now.

http://www.cbucommons.ca/psych/courses/ ... sclerosis/
Elevated aldosterone levels in heart failure may have a detrimental effect on the autonomic nervous system. First, aldosterone infusion directly reduced baroreceptor discharge from the carotid sinus in dog [5]. Second, aldosterone blunts the human baroreflex response [6,7]. Third, aldosterone may potentiate the effects of catecholamine [8]. Fourth, aldosterone blocks myocardial uptake of norepinephrine (NA) in vivo in an animal model [9].

Mechanisms of spironolactone include following aspects [11~13], antagonizing over-activated renin-angiotensin-system (RAS), decreasing the heart burden by diuresis, decreasing incidence of arrhythmia and sudden death from low blood potassium and magnesium, inhibiting ventricle remodeling, alleviating fibrosis of myocardial and vascular which lead to arrhythmia, increasing synthesis of nitric oxide (NO) by melioration of vascular endothelial function, increasing activity of vagus nerves and circadian rhythms of HRV, decreasing the incidence of sudden death by increase of myocardial NA uptake.


http://www.experts.scival.com/uic/pubDe ... n&u_id=612
A study by Polak, Kalinin and Feinstein (2010) looked at the reduction of the neurotransmitter norepinephrine (NE), found in the central nervous system, and damage to the locus coeruleus (LC), which produces norepinephrine in the brain stem. Neurotransmitters such as norepinephrine are chemicals used by neurons, or brain cells, to communicate with each other. The study was directed towards patients with multiple sclerosis and animals with experimental autoimmune encephalomyelitis (EAE, an animal model of MS where experimenters immunize animals and they develop symptoms closely related to MS, though the two are not exactly the same). For this study, infant female mice were injected with specific chemicals to induce EAE. After 60 days they then measured the NE levels in these mice, as well as the NE levels of humans suffering from MS. They found that both groups demonstrated reduced NE levels when compared to control groups, and the humans showed evidence of inflammation in and around the LC. These results are comparable to other studies in suggesting an alteration of NE levels in EAE cases. This suggests that loss of NE production is the cause of the decreased quantity, as opposed to other possibilities including increased metabolism or increased reuptake (reabsorption of the NE by the cells that released it). While it still can’t be determined whether low levels of norepinephrine are the cause of MS, they are at least responsible for several symptoms including memory problems, depression, and lack of arousal. Therefore, defining the cause of lowered norepinephrine levels is extremely important for these patients.
A study by Simonini and colleagues (2009) attempted to see whether increasing levels of NE in the CNS would provide any benefit in neurological diseases such as MS by decreasing inflammation. In this study, researchers injected infant female mice with EAE and altered their NE levels within the CNS in a controlled setting. Researchers used lesions in the locus coeruleus to reduce NE levels in of mice by administering a toxin that acts specifically on LC neurons. Mice were then given a reuptake inhibitor, which decreases the natural reabsorbtion of their NE. Researchers noted that after 3 weeks, there had been no changes in the severity of their EAE. Researchers then tested to see if giving the mice a precursor of NE, which their body would then turn into excess NE, would have any effects on their symptoms. They found that this neutralized their symptoms, but did not change the clinical severity of their EAE. Researchers then tested a combination of the reuptake inhibitor combined with the precursor to see if that would provide any advantage. The results of this combination proved to be quite substantial. The severity of EAE was considerably enhanced, suggesting that increasing CNS NE levels can have meaningful positive effects on EAE severity, although to achieve the full desired effects they require the combination treatment.

http://link.springer.com/article/10.102 ... 9?LI=true#
We previously demonstrated that atrial natriuretic factor and B- and C-type natriuretic peptides (ANF, BNP, and CNP, respectively) modified catecholamine metabolism by increasing the neuronal uptake and decreasing the neuronal release of norepinephrine in the rat hypothalamus
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Re: Aldosterone and MS

Postby Anonymoose » Tue Dec 25, 2012 6:28 pm

People with ACE DD genotype produce significantly more aldosterone than other ACE genotypes.
http://onlinelibrary.wiley.com/doi/10.1 ... ated=false
Angiotensin-converting enzyme I/D gene polymorphism and risk of multiple sclerosis

L. Lovrečić1, S. Ristić2, N. Starčević-Čizmarević2, S. Š. Jazbec3, J. Sepčić4, M. Kapović2, B. Peterlin1
Article first published online: 26 JUN 2006
DOI: 10.1111/j.1600-0404.2006.00711.x
Issue
Acta Neurologica Scandinavica
Volume 114, Issue 6, pages 374–377, December 2006

Objectives –  Angiotensin-converting enzyme (ACE) activity is increased in blood and cerebrospinal fluid of patients with multiple sclerosis (MS). In addition, in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, the blockade of ACE suppresses the disease itself. To analyze the genetic association of the ACE gene with MS, we examined ACE gene insertion/deletion (I/D) polymorphism in MS patients.

Materials and methods –  A total of 313 MS patients from Slovenia and Croatia and 376 healthy controls were genotyped by polymerase chain reaction method.

Results –  We found statistically significant differences in the distribution of ACE I/D allele frequencies (P < 0.01) and genotypes (P < 0.04) in male patients. ACE DD genotype was associated with MS in men at an odds ratio of 1.86 (95% CI 1.09–3.19, P = 0.02).

Conclusions –  DD genotype of ACE gene might contribute to a higher risk of developing MS in men.
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Re: Aldosterone and MS

Postby Anonymoose » Wed Dec 26, 2012 7:50 pm

The Aldo blocker used in article below was spironolactone which is known to be estrogen-like and cause gynecomastia/man tatas (second link below). Estrogen has protective qualities for the vascular endothelium in premenopausal women (third study link below) and it shifts the RAS balance towards vasodilation reducing hypertension. Perhaps the reason spironolactone does not reverse vascular damage in females is that premenopausal females already have high levels of circulating estrogen and the spironolactone doesn't make a big difference in that regard. Vascular remodeling becomes much more of an issue in postmenopausal women.

Could this be part of the reason why ms progresses faster in men? They don't have adequate levels of estrogen to protect their blood vessels from aldosterone induced damage? Does ms progress faster in women after menopause for the same reason?

Aldosterone-blocker can reverse aldosterone induced wall thickening of blood vessels in males.
http://news.georgiahealth.edu/archives/282
Hormone aldosterone is promising target for stroke treatment

Posted on November 30, 2005 by Staff

A bi-polar hormone that can contribute to strokes and
minimize their damage is emerging as a therapeutic target in the battle
against these brain attacks, researchers say.

“It costs about $56 billion a year to look after stroke
patients, never mind the quality-of-life issues for these patients,” says
Dr. Anne M. Dorrance, Medical College of Georgia physiologist and senior
author of a review article on the cover of the November issue of Trends
in Endocrinology and Metabolism.

Despite better management of blood pressure – the
number-one risk factor for strokes – stroke incidence is not declining and
aging baby boomers likely will cause rates to spike, says Dr. Dorrance.

She is among an increasing number of scientists who think
the hormone, aldosterone, is part of the problem and blocking it may be part
of the solution. Scientific momentum surrounding the hormone secreted by the
adrenal gland prompted the journal to ask Dr. Dorrance to write the article,
“Aldosterone: Good Guy or Bad Guy in Cerebrovascular Disease.”

She calls aldosterone “a double-edged sword” that helps
maintain healthy blood pressure but also dangerously reshapes blood vessels
and makes the heart fibrotic. Its conflicting roles in the body are clearly
played out in the brain of hypertensives.

“What aldosterone does under normal circumstances is
regulate sodium balance in the body,” says Dr. Dorrance. When sodium levels
rise, aldosterone levels drop so the kidneys will eliminate more sodium to
help maintain a healthy blood pressure and vice versa. “Ten years ago, we
would have told you all aldosterone does is work on the kidneys,” she says.

In recent years, Dr. Dorrance and others have learned
aldosterone works in many ways – many of them bad – inside blood vessels
throughout the body and brain where there are many aldosterone receptors.

As with most things, too much aldosterone – resulting
from an adrenal gland tumor or abnormal production for unknown reasons – is
what causes problems, such as proliferation of the smooth muscle cells that
make up the elastic walls of blood vessels. Instead of the middle filling up
with plaque as it does in atherosclerosis, the middle, or lumen, of the
blood vessel shrinks because the walls thickens. To further set the stage
for stroke, the thicker walls are less stretchy, Dr. Dorrance says.

Conversely, after a stroke, emerging evidence suggests
aldosterone helps neurons survive. “This is still a very big ‘perhaps,’ but
perhaps at the time of a stroke, it may be beneficial, but only within the
brain,” Dr. Dorrance says of high aldosterone levels. “There is a huge
caveat because aldosterone does not get into the brain terribly well.”

Other good news emerging is that adolesterone blockers,
such as spironolactone and a newer, more specific blocker eplerenone, may
help turn the tide. Spironolactone was developed as an antihypertensive
years ago but didn’t work very well, Dr. Dorrance says. Then, a University
of Michigan study in the mid-1980s showed heart failure patients who got the
drug in addition to standard treatment, such as beta blockers and ACE
inhibitors, basically stopped dying, says Dr. Dorrance, who came from the
University of Michigan to MCG as a postdoctoral fellow in 2000.

Unfortunately spironolactone also blocks testosterone so
it increased men’s breast size. Last year, a more-specific second generation
of the drug, eplerenone, received Food and Drug Adminstration approval.

Still neither version has become a medicine cabinet
mainstay. However the potential for aldosterone blockers may still be
unfolding as researchers such as Dr. Dorrance discover what the hormone does
and what blocking it prevents.

In an animal model of stroke and hypertension, Dr.
Dorrance and MCG graduate student Christine Rigsby, a paper co-author, have
shown spironolactone won’t lower blood pressure but will reverse the
wall-thickening effect of aldosterone, at least in males.

Within six weeks, “the blood vessels look like a
normotensive animal, like the animal never had high blood pressure,” says
Dr. Dorrance. “But when you block aldosterone in the females, there is no
beneficial effect,” she says of the increasingly complex story. Her lab is
looking at whether blockers become protective after menopause.

Gender difference hold up in aldosterone’s effect on the
heart as well. One of the many findings of the Framingham Heart Study, a
long-term study of thousands of residents in a Boston suburb, was that in
women, higher levels of aldosterone correlate with worsening enlargement of
the pumping chamber of the heart. “That does not mean aldosterone doesn’t
impact a man’s heart in some way, but it’s definitely not as direct an
effect,” says Dr. Dorrance.

“We are literally at the tip of the iceberg,” she says.
Some scientists suspect the level of adolsterone receptors, not the hormone
level, may be the real culprit.

Either way, there is little doubt aldosterone’s obscurity
is over. “I think we are beginning an extremely complicated and terribly
exciting 10 to 15 years of research as we try to unravel what is happening
and why,” she says. “I think at the end, there will be better drugs and
better information so clinicians will know when patients would benefit from
these aldosterone blockers.”

Part of the excitement will come in identifying the
pathways of aldosterone’s many actions. Dr. Dorrance thinks a relationship
between aldosterone and epidermal growth factor, for example, causes the
dangerous thickening of blood vessel walls in the brain. “It’s not just a
blood pressure-dependent effect. This is something that is much more active
than that. I do get up in the middle of the night wondering why it happens.
It fascinates me.”

Dr. William E. Cannady, an MCG School of Medicine
graduate who worked in Dr. Dorrance’s lab, also is a paper co-author.

http://www.cmaj.ca/content/176/5/620.2.short
Spironolactone-induced gynecomastia

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831126/
These findings indicate that E2 (estrogen)can preserve endothelial mitochondrial function and provide protection against ischemic injury through ER-mediated mechanisms.

http://ajpregu.physiology.org/content/273/6/R1908.short
Estrogen protects transgenic hypertensive rats by shifting the vasoconstrictor-vasodilator balance of RAS
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Re: Aldosterone and MS

Postby Anonymoose » Sat Dec 29, 2012 8:06 pm

Aldosterone and spasticity?

http://circ.ahajournals.org/content/109/10/1284.short
The results implicate aldosterone as a major link between sarcomeric mutations and cardiac phenotype in HCM and, if confirmed in additional models, signal the need for clinical studies to determine the potential beneficial effects of MR blockade in human HCM.

http://onlinelibrary.wiley.com/doi/10.1 ... 1063.x/pdf
Interestingly, the muscle fibers from patients with spasticity were over twice as stiff (based on tangent modulus) as the fibers from the patients without spasticity. Furthermore, the resting sarcomere length (i.e. the length of the sarcomeres when the muscle cell was completely unloaded) was significantly shorter in spastic muscle cells compared with normal cells. These two findings suggest that the structures within the muscle cell responsible for setting resting sarcomere length 53 and determining cellular stiffness are altered in spastic muscle. The most obvious candidate for this structure is the giant intracellular cytoskeletal protein, titin. 54
In frog skeletal muscles, titin has been demonstrated to bear almost the entire elastic load during passive elongation, and bears significant passive load in human muscle. 55 There are no definitive data demonstrating that titin is actually altered secondary to spasticity but there is circumstantial evidence to suggest that it is possible. It is known, based on the differences in complementary DNA sequences, that titin can exist in multiple isoforms in heart and skeletal muscles. 54 It is also known that the titin isoform in heart muscle is substantially stiffer and shorter than the titin isoforms in most skeletal muscles. Furthermore, it has been demonstrated that the titin isoform can change within heart muscle under pathological conditions. 56 As an example of the ability of the titin isoform to change, ischemia-induced cardiomyopathy increases myocardial stiffness secondary to up-regulated collagen expression. In addition to collagen proliferation, however, investigators discovered a ‘switch’ from a compliant to a stiffer isoform of titin. 56
It is, therefore, reasonable to speculate that titin isoforms may be altered in skeletal muscles of patients with spastic limbs, although definitive demonstration of this change has not been reported. Investigations into the alterations that occur in titin in spastic skeletal muscle certainly seem warranted.

need to find missing links...
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Re: Aldosterone and MS

Postby Anonymoose » Sun Dec 30, 2012 11:09 am

Cardiac muscles have n2b and n2ba titan isoforms. N2ba is described as a more compliant isoform and n2b is the stiffer isoform. Aldosterone appears to increase n2b and decrease n2ba yielding a stiffer, less compliant muscle (as seen in spasticity). While n2b and n2ba titins are only found in cardiac muscle, aldosterone may have similar influence on titin isoforms in skeletal muscles. Still trying to dig that up...

http://link.springer.com/content/pdf/10 ... 007-6057-8
Long-term therapy with eplerenone significantly increased mRNA expression of N2BA-titin isoform and decreased mRNA expression of N2B-titin isoforms to near NL levels
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Re: Aldosterone and MS

Postby CaliReader » Tue Jan 01, 2013 11:29 am

Anonymoose, thanks for all the background information. There is a lot to digest here.

Your link re norepinephrine sent me on a tangent. I had been considering adding an SSRI anti-depressant because of the prozac study showing effect on disease activity and for my husband's benefit. Apparently MS related depression is often reported as the number one most difficult issue for spouses, significant others and care givers to cope with.

Now, given norepinephrine's documented role in MS, I think I will ask for an SNRI instead. It can't hurt, assuming I can cope with the side effects. I'm 43 and spent my previous life avoiding drugs and doctors. Ugh.

I don't have high blood pressure. If anything it's too low, so I don't think I will be able to successfully ask for an antihypertension drug.

The hormonal connections to MS are a fascinating tapestry of interconnected stuff. I'm only 3 months in to my MS related studies, but I can't help but thinking that changing the abnormal hormone levels could be a back door step toward more effective treatment.
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Re: Aldosterone and MS

Postby Anonymoose » Tue Jan 01, 2013 2:28 pm

Hey Cali,

I've spent a lifetime avoiding doctors and drugs too. I knew I had MS for 2.5 years before I actually went to a neurologist. :P

Jumping into anti-depressants is a pretty big deal for someone who isn't excited about taking meds. I've never taken anti-D's but know that it is HARD to get off them once you start. And it is HARD to find the one that works. They also come with a slew of bad side effects. I did a quick google and found indications (not great sources so not linking) that ssri's increase production of aldosterone. Have you tried St. Johns Wort? It allegedly reduces cortisol secretion and depression. Exercise? Chocolate? Accupuncture? Anything but the Anti-D's (unless you are really, really seriously clinically depressed). Sometimes depression isn't "depression." Sometimes it's having healthy, normal reactions to life events that shake our foundations and force us to redefine our course and expectations.

As for having borderline low blood pressure, I'm not sure taking an aldosterone blocker would necessarily negatively impact your blood pressure status. There are other mechanisms in the body that control blood pressure and they would likely take over to compensate for any effect (other than K/Na balance) an aldosterone block would have. Eplerenone not only blocks aldosterone, it blocks cortisol from docking in MR receptors and triggering reactions. So your concern about excess cortisol could be addressed to a degree as well. They can fine tune the dosage you take by measuring K and blood pressure too. I don't have a blood pressure issue (that I know of...lol) and my neurologist is comfortable prescribing eplerenone for me. Another thing to keep in mind is that aldosterone is blocked greatly by progesterone during most normal pregnancies and the body somehow copes.

The endocrine system is amazingly intricate and "they" aren't even aware of all of the ways hormones work within our bodies. It's a goldmine of possibilities for treatment of any number of disorders and diseases. I definitely see treatments for MS happening through endocrinology within the next ten years. Oh what an exciting time to have MS! <--sarcasm...kind of. :)
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Re: Aldosterone and MS

Postby Anonymoose » Wed Jan 02, 2013 8:42 am

Efonidipine/Landel...another option for reducing aldosterone-related damage. Bonus factors: No risk of hyperkalemia AND it reduces cortisol secretion as well. I might be asking my neurologist for this instead of eplerenone.

**edit efonidipine not available in us. Will have to look at other calcium channel blockers.

http://journals.lww.com/cardiovascularp ... ne.19.aspx
Inhibitory Effect of Efonidipine on Aldosterone Synthesis and Secretion in Human Adrenocarcinoma (H295R) Cells
Imagawa, Keiichi PhD; Okayama, Satoshi MD; Takaoka, Minoru MD; Kawata, Hiroyuki MD, PhD; Naya, Noriyuki; Nakajima, Tamio MD; Horii, Manabu MD; Uemura, Shiro MD, PhD; Saito, Yoshihiko MD, PhD

Abstract
Targeting aldosterone synthesis and/or release represents a potentially useful approach to the prevention of cardiovascular disease. Aldosterone production is stimulated by angiotensin II (Ang II) or extracellular K+ and is mediated mainly by Ca2+ influx into adrenal glomerulosa cells through T-type calcium channels. We therefore examined the effects of efonidipine, a dual T-type/L-type Ca2+ channel blocker, on aldosterone secretion in the H295R human adrenocarcinoma cell line; 100 nmol/L Ang II and 10 mmol/L K+ respectively increased aldosterone secretion from H295R cells 12-fold and 9-fold over baseline. Efonidipine dose-dependently inhibited both Ang II- and K+-induced aldosterone secretion, and nifedipine, an L-type Ca2+ channel blocker, and mibefradil, a relatively selective T-type channel blocker, similarly inhibited Ang II- and K+-induced aldosterone secretion, but were much less potent than efonidipine. Efonidipine also lowered cortisol secretion most potently among these drugs. Notably, efonidipine and mibefradil also significantly suppressed Ang II- and K+-induced mRNA expression of 11-β-hydroxylase and aldosterone synthase, which catalyze the final two steps in the aldosterone synthesis, whereas nifedipine reduced only K+-induced enzyme expression. These findings suggest that efonidipine acts via T-type Ca2+ channel blockade to significantly reduce aldosterone secretion, and that this effect is mediated, at least in part, by suppression of 11-β-hydroxylase and aldosterone synthase expression.



More recent paper
http://www.hindawi.com/journals/ije/2012/519467/
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Re: Aldosterone and MS

Postby CaliReader » Wed Jan 02, 2013 1:08 pm

Thanks for the reply. I'm taking your advice for now re anti-D' meds. Haven't yet started taking any drugs, but this is an intimidating challenge we face.

I will look forward to hearing how the anti-aldosterone treatment works for you.
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Re: Aldosterone and MS

Postby Anonymoose » Wed Jan 02, 2013 4:24 pm

Oh this is making me mad. Yet another good CCB not available in US. Suppresses cortisol too. My son says he won't move to Japan for this. :roll: Incidentally, if you are interested in the types of ccbs and how they work, this is a great paper for learning.
http://cdn.intechopen.com/pdfs/34158/In ... e_drug.pdf
Dual L/N-Type Ca2+ Channel Blocker: Cilnidipine as a New Type of Antihypertensive Drug 33
Mode of action
Inhibition of L-type Ca2+ channels (vascular smooth muscle, in vitro); inhibition of N-type Ca2+ channels (sympathetic neuron, in vitro)
Pharmacology
1) Cardiovascular action
Vascular relaxation (in vitro); hypotensive action (in vivo)
2) Anti-sympathetic action
Decrease of catecholamine release, tissue (kidney) norepinephrine level, (in vitro, in vivo); inhibition of sympathetic tachycardia and cold stress-induced vasoconstriction (in vivo); decrease in plasma/urinary norepinephrine, muscle sympathetic nerve activity, low frequency/high frequency ratio (LF/HF ratio), and plasma level of ß-thromboglobulin (clinical)
3) Suppression of renin- angiotensin-aldosterone system
Decrease in plasma level of angiotensin II and aldosterone (in vivo, clinical); inhibition of aldosterone production (adrenocortical cells, in vitro); inhibition of reflex aldosterone production, and angiotensin II-renin feedback (in vivo)
4) Anti-oxidation
Inhibition of NADPH oxidase-derived superoxide production (kidney, in vivo)
5) Others
Improvement of insulin resistance (in vivo); increases of nitric oxide production (in vitro); protection from retinal neuronal injury (in vivo); anti-nociception (in vivo)
Antihypertensive action
1) Animal model
Antihypertensive action in spontaneously hypertensive rats, stroke-prone spontaneously hypertensive rat, renal hypertensive rats, DOCA-salt hypertensive rats, Otsuka Long-Evans Tokushima Fatty rat, Dahl salt sensitive rat and 2-kidney 1-clip hypertensive dogs (in vivo)
2) Human
Essential hypertension; severe hypertension; hypertension with chronic kidney disease, cerebrovascular disease or diabetes (clinical)
Actions in key organs
1) Kidney
Increase in renal blood flow; dilation of afferent and efferent arterioles; natriuresis; inhibition of renal nerve stimulation- induced antinatriuresis; suppression of albuminuria; glomerular hypertrophy and interstitial fibrosis; decrease in renal angiotensin II content (in vivo); decrease in albuminuria and urinary protein (clinical)
2) Heart
Increase in coronary blood flow (in vitro, in vivo); suppression of vasopressin-induced ST depression; reduction of the myocardial infarct size and incidence of ventricular premature beats after ischemia-reperfusion; abbreviation of abnormally prolonged ventricular repolarization (in vivo); decrease in BNP, LV mass index, heart rate and cardiothoracic ratio (clinical)
3) Brain
Downward shift of the lower limit of autoregulation for cerebral blood flow; reduction of the cerebral infarction size (in vivo); increase in cerebral blood flow (clinical)
Table 1. Summary of pharmacological effects of cilnidipine
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Re: Aldosterone and MS

Postby Anonymoose » Thu Jan 03, 2013 3:24 pm

Yay! Something less scary than CCBs in the pipeline. LCI699, an aldosterone synthase inhibitor that reduces cortisol as well. LCI699 is in phase II trials in the US (and many other countries). I wish they would hurry up and pass it through!

Current and completed US clinical trials http://clinicaltrials.gov/ct2/results?t ... rch=Search

http://www.ncbi.nlm.nih.gov/pubmed/22947355
The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: a phase II, randomized, double-blind, placebo-controlled, multicenter study.
Andersen K, Hartman D, Peppard T, Hermann D, Van Ess P, Lefkowitz M, Trapani A.
Source
Encode Clinic, Reykjavik, Iceland. andersen@landspitali.is
Abstract
Blockade of the renin-angiotensin-aldosterone system (RAAS) is an established method to lower blood pressure in patients with hypertension. Aldosterone, the end product of the RAAS cascade, acts by increasing salt reabsorption in the kidney and catecholamine release from the adrenal medulla. Currently available aldosterone inhibitors have the disadvantage of increasing circulating aldosterone and thus may lead to aldosterone breakthrough. Aldosterone synthase inhibition (ASI) is a novel approach to suppressing the RAAS. Due to homology between the enzymes responsible for aldosterone synthesis (CYP11B2) and cortisol synthesis (CYP11B1), the blockade of aldosterone synthesis may also suppress cortisol release. The authors evaluated the effect of the novel ASI LCI699 on the cortisol response to adrenocorticotropic hormone (ACTH) stimulation in patients with hypertension in order to find the maximally tolerated dose (MTD) in this patient population. Among the 63 patients evaluated, there was a dose- and time-dependent effect of LCI699 on both aldosterone and ACTH-stimulated cortisol. Based on exposure-response analysis, the MTD was estimated to be 1.30 mg once daily with a 90% prediction interval of 0.88 mg once daily to 1.81 mg once daily. No patients required intervention for adrenal insufficiency. LCI699 was well tolerated with no serious adverse events.
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Re: Aldosterone and MS

Postby Anonymoose » Fri Jan 04, 2013 3:52 pm

Aldosterone and IL-1

IL-1 induces a surge in ACTH, which triggers aldosterone and cortisol production (abstract below). IL-1 inhibits aldosterone production via RAAS but not ACTH. (http://endo.endojournals.org/content/125/6/3084.short) Aldosterone increases IL-1 production which triggers more ACTH release which triggers more aldosterone. Cortisol is supposed to stop the release of ACTH (http://courses.washington.edu/conj/bess ... dback.html). But, if IL-1 stimulates ACTH in hypothalamus and pituitary glands directly (bypassing CRH) as a result of MS lesion suppressed CRH neurons (ref below), cortisol cannot stop the production of ACTH and resulting cortisol and aldosterone.

Would blocking aldosterone keep the hpa axis dysregulation from getting too far out of control??

http://www.sciencedirect.com/science/ar ... 1X84710709
Induction of Pituitary Sensitivity to Interleukin-1: A New Function for Corticotropin-Releasing Hormone
L.C. Payne, D.A. Weigent, J.E. Blalock
Univ Alabama, Dept Physiol & Biophys, Birmingham, AL 35294, USA and Univ Alabama, Ctr Neuroimmunol, Birmingham, AL 35294, USA
http://dx.doi.org/10.1006/bbrc.1994.1070, How to Cite or Link Using DOI

Abstract
Activation of the hypothalamic-pituitary-adrenal axis to release corticotropin-releasing hormone (CRH), corticotropin (ACTH), and glucocorticoids during inflammatory stress is now considered a key function of interleukin-1 (IL-1). Current dogma suggests that in vivo ACTH release due to IL-1 is indirect and entirely results from IL-imediated-CRH release from the hypothalamus. The present findings show that low levels of exogenous or endogenous CRH can sensitize the pituitary gland to the direct ACTH releasing activity of IL-1. Once sensitized, IL-1 induced ACTH release is not inhibitable by the CRH antagonist, α-helical (αh) CRF [9-41]. Thus, IL-1 effects ACTH release at the level of both the hypothalamus and pituitary gland. Perhaps more importantly, the results suggest pituitary sensitization to cytokines, such as IL-1, as a new function for CRH. This action would represent a novel interactive point between the nervous, endocrine, and immune systems whereby very mild psychological or physical stress could have a profound impact on an inflammatory response by increasing pituitary sensitivity to immunological mediators such as IL-1.


Read for general understanding...LONG! From 1999 so not up to date but good explanation.
Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action
http://physrev.physiology.org/content/79/1/1.full

http://cjasn.asnjournals.org/content/4/10/1685.full
High aldosterone levels are associated with inflammatory markers, including IL-6, IL-1 β, monocyte chemo-attractant protein-1, reactive oxygen species, increased type IV collagen production, and alterations of plasminogen activator inhibitor and osteopontin expression (26,33–35).

http://www.direct-ms.org/pdf/Immunology ... 20axis.pdf
Preliminary data show suppression of the activation of CRH neurons by active hypothalamic MS lesions.

http://archneur.jamanetwork.com/article ... eid=773552
patients with multiple sclerosis had higher scores on depression and anxiety scales and exhibited a failure of suppression of cortisol release after dexamethasone pretreatment.
This indicates that CRH is probably being bypassed in pwMS.
Last edited by Anonymoose on Fri Jan 04, 2013 6:14 pm, edited 1 time in total.
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Re: Aldosterone and MS

Postby lyndacarol » Fri Jan 04, 2013 5:40 pm

I am particularly interested in "High aldosterone levels are associated with inflammatory markers, including IL-6…"

This cytokine seems to come up quite often in my reading.
My hypothesis: excess insulin (hyperinsulinemia) plays a major role in MS, as developed in my initial post: http://www.thisisms.com/forum/general-discussion-f1/topic1878.html "Insulin – Could This Be the Key?"
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lyndacarol
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Re: Aldosterone and MS

Postby Anonymoose » Sat Jan 05, 2013 10:37 am

Another genetic influence on aldosterone levels
http://onlinelibrary.wiley.com/doi/10.1 ... ated=false
Effect of variation in CYP11B1 and CYP11B2 on corticosteroid phenotype and hypothalamic–pituitary–adrenal axis activity in hypertensive and normotensive subjects

E. M. Freel1, M. Ingram1, A. M. Wallace2, A. White3, R. Fraser1, E. Davies1, J. M. C. Connell1
Article first published online: 2 NOV 2007

DOI: 10.1111/j.1365-2265.2007.03116.x

© 2007 The Authors
Issue
Clinical Endocrinology
Volume 68, Issue 5, pages 700–706, May 2008


Summary
Background  Aldosterone is important in the development of hypertension. We have shown that a single nucleotide polymorphism (SNP) (–344T) in the 5′ regulatory region (UTR) of the gene encoding aldosterone synthase (CYP11B2) associates with aldosterone excess and hypertension as well as altered adrenal 11-hydroxylation efficiency (deoxycortisol to cortisol). This conversion is carried out by the enzyme 11β-hydroxylase, encoded by the adjacent gene, CYP11B1. We proposed that the effects of CYP11B2 are explained by linkage disequilibrium (LD) across the CYP11B locus. We have demonstrated high LD across this locus and identified two SNPs in the 5′ UTR of CYP11B1 (–1859 G/T, –1889 A/G) that associate with reduced transcription in vitro and altered 11-hydroxylation efficiency in vivo. Accordingly, we hypothesized that the reduced adrenal 11-hydroxylation may lead to chronic resetting of the pituitary–adrenal axis, with chronically increased ACTH drive resulting in aldosterone excess.

Methods  To test this, we examined hypothalamic–pituitary–adrenal (HPA) axis activity in hypertensive and normotensive individuals stratified according to genotype at CYP11B2 (–344T/C) and CYP11B1 (–1859 G/T, –1889 A/G). Fifty-six subjects homozygous for CYP11B2 SNP (27 TT, 12 CC), and 38 homozygous for CYP11B1 SNPs (18 TTGG, 20 GGAA) were recruited. Diurnal variation and the effects of dexamethasone suppression and ACTH stimulation on plasma aldosterone, cortisol and ACTH under controlled conditions were studied.

Results  Subjects with SNPs associated with reduced 11-hydroxylation efficiency (–344T CYP11B2; TTGG CYP11B1) showed reduced inhibition of ACTH after dexamethasone (P = 0·05) and an altered cortisol–ACTH relationship (decreased cortisol–ACTH ratio, P < 0·02). The same individuals also demonstrated close correlations between plasma cortisol and aldosterone (–344T CYP11B2 r = 0·508, P < 0·004; TTGG CYP11B1 r = 0·563, P < 0·003) suggesting that there was common regulation (possibly ACTH) of these hormones in genetically susceptible subjects.

Conclusions  Variation in CYP11B2 and CYP11B1 associates with chronic up-regulation of the HPA axis. These novel data support the suggestion that chronic aldosterone excess, in genetically susceptible individuals, may be a consequence of increased ACTH drive to the adrenal and identify novel molecular mechanisms that may lead to the development of hypertension within the general population.

Last edited by Anonymoose on Sat Jan 05, 2013 10:42 am, edited 1 time in total.
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Re: Aldosterone and MS

Postby Anonymoose » Sat Jan 05, 2013 10:41 am

Eplerenone reduces proinflammatory cytokines and hypothalamic activation.
http://circres.ahajournals.org/content/99/7/758.short
Novel Effect of Mineralocorticoid Receptor Antagonism to Reduce Proinflammatory Cytokines and Hypothalamic Activation in Rats With Ischemia-Induced Heart Failure
Yu-Ming Kang, Zhi-Hua Zhang, Ralph F. Johnson, Yang Yu, Terry Beltz, Alan Kim Johnson, Robert M. Weiss, Robert B. Felder
+ Author Affiliations

From the Departments of Internal Medicine (Y.-M.K., Z.-H.Z., Y.Y., R.M.W., R.B.F.) and Psychology (R.F.J., T.B., A.K.J.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa; and Veterans Affairs Medical Center (R.M.W., R.B.F.), Iowa City.
Correspondence to Robert B. Felder, MD, University of Iowa College of Medicine, E318-GH, 200 Hawkins Dr, Iowa City, IA 52242. E-mail robert-felder@uiowa.edu
Abstract

Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-α in heart failure (HF) rats. TNF-α and other proinflammatory cytokines activate neurons in the paraventricular nucleus (PVN) of hypothalamus, including corticotropin-releasing hormone (CRH) neurons, by inducing cyclooxygenase (COX)-2 activity and synthesis of prostaglandin E2 by perivascular cells of the cerebral vasculature. We tested the hypothesis that systemic treatment with a MR antagonist would reduce hypothalamic COX-2 expression and PVN neuronal activation in HF rats. Rats underwent coronary ligation to induce HF, confirmed by echocardiography, or sham surgery, followed by 6 weeks treatment with eplerenone (30 mg/kg per day, orally) or vehicle (drinking water). Eplerenone-treated HF rats had lower plasma TNF-α, interleukin (IL)-1β and IL-6, less COX-2 staining of small blood vessels penetrating PVN, fewer PVN neurons expressing Fra-like activity (indicating chronic neuronal activation), and fewer PVN neurons staining for TNF-α, IL-1β, and CRH than vehicle-treated HF rats. COX-2 and CRH protein expression in hypothalamus were 1.7- and 1.9-fold higher, respectively, in HF+vehicle versus sham+vehicle rats; these increases were attenuated (26% and 25%, respectively) in HF+eplerenone rats. Eplerenone-treated HF rats had less prostaglandin E2 in cerebrospinal fluid, lower plasma norepinephrine levels, lower left ventricular end-diastolic pressure, and lower right ventricle/body weight and lung/body weight ratios, but no improvement in left ventricular function. Treatment of HF rats with anticytokine agents, etanercept or pentoxifylline, produced very similar results. This study reveals a previously unrecognized effect of MR antagonism to minimize cytokine-induced central neural excitation in rats with HF.
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