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Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2361-6. Epub 2007 Jul 6.

Zinc dyshomeostasis in rats with aldosteronism. Response to spironolactone.

Thomas M, Vidal A, Bhattacharya SK, Ahokas RA, Sun Y, Gerling IC, Weber KT.


Source

Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.


Abstract

Zinc is a structural constituent of many proteins, including Cu/Zn superoxide dismutase (SOD), an endogenous antioxidant enzyme. Hypozincemia has been found in patients hospitalized with congestive heart failure, where neurohormonal activation, including the renin-angiotensin-aldosterone system (RAAS), is expected and oxidative stress is present. This study was undertaken to elucidate potential pathophysiological mechanisms involved in Zn dyshomeostasis in aldosteronism. In rats receiving aldosterone/salt treatment (ALDOST) alone for 1 and 4 wk or in combination with spironolactone (Spiro), an ALDO receptor antagonist, we monitored 24-h urinary and fecal Zn excretion and tissue Zn levels in heart, liver, and skeletal muscle, together with tissue metallothionein (MT)-I, a Zn(2+)-binding protein, and Cu/Zn-SOD activities in plasma and tissues. When compared with unoperated, untreated, age-/sex-matched controls, urinary and, in particular, fecal Zn losses were markedly increased (P < 0.05) at days 7 and 28 of ALDOST, leading to hypozincemia and a fall (P < 0.05) in plasma Cu/Zn-SOD activity. Microscopic scars and perivascular fibrosis of intramural coronary arteries first appeared in the right and left ventricles at week 4 of ALDOST and were accompanied by increased (P < 0.05) tissue Zn, MT-I, and Cu/Zn-SOD activity, which were not found in uninjured liver or skeletal muscle. Spiro cotreatment prevented cardiac injury and Zn redistribution to the heart. Thus increased urinary and fecal Zn losses, together with their preferential translocation to sites of cardiac injury, where MT-I overexpression and increased Cu/Zn-SOD activity appeared, contribute to Zn dyshomeostasis in rats with aldosteronism, which were each prevented by Spiro. These findings may shed light on Zn dyshomeostasis found in patients with decompensated heart failure.

cheerleader wrote:Looking at the cellular factors in the breakdown of the cerebral endothelium is certainly a worthwhile pursuit, and there are labs around the world doing this. But it's important to understand that Dr. Zamboni's theory involves the mechanisms of shear stress, which are hindered by venous reflux, venous congestion and endothelial dysfunction.

This process breaks down the tight junctions of endothelial cells, and allows plasmic particles access into brain tissue. Inhibiting these plasmic particles is one way to solve the problem of a permeable BBB....but understanding the mechanistic nature of blood flow, and the importance of laminer shear stress is another.

BBB endothelial cells in vivo are continuously exposed to laminar shear stress to which they respond by structural (cell orientation with flow direction; redistribution of cell fibers and flattening) and functional remodeling showing significant evidences of differentiation [21-24].

One of the main functions of the BBB is shielding of the brain from unwanted and potentially harmful substances. Tight junction protein complexes provide a mechanical means to seal the paracellular pathways between adjacent endothelial cells [8,24]. Our study shows that exposure to flow increases the RNA levels of genes encoding for a variety of tight junctional proteins (see Figure 1A) including the intracellular scaffold proteins Zonula occludens-1 (ZO1) and 2 (ZO-2) which link the junctional molecules claudin and occludin to intracellular actin and the cytoskeleton. Claudin 3, 5 and actin gene espression were also upregulated by the exposure to laminar shear stress thus strongly suggesting that acting as a key regulator of TJ expression. In addition to TJ protein upregulation we also found a significant increase the RNA and protein levels of several cadherins. These are a class of type-1 transmembrane proteins which play important roles in cell adhesion, through the formation of adherens junctions. Our data showed the up-regulation of N-, P- and VE-cadherin. We also observed an increase in the RNA and protein levels of E-cadherin. However, even though the upregulation of E-cadherin (commonly though not exclusively expressed in epithelial cells [25,26]) was statistically significant; its overall RNA and total protein expression levels were very modest in comparison to that of the other adherens junction components.

The result is the formation of tight barrier with high trans-endothelial electrical resistance that can efficiently discriminate the passage of substances according to their permeability coefficient. In the absence of intraluminal flow despite the presence of abluminal astrocytes the resulting barrier is much less stringent and does not provide selective permeability (Figure 1D). This demonstrates that glial stimuli are important but not sufficient to establish a functional BBB and that exposure to flow provides the missing modulatory element to enable BBB properties.

http://www.biomedcentral.com/1471-2202/12/40

Flow maintains the BBB. Hypoperfusion damages the BBB. Dr. Zamboni's theory is suggesting that we can we increase perfusion, shear stress and cerebral endothelial function by repairing venous malformations and improving venous return. Which is stepping back from the cellular discussion, and looking at the mechanism.
Flow.
cheer

VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown
Azeb Tadesse Argawa, Blake T. Gurfeina, Yueting Zhanga, Andleeb Zameera and Gareth R. Johna,b,1
Author Affiliations

Edited by Berislav Zlokovic, University of Rochester Medical Center, Rochester, NY, and accepted by the Editorial Board December 5, 2008 (received for review September 2, 2008)


Abstract
Breakdown of the blood-brain barrier (BBB) is an early and significant event in CNS inflammation. Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5) and occludin (OCLN) as targets of VEGF-A action. Down-regulation of CLN-5 and OCLN accompanied up-regulation of VEGF-A and correlated with BBB breakdown in experimental autoimmune encephalomyelitis, an animal model of CNS inflammatory disease. In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA. In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function. Importantly, functional studies revealed that expression of recombinant CLN-5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in paracellular permeability, whereas recombinant OCLN expressed under the same promoter was not protective. Previous studies have shown CLN-5 to be a key determinant of trans-endothelial resistance at the BBB. Our findings suggest that its down-regulation by VEGF-A constitutes a significant mechanism in BBB breakdown.

I've been studying the results of CCSVI treatment for months and it's led me to feel that CCSVI is not the cause of MS. Rather, it's another symptom/result of a biological malfunction that is causing a wide range of MS symptoms, including symptoms we don't even attribute to MS. I am sure there are any number of people out there with shear stress abnormalities who do NOT have MS. There is a missing piece in the CCSVI/MS puzzle. I want to find that piece because, frankly, CCSVI surgery scares the benoodles out of me.

Forgot to tie up the aldosterone-CCSVI package neatly...aldosterone can cause vascular hypertension which can and does over time damage valves. Damaged valves are implicated in CCSVI. Also, is it possible that the narrowed veins are chronically constricted due to baroreflex/sympathetic nervous system dysfunction? Do they react to baroreflex tests or other means of dilation/constriction?

Cece wrote:How does hypertension damage valves? I would be interested in this.
Baroreflex tests, interesting. The narrowed veins have been shown in Zamboni's research to have abnormal levels of collagen. If the collagen stiffens the vein, that could make it more constricted? Sympathetic nervous system dysfunction is a possibility but it does not cause sudden cut-offs in the outflow. My own MRV shows pretty good-looking veins on both sides coming to a sudden stop where the valve abruptly blocked the flow. That's not a case of constriction throughout the vein, but singular outflow obstructions in each vein.

Hypertension-induced venous valve remodeling ☆

Presented as a poster at the Fifteenth Annual Meeting of the American Venous Forum, Cancún, Mexico, Feb 20-23, 2003.
Shinya Takase, MDa,
Luigi Pascarella, MDb,
John J Bergan, MDb, , ,
Geert W Schmid-Schönbein, PhDa
Abstract

Introduction

In human beings, chronic venous insufficiency is linked to venous hypertension. This in turn is associated with venous valve incompetence. This study was designed to test the hypothesis that venous hypertension serves to initiate a process that results in the venous valve and venous wall damage observed in venous insufficiency.



Conclusion

This study indicates that acute venous hypertension is accompanied by significant venous distention and some valve damage as early as 3 weeks after fistula creation. Inflammatory markers appear, along with leukocyte infiltration and increased adhesion molecule expression. We could not detect significant enhancement of MMP levels or nuclear transcription factors NFκB. It is uncertain whether this lack of evidence may be partially due to the enhanced apoptosis in venous valves and vein wall. Further details of the inflammatory cascade during venous hypertension need to be studied to improve current interventions.

Basal and ACTH-Stimulated Plasma Aldosterone Concentrations are Normal or Increased in Dogs With Trichuriasis-Associated Pseudohypoadrenocorticism

Thomas K. Graves1,†,
William D. Schall1,
Kent Refsal2,
Raymond F. Nachreiner2

Article first published online: 28 JUN 2008
We measured plasma concentrations of Cortisol and aldosterone before and after administration of adrenocorticotropin (ACTH) in dogs with trichuriasis. These dogs had physical examination, historical, and serum electrolyte findings suggestive of hypoadrenocorticism; trichuriasisassociated pseudohypoadrenocorticism has been reported previously. We found normal basal and ACTH-stimulated plasma Cortisol concentrations. Basal and ACTH-stimulated plasma aldosterone concentrations were normal in 2 dogs and increased in 3 dogs, suggesting that the electrolyte abnormalities seen in this clinical syndrome are not due to aldosterone deficiency.

Neurokinin B Acts via the Neurokinin-3 Receptor in the Retrochiasmatic Area to Stimulate Luteinizing Hormone Secretion in Sheep

Heather J. Billings,
John M. Connors,
Stephanie N. Altman,
Stanley M. Hileman,
Ida Holaskova,
Michael N. Lehman,
Christina J. McManus,
Casey C Nestor,
Britni H. Jacobs and
Robert L. Goodman

- Author Affiliations

Departments of Neurobiology and Anatomy (H.J.B.) and Physiology and Pharmacology (J.M.C., S.N.A., S.M.H., I.H., C.J.M.; C.CN., B.H.J., R.L.G.), Robert C. Byrd Health Sciences Center, Morgantown, West Virginia 26506-9128; and Department of Anatomy and Cell Biology (M.N.L.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1

Address all correspondence and requests for reprints to: Heather J. Billings, Ph.D., Department of Neurobiology and Anatomy, West Virginia University, Health Sciences Center, P.O. Box 9128, Morgantown, West Virginia 26506-9128. E-mail: hbillings@hsc.wvu.edu.


Abstract

Recent data have demonstrated that mutations in the receptor for neurokinin B (NKB), the NK-3 receptor (NK3R), produce hypogonadotropic hypogonadism in humans. These data, together with reports that NKB expression increases after ovariectomy and in postmenopausal women, have led to the hypothesis that this tachykinin is an important stimulator of GnRH secretion. However, the NK3R agonist, senktide, inhibited LH secretion in rats and mice. In this study, we report that senktide stimulates LH secretion in ewes. A dramatic increase in LH concentrations to levels close to those observed during the preovulatory LH surge was observed after injection of 1 nmol senktide into the third ventricle during the follicular, but not in the luteal, phase. Similar increases in LH secretion occurred after insertion of microimplants containing this agonist into the retrochiasmatic area (RCh) in anestrous or follicular phase ewes. A low-dose microinjection (3 pmol) of senktide into the RCh produced a smaller but significant increase in LH concentrations in anestrous ewes. Moreover, NK3R immunoreactivity was clearly evident in the RCh, although it was not found in A15 dopaminergic cell bodies in this region. These data provide evidence that NKB stimulates LH (and presumably GnRH) secretion in ewes and point to the RCh as one important site of action. Based on these data, and the effects of NK3R mutations in humans, we hypothesize that NKB plays an important stimulatory role in the control of GnRH and LH secretion in nonrodent species.

Hyperaldosteronism - primary and secondary

Primary and secondary hyperaldosteronism are conditions in which the adrenal gland releases too much of the hormone aldosterone.

Causes

People with primary hyperaldosteronism have a problem with the adrenal gland that causes it to release too much aldosterone.

In secondary hyperaldosteronism, the excess aldosterone is caused by something outside the adrenal gland that mimics the primary condition.

Primary hyperaldosteronism used to be considered a rare condition, but some experts believe that it may be the cause of high blood pressure in some patients. Most cases of primary hyperaldosteronism are caused by a noncancerous (benign) tumor of the adrenal gland. The condition is most common in people ages 30 - 50.

Secondary hyperaldosteronism is usually due to high blood pressure. It is also related to disorders such as:
•Cirrhosis of the liver
•Heart failure
•Nephrotic syndrome

Symptoms
•Fatigue
•Headache
•Muscle weakness
•Numbness
•Paralysis that comes and goes

Influence of Antiopioids on Luteinizing Hormone Pulsatility in Aging Men*

A. VERMEULEN†,
J. P. DESLYPERE and
J. M. KAUFMAN

- Author Affiliations

Department of Endocrinology, University Hospital 9000 Ghent, Belgium



Abstract

To investigate whether changes in opioid tone play a role in the age-associated changes in LH release in men, the influence of an antiopioid, naltrexone, on plasma LH levels and LH pulses was studied in a group of young and elderly normal men. The young and elderly menhad similar basal LH pulse frequencies, but the frequency of high amplitude (>2 IU/ L) LH pulses, mean LH pulse amplitude, maximal LH pulse amplitude and pulse area, were lower in the elderly men. Naltrexone administration (40 mg at 0630 and 2200 h the day before blood sampling and at 0630 h, 30 min before starting frequentblood sampling at 10-min intervals for 12 h) to young men (n = induced a significant increase in individual mean baselineplasma LH levels, LH pulse frequency, and the sum of LH pulse amplitudes. In elderly men (n = 11) only a borderline significant increase in baseline plasma LH levels occurred, and neither LH pulse frequency nor the sum of the amplitudes of LH pulses increased. We suggest that in elderly men either opioid tone or the response of the gonadotrophs to endogenous LHRH is decreased.

jimmylegs wrote:this may be out of sequence on the thought process, but thought i'd drop in with some info on target levels.

http://www.stopthethyroidmadness.com/lab-values/ (info is not referenced but possibly of use as a starting point)
"ALDOSTERONE test: Measures the adrenal hormone aldosterone which helps regulate levels of sodium and potassium in your body–i.e. it helps you retain needed salt, which in turn helps control your blood pressure, the distribution of fluids in the body, and the balance of electrolytes in your blood. If you are mid-or-below in the range, which is often 4.0 – 31.0 ng/dl , there is reason to be suspicious that your adrenals aren’t producing enough, since healthy adrenals will generally put you in the upper range.
This is best tested in the morning and with no salt intake for 24 hours. Women need to do it in the first week after their period, since rising progesterone can also raise your aldosterone. Center of this range is 17.5.
Testing should not be done with severe illness (aldosterone falls in response to severe illness), during periods of intense stress (aldosterone rises), or right after strenuous exercise (aldosterone rises). Being pregnant can result in doubled amounts of aldosterone.
Women should test their aldosterone in the first week after menstruation when progesterone is the lowest (higher progesterone raises aldosterone)"

wiki gives the range as about 7-30 ng/dl. again, unreferenced on the surface. possibly refs avail with some digging. https://en.wikipedia.org/wiki/Reference ... lood_tests

suboptimal aldosterone associated with hearing loss...
Aldosterone Provides New Treatment for Age-Related Hearing Loss http://www.naturalnews.com/026096.html

Idiopathic Intracranial Hypertension Associated with Either Primary Or Secondary Aldosteronism

Khan, M. Usman MD; Khalid, Heena MD; Salpietro, Vincenzo MD; Weber, Karl T. MD
Published Ahead-of-Print
Abstract
Background: Idiopathic intracranial hypertension (IIH) is a syndrome consisting of headache, visual field defects and papilledema of uncertain etiology. The prospect was raised previously as to an association between aldosteronism and increased intracranial pressure in 2 middle-aged women with IIH and primary aldosteronism (PAL). Since then, 2 additional adults were identified and 2 other cases were reported from the United Kingdom, whereas 6 cases of IIH and secondary aldosteronism (SAL) in children have been reported in the English literature worldwide.

Methods: A retrospective analysis of cases from author institutions and published literature comparing clinical features, laboratory findings and therapeutic interventions in these 12 cases.

Results: The female-to-male ratio was 10:2. The mean age of the PAL patients was 49 +/- 3 years-all hypertensive, with adrenal pathology in most. The mean age of the SAL patients was 11 +/- 2 years-mostly normotensive, with 3 having Bartter's and 2 Gitelman syndromes, and 1 renal congenital hypoplasia. Plasma aldosterone levels were elevated (31 +/- 5 ng/dL) in PAL and SAL, whereas plasma renin activity was suppressed in PAL. Hypokalemia (3.2 +/- 0.2 mmol/L), hypomagnesemia (1.6 +/- 0.3 mg/dL) and a putative metabolic alkalosis (serum HCO3 30 +/- 1 mmol/L) were observed. IIH symptoms were controlled by spironolactone in 5, amiloride in 1, correction of hypokalemia and hypomagnesemia in 2, discontinuation of nonsteroidal anti-inflammatory drugs in 2, and reduction of body weight in 1. One patient required serial lumbar punctures, 2 a ventriculoperitoneal shunt, whereas all 3 patients with adrenal adenoma underwent surgical resection.

Conclusions: An association between IIH and PAL occurs in hypertensive middle-aged women, whereas normotensive girls having an inherited renal tubular defect may have IIH with SAL. Patients with IIH should be evaluated for aldosteronism and considered for spironolactone therapy.
(C) Copyright 2012 Southern Society for Clinical Investigation

jimmylegs wrote:iima, what sort of progesterone/luteal phase issues?


Suggested lower cutoffs of serum zinc concentrations for assessing zinc status: reanalysis of the second National Health and Nutrition Examination Survey data (1976–1980)
http://ajcn.nutrition.org/content/78/4/756.short
"Estrogen and progesterone are associated with lower serum zinc concentrations in women when these hormones are at their highest concentrations during the ovulatory and luteal phases of the menstrual cycle (24)."

could be d/t higher zinc demand during that particular phase...?

Zinc deficiency and supplementation in ovariectomized rats: their effect on serum estrogen and progesterone levels and their relation to calcium and phosphorus.
http://www.ncbi.nlm.nih.gov/pubmed/19339224
Abstract
The aim of this study is to examine how zinc deficiency or supplementation affects estrogen and progesterone and calcium and phosphorus levels in the serum. The study was carried out on 40 adult female rats of Sprague-Dawley species.
The rats were allocated to four groups: Group 1: Control, Group 2: Ovariectomized (OVX) control. Group 3: OVX-Zinc-supplemented. Group 4: OVX-Zinc-deficient. ... Group 1 had the highest estrogen levels (p<0.05). Estrogen levels in group 3 were higher than those in groups 2 and 4 (p<0.05). The lowest estrogen levels were found in group 4 (p<0.05). Progesterone levels were higher in group 1 than in groups 2, 3 and 4 and the same parameter in group 3 was higher than those in groups 2 and 4. ... Group 3 had the highest serum zinc levels (p<0.05).

A direct effect of aldosterone on endothelin-1 gene expression in vivo.

Wong S, Brennan FE, Young MJ, Fuller PJ, Cole TJ.


Source

Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.


Abstract

Aldosterone regulates sodium reabsorption in epithelial tissues such as the kidney and colon, via a pathway involving the activation of intracellular mineralocorticoid receptors (MR), induction of specific target genes, and a subsequent increase in sodium channel activity. Characterized aldosterone target genes in epithelia include the serum and glucocorticoid-regulated kinase 1 and the corticosteroid hormone-induced factor. Endothelin-1 (ET-1) is a potent vasoconstrictor that alters both sodium transport and hydrogen ion secretion in the kidney. Recent studies in a mouse medullary collecting duct cell line and rat A-10 smooth muscle cells have demonstrated an acute response of ET-1 gene expression to aldosterone. In the present study, we have investigated the ET-1 gene in vivo as a potential direct aldosterone-regulated target gene in the kidney and colon. Adrenalectomized rats given a single dose of aldosterone were found to have a 2-fold increase in ET-1 mRNA levels in the kidney and colon after 1 h. No significant changes in mRNA levels were detected for the related isoforms ET-2 or ET-3. Cotreatment with aldosterone and potassium canrenoate, a MR antagonist, blocked induction of ET-1 mRNA, suggesting that induction was mediated via the MR. In a time course study, ET-1 mRNA levels were induced rapidly by aldosterone, with levels of ET-1 mRNA maximally increased 2- and 2.5-fold after 1 h in the kidney and colon, respectively. These results suggest that ET-1 is a direct aldosterone gene target in the kidney and colon and may play an important role in aldosterone-regulated ion homeostasis.