Calcium sparklets, TRPV channels and vanilla

     Calcium sparklets are not a good thing, not in excess at least. This is just a few interesting articles that have TRPV channels in common. The calcium channels cause problems in a variety of ways for some people. Identifying who is at risk for problems with fluid balance could help prevent the chronic degenerative changes that can result from electrolyte imbalance. (This post led to parts of this webpage: Relaxation & Stress)
     I was amused when the search term ‘sparklets’ turned up something pertinent to my field of interest. TRPV channels and vanilloid receptors with overactive calcium flow can increase pain and other types of muscle and nerve signals.

Calcium sparklets are not a type of chewing gum. They are a sudden increase in flow of calcium through certain calcium channels in vascular tissue. A specific chemical trigger called protein kinase Calpha (PKCalpha) was found to signal L type calcium channels into increased calcium flow [3]. The sparklets occurred in diabetic vascular tissue following high blood sugar levels [2]. A cooperative action taking place with as few as three calcium channels needing to be open for maximal vasodilation to occur [1].
TRPV4 are a type of vanilloid receptor. Loss of function due to genetic difference has been associated with hyponatremia, low sodium blood levels. [6]

“TRPV4 is activated by hypotonicity in vitro, and perturbations of even a few mOsmol/kg H2O were sufficient to achieve this effect (5–7); such exquisite sensitivity closely parallels the in vivo mechanism whereby a change of only a few mOsmol/kg H2O influences release of arginine vasopressin. In rodents, TRPV4 is expressed in the blood–brain barrier-deficient central osmosensing nuclei (5, 35), and targeted deletion of the TRPV4 gene gives rise to aberrant osmoregulation in murine models (20, 21).” [6]

     Time to bake something with vanilla. The above paragraph’s reference to a blood-brain barrier deficiency having a genetic component suggests that susceptibility to headaches also could have a genetic component. The change in osmoregulation means that membranes could be more resistant to fluid and particles crossing or more open and barrierless (and  prone to get migraines). The problem could combine a deficiency in ability to transport needed nutrients into the cell with an increase in leakiness of important things out of or into the cell. The lack of nutrients like magnesium would further reduce the calcium channel blocking potential of the cell.
     So is vanilla something that some people genetically need more of? good question. And the bigger bell ringing loud was the risk of hyponatremia means that a low salt diet could lead to even lower levels of sodium in the blood.
     TRPV receptors have to do with pain control as well as flow of fluid and electrolytes (osmoregulation). Vanillin receptors can have a calming effect on the body and sooth pain. Baked goods with vanilla have a little extra besides love soothing the body. (So does hot pepper though – capsaicin).

Magnesium flow through the proton gates that the TRPV group of receptors control is what helps reduce  pain (when there is enough magnesium) and what causes pain signals when there isn’t enough to protect the cell interior from calcium entry. Calcium signals overwork, which leads to pain.
Calcium channel blocker medications are trying to close the gates and keep the calcium out – magnesium would be super delighted to do that if enough were being absorbed from the intestines (too full of calcium and active hormone D3).

     A study on the use of magnesium with opioid pain killers demonstrated the power of magnesium’s effect on for helping reduce diabetic pain. Diabetics normally do not find pain relief from opioids but when magnesium was given in advance the pain killer worked – and the pain killing effect continued for three days after the opioid medication effect would have worn off. The research discussion seemed to focus on using 30 mg with IVs of  morphine or other opioid and didn’t not address the fact that the 300 mg dose had reduced pain on its own, without opioid medication. [18]
  • by Sonkusare SK et al, Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science. 2012 May 4;336(6081):597-601. []
  • Calcium and diabetic vascular dysfunction, Focus on “Elevated Ca2+sparklet activity during acute hyperglycemia and diabetes in cerebral arterial smooth muscle cells,  by Katherine M. Dunn, KM and Mark T. Nelson (11/11/09 Am J Physiol Cell PhysiolFebruary 1, 2010 vol. 298 no. 2 C203-C205) “This report is also the first to describe a molecular mechanism by which hyperglycemia produces increased [Ca2+]in VSM and suggests that this mechanism of Ca2+ sparklet activation may be uniquely initiated by hyperglycemia.”    [ article]
  • Article by Amberg GC et al “Calcium sparklets regulate local and global calcium in murine arterial smooth muscle” J Physiol. 2007 Feb 15;579(Pt 1):187-201. Epub 2006 Dec 7. [Free article]
  • The first three are from a search for ‘sparkles’ in pubmed, no sparkles-but autosuggester came up with ‘calcium sparklet’ and the whole list looks interesting: []-Truth can be stranger than fiction.

4. A different search ‘magnesium deficiency hyperglycemia‘ provided a summary worth reading :  Magnesium and Potassium in Lone Atrial Fibrillation, by Patrick Chambers, MD, pdf file: [] *** this needs to be added to the IoM 1997 report on magnesium. Lefthandedness section near the bottom notes an increase calcium flow across cell membranes in left handers. A genetic difference that can lead to an increase in the isoprenoid pathway and inhibition of Na/K pumps in the membranes is suggested to occur in some left handed people. The difference can lead to an increased need for magnesium.

5. Reminder – vascular calcification is somewhat reversible and a simple way to start is to add less by limiting the amount of calcium taken in daily. Two servings a day of calcium rich foods is adequate for most people; there is also calcium in smaller amounts in many other foods too. Calcification of Soft Tissue, hardening organs and softening bones (post, 8/19/11 )

6. A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia, by Wei Tian, et al []

7. Physiology and Pharmacology of the Vanilloid Receptor, by Angel Messeguer, Rose Planells-Cases, and Anton Ferrer-Montiel (Curr. Neuropharmacol., 2006 January: 4(1) : 1-15) [link]

Excerpt:  In addition to the contribution of the vanilloid receptor as a target of the neurogenic inflammation underlying different diseases, TRPV1 is gaining interest for the treatment of neuropathic, postoperative and chronic pain and, recently, for the therapy of epithelial disorders. Thus, for instance, topical capsaicin or resiniferotoxin have been used in postherpetic neuralgia, diabetic neuropathy, postmastectomy pain and arthritis [64,103]. Recently, TRPV1 has been clearly validated as a key target for management of chronic pain in bone cancer [42]. As a result, the development of specific TRPV1 antagonists is a central focus of current drug discovery

***antagonist equals block – the vanilloid receptors are also involved in soothing – feed and educate the receptors because they all serve multiple purposes. Pain has a purpose – to signal that something is wrong. Masking pain with antagonists that deaden a function – to signal a problem – was a very disappointing climax to that paragraph. TRPV1 receptors and all the rest of the gang are very exciting – let’s not waste more money and time inventing synthetic antagonists to a message system that is very intertwined in controlling gates and flow of substance. the pain is there for a reason – starvation – lack of building blocks – lack of function.

8. More on vanilla from “Confessions of a Cardamom Addict” blogspot – blog part one–  –blog part two – ***These cover the history, processing, environmental concerns, major botanical varieties.

18(vit D bib.). [] Magdalena Bujalska, Helena Makulska-Nowak, Stanis³aw W. Gumuka Magnesium ions and opioid agonistsin vincristine-induced neuropathy , Department of Pharmacodynamics, Medical University of Warsaw, Krakowskie Przedmieoecie 26/28, PL 00-927 Warszawa, Poland

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes. Thanks.

Calcification of soft tissue – hardening organs and softening bone

     Vascular calcification is better known as atherosclerosis. Cholesterol plaques in blood vessels are generally a mixture of calcium with the fat. Calcification also occurs in arthritis as bone spurs and calcium can collect in organs and glands and impair their function. The pineal gland is very tiny and located within the brain. It it responsible for the melatonin hormone that helps us sleep. A calcified pineal gland no longer helps with sleep but the condition may be reversible by limiting intake of calcium and increasing intake of magnesium.     Reversing calcification may start with reducing calcium intake. The following article mentions a link between higher intake of calcium and worsening of coronary artery calcification and numbers of deaths within a group of end stage renal disease patients. Magnesium is wasted by healthy kidneys and little is recycled/reclaimed the way calcium and sodium are conserved by healthy kidneys – add end stage renal disease and magnesium is leaking out faster then intestinal absorption can occur even if the magnesium was in the food or drink or supplement.

Calcium can not make strong bones if nothing is keeping it from leaking out in response to the stress chemicals’ fight or flight messages. People suffer from osteoporosis and weak bones along with hardening of the arteries and organs –  excess calcium and vitamin D might be part of the problem. Too much active vitamin D can add to calcium imbalance because it signals the bones to let go of stored calcium and magnesium.

The minerals are also released during stress reactions in case there is a need to run from danger or heal a wound. White blood cells around wounds have the enzyme needed to activate vitamin D to the hormone form.

What do you know – it is important to mellow out and de-stress to help keep bone tissue hard and organ tissue soft.

  1. [ Calcification Mechanisms, by Cecilia M. Giachellidoi: 10.1097/01.ASN.0000145894.57533.C4 JASN December 1, 2004 vol. 15 no. 12 2959-2964

“In a landmark study, Goodman et al. (24)  found that coronary artery calcification occurred in young patients with ESRD (end stage renal disease) decades before this pathology was observed in the normal population. Furthermore, progression of vascular calcification in this group was positively correlated with serum P levels, Ca x P, and daily intake of Ca (24).”

***Vascular calcification has been correlated to higher intakes of calcium and phosphorus in this research article. Cardiovascular deaths are common among end stage renal disease and/or diabetic patients – I suggest they should be limiting calcium and phosphorus and increasing their magnesium intake in order to reduce risks of calcium overload. In the average human the kidneys favor calcium absorption and retention and waste magnesium.
Over the course of mankind the body adapted to a food and water supply that was abundant in magnesium and limited in calcium content. Calcium is important for strong bones but only in combination with other nutrients. Vitamin K (brown rice, green leafy vegetables and good guy bacteria in our intestines are sources) is essential for blood clotting and for healthy bones. Strontium is a trace mineral that may be essential to healthy bones and of course magnesium is the trace mineral that helps keep calcium inside of the bone where it belongs. Excessive levels of active vitamin D tell the bone to release the stored minerals. Active vitamin D (a very strong steroid based hormone in actuality) can switch on and off 900+ genes.
The study found (unsurprisingly) that the end stage renal disease patients who were treated with the typical phosphate binding medications that contained calcium had 28% progression of calcification compared to the experimental group who were given a phosphate binding agent that didn’t contain calcium. [12]

Let’s keep the calcium in the bone tissue where it belongs.

The article Vascular Calcification Mechanisms [1] presents four potential ways the soft tissue calcification may develop.

“First, human and mouse genetic findings have determined that blood vessels normally express inhibitors of mineralization, such as pyrophosphate and matrix gla protein, respectively, and that lack of these molecules (“loss of inhibition”) leads to spontaneous vascular calcification and increased mortality (10,29).”

Second – genetic/phontypic changes leading to production of bone proteins within the blood vessel may occur (the blood vessel cell switches on bone cell mechanisms).

“Third, bone turnover leading to release of circulating nucleational complexes has been proposed to explain the link between vascular calcification and osteoporosis in postmenopausal women (41–43).”

“Fourth, cell death can provide phospholipid-rich membranous debris and apoptotic bodies that may serve to nucleate apatite, especially in diseases where necrosis and apoptosis are prevalent, such as atherosclerosis (34,44,45).”

*** Magnesium deficiency could effect the enzyme production necessary for producing the “inhibitors” of bone formation produced in functioning blood vessels. Magnesium is crucial to over 300 enzymes. It is also essential for the growth of healthy white blood cells. A plentiful supply of white blood cells would engulf waste products of apoptosis and the dead cell material wouldn’t be left messing up vessel walls. Chronic magnesium deficiency will promote bone turnover in order to access the stored magnesium found within. Long term kidney problems may be reducing the amount of magnesium that the body can retain and further through off the calcium/magnesium balance.
Chronically elevated active D would chronically cause demineralization of the bones and also might be switching on and off genes in areas of the body (blood vessels for example) that shouldn’t be forming bone tissue. I would be very curious what the end stage renal disease patients’ 1, 25 D levels (hormone) are compared to their 25 D levels (vitamin).  My 1, 25 D levels have been at the high end of normal and 25 D levels below normal (“deficient”) for five years of testing. I have been actively avoiding supplements and foods with vitamin D and much time in the sun during that time because I have found it reduces my symptoms of  muscle knots (fibromyalgia), I also have taken magnesium supplements regularly.
A 200-500 mg supplement taken along with food generally will not cause the smooth muscles of the intestines to relax into a sudden bowel movement. Magnesium supplements are non-toxic but if absorbed too rapidly can cause too much muscle relaxation in the bowels or heart. Fluttery weak heart beats may result if you hang out in an Epsom salt bath for a long time due to the relaxation of too many of the muscle fibers at the same time. Magnesium taken with food or in the glycinate form does’t seem to have the over relaxing effect on the bowels.
Magnesium helps keep the calcium in the bone and out of the soft tissue. Use the calcium channel blocker that Mother Nature provided – magnesium. Eat more nuts, beans, seeds, green leafy vegetables. and chocolate every day for strong bones and soft organs!

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

From Vitamin D bibliography [link]:

10. Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, Schauer G, Lehmann M, Roscioli T, Schnabel D, Epplen JT, Knisely A, Superti-Furga A, McGill J, Filippone M, Sinaiko AR, Vallance H, Hinrichs B, Smith W, Ferre M, Terkeltaub R, Nurnberg P: Mutations in ENPP1 are associated with “idiopathic” infantile arterial calcification. Nat Genet 34: 379–381, 2003[CrossRef][Medline]
12. Sangiorgi G, Rumberger JA, Severson A, Edwards WD, Gregoire J, Fitzpatrick LA, Schwartz RS: Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: A histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol 31: 126–133, 1998[Abstract/Free Full Text]

29. Luo G DP, McKee MD, Pinero GJ, Loyer E, Behringer RR, and Karsenty: G Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386(March 6): 78–81, 1997[CrossRef][Medline]

34. Tanimura A, McGregor DH, Anderson HC: Matrix vesicles in atherosclerotic calcification. Proc Soc Exp Biol Med 172: 173–177, 1983[CrossRef][Medline]

  1. Price PA, Caputo JM, Williamson MK: Bone origin of the serum complex of calcium, phosphate, fetuin, and matrix Gla protein: Biochemical evidence for the cancellous bone-remodeling compartment. J Bone Miner Res 17: 1171–1179, 2002[CrossRef][Medline]
  2. Price PA, Faus SA, Williamson MK: Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol 21: 817–824, 2001[Abstract/Free Full Text]
  3. Price PA, June HH, Buckley JR, Williamson MK: Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol 21: 1610–1616, 2001[Abstract/Free Full Text]
  4. Proudfoot D, Skepper JN, Hegyi L, Bennett MR, Shanahan CM, Weissberg PL: Apoptosis regulates human vascular calcification in vitro: Evidence for initiation of vascular calcification by apoptotic bodies. Circ Res 87: 1055–1062, 2000[Abstract/Free Full Text]
  5. Schoen FJ, Tsao JW, Levy RJ: Calcification of bovine pericardium used in cardiac valve bioprostheses. Am J Pathol 123: 134–145, 1986[Abstract]
  • [ Sahai, Modeling apatite nucleation in the human body and in the geochemical environment American Journal of Science, Vol. 305, June/September/October 2005, P.661-672; doi:10.2475/ajs.305.6-8.661

“Magnesium inhibits nucleation by adsorbing faster than calcium, as an outer-sphere surface complex, at the active site.”