Plasma Concentrations of Calcium and Phosphate

Plasma Concentrations of Calcium and Phosphate Although the mean response to changes in plasma cedcium is a chemge in the secretion of peuathyroid hormone, the activity of calcidiol 1-hydroxyleise in kidney slices is decreased directly by high concentrations of cedcium in the incubation medium. Cedcium heis no direct effect on the activity of calcidiol 24-hydroxylase under these conditions. Strontium and cadmium edso inhibit ctdcidiol 1-hydroxylase. 

The main function of vitamin D is in the control of calcium homeostasis (section 11.15.1) and, in turn, vitamin D metabolism is regulated, at the level of 1- or 24-hydroxylation, by factors that respond to plasma concentrations of calcium and phosphate ... 

The concentration of PTH in plasma is determined by its synthesis and secretion by the parathyroids and its metabolism and clearance by the Hver and kidneys. PTH acts directly on bone and kidney, and indirectly on intestine to regulate the concentration of calcium and phosphate in plasma. 

Osteoblasts secrete osteoid, a matrix rich in type I collagen fibers and vesicles. Precipitation of calcium phosphate is inhibited by a high concentration of pyrophosphate in stromal interstitial fluids, and a high concentration also of albumin and citrate in blood plasma. Pyrophosphate is derived from (1) transport out of the cytosol, and (2) synthesis from nucleoside triphosphates in the stromal interstitial fluid that permeates the osteoid matrix. Precipitation occurs only when calcium and phosphate ions are taken up into vesicles whose inner membrane is composed of phosphatidylserine. The high concentration of calcium and phosphate ions in the vesicle is mediated by annexin and type HI Pi Na-dependent transporters. This overwhelms the pyrophosphate and nucleation occurs. As the precipitate grows and ruptures the membrane, tissue-nonspecific alkaline phosphatase is activated to remove pyrophosphate from the osteoid matrix fluid so that calcium phosphate precipitates around phosphorylated serine residues within the collagen fibers. 

Talmage (T4) has determined the concentrations of calcium and phosphate in rat plasma after high-speed centrifugation. He has studied normal plasma and plasma to which calcium, phosphate and calcium orthophosphate had been added as well as plasma obtained after nephrectomy. There was a substantial variation in the final [Ca] [P] products (82-120) high products were obtained when the plasma phosphate concentration was high, as after nephrectomy. However, when his data are recalculated as [Ca] [P] as shown in Table 8, there is much less varia-... 

Three hormones regulate turnover of calcium in the body (22). 1,25-Dihydroxycholecalciferol is a steroid derivative made by the combined action of the skin, Hver, and kidneys, or furnished by dietary factors with vitamin D activity. The apparent action of this compound is to promote the transcription of genes for proteins that faciUtate transport of calcium and phosphate ions through the plasma membrane. Parathormone (PTH) is a polypeptide hormone secreted by the parathyroid gland, in response to a fall in extracellular Ca(Il). It acts on bones and kidneys in concert with 1,25-dihydroxycholecalciferol to stimulate resorption of bone and reabsorption of calcium from the glomerular filtrate. Calcitonin, the third hormone, is a polypeptide secreted by the thyroid gland in response to a rise in blood Ca(Il) concentration. Its production leads to an increase in bone deposition, increased loss of calcium and phosphate in the urine, and inhibition of the synthesis of 1,25-dihydroxycholecalciferol. 

Vitamin D hormone is derived from vitamin D (cholecalciferol). Vitamin D can also be produced in the body it is formed in the skin from dehydrocholesterol during irradiation with UV light. When there is lack of solar radiation, dietary intake becomes essential, cod liver oil being a rich source. Metabolically active vitamin D hormone results from two successive hydroxylations in the liver at position 25 (- calcifediol) and in the kidney at position 1 (- calcitriol = vitamin D hormone). 1-Hydroxylation depends on the level of calcium homeostasis and is stimulated by parathormone and a fall in plasma levels of Ca2+ and phosphate. Vitamin D hormone promotes enteral absorption and renal reabsorption of Ca2+ and phosphate. As a result of the increased Ca2+ and phosphate concentration in blood, there is an increased tendency for these ions to be deposited in bone in the form of hydroxyapatite crystals. In vitamin D deficiency, bone mineralization is inadequate (rickets, osteomalacia). Therapeutic use aims at replacement. Mostly, vitamin D is given in liver disease, calcifediol may be indi-... 

Q4 The parathyroids produce a peptide hormone, PTH, which controls the level of calcium in the body. A sensor on the surface of the parathyroid cells monitors blood calcium concentration and PTH is secreted in response to a fall in plasma calcium ion concentration. An increase in the level of PTH leads to hypercalcaemia (raised blood calcium) conversely, a reduction in the level of PTH leads to hypocalcaemia. PTH acts on the kidney to reduce reabsorption of phosphate and at the same time to increase reabsorption of calcium. In addition, it promotes the release of calcium and phosphate into the blood by activating osteoclasts, which break down the inorganic matrix of bone. PTH also increases the absorption of calcium by the mucosal cells of the intestine. The latter is a rather slow, indirect action mediated by PTH stimulation of calcitriol secretion by the kidney. 

ESTRAMUSTINE CALCIUM AND DAIRY PRODUCTS i plasma concentrations of estramustine and risk of poor therapeutic response Due to l absorption of estramustine owing to the formation of a calcium-phosphate complex Administer estramustine 1 hour before or 2 hours after dairy products or calcium supplements... 

Intoxication with vitamin D causes weakness, nausea, loss of appetite, headache, abdominal pains, cramps, and diarrhea. More seriously, it also causes hypercalcemia, with plasma concentrations of calcium between 2.75 to 4.5 mmol per L, compared with the normal range of 2.2 to 2.5 mmol per L. At plasma concentrations of calcium above 3.75 mmol per L, vascular smooth muscle may contract abnormally, leading to hypertension and hypertensive encephalopathy. Hypercalciuria may also result in the precipitation of calcium phosphate in the renal tubules and hence the development of urinary calculi. Hypercalcemia can also result in calcinosis - the calcification of soft tissues, including kidneys, heart, lungs, and blood vessels. This is assumed to be the result of increased calcium uptake into tissues in response to excessive plasma concentrations of the vitamin and its metabolites. 

VITAMIN D DEFICIENCY Vitamin D deficiency is associated with inadequate absorption of calcium and phosphate. The resulting decrease in Ca stimulates PTH secretion, which acts to restore plasma Ca + at the expense of bone. Plasma phosphate concentration will remain low due to the phosphaturic effect of PTH. In children, the failure to mineralize newly formed bone results in rickets, a growth disorder in which the long bones may be bowed due to inadequate calcification. 

Similarly, approximately 500 to 600 g of phosphate are present, 85% of which Is found in the bone. The normal plasma concentration of calcium Is approximately 4.5 to 5.7 mEq/L, 50% of which Is protein bound. The remainder of the calcium is either complexed to corresponding counterions (46%) or exists in its ionized form (4%). It Is only the ionized form of calcium that is tightly hormonally regulated (varies less than 5-10%) (1,2). Because serum calcium concentrations fluctuate, so do the plasma levels of the hormones associated with calcium homeostasis. Serum phosphorous levels vary with age, diet, and hormonal status. The most common... 

Contrary to PTH, calcitonin has a lowering action on blood Ca activity. It is synthesized in the parafollicular cells (C cells) in the thyroid. An increased blood Ca activity leads to calcitonin secretion, and within a few minutes both calcium and phosphate concentrations in plasma are lowered. This effect is accomplished by an effect on the bone cells, where calcium is bound as hydroxyapatite. Besides this effect, calcitonin also decreases intestinal uptake and renal reabsorption. Calcitonin inhibits the osteoclasts ( bone eater cells ) and hence reduces the amount of calcium and phosphate released from bone to the extracellular fluid. The effect on the kidneys leads to an increased excretion of calcium, phosphate, sodium, chloride, and water. 

Calcitriol increases the intestinal absorption of calcium and phosphate by stimulating the active system for transport of calcium. It also stimulates the synthesis of the calcium-binding protein in the mucosa cells. Calcitriol is more than five times as active as 25(OH)D3 with respect to its effect on the intestinal calcium absorption and more than 100 times as effective as an absorber of Ca ftom the skeleton. The concentration of calcitriol in plasma is about 70 pmol/liter, which is about 1000 times lower than the concentration of 25(OH)D3. 

If vitamin D has no effect on calcium absorption, it does affect calcium mobilization and thereby restores plasma concentrations of calcium. This finding explains why vitamin D deficiency was associated with hypocalcemia. The effect on the bone seems to require a synergetic action of vitamin D and parathormone. The 1,25-hydroxylated derivative seems to be the major active compound causing calcium release from the bone. The 25-hydroxyl derivative has, however, been shown to be active as well. Finally, vitamin D increases renal proximal tubular reabsorption of phosphate in normal and vitamin D deficient animals. Consequently phosphate excretion is decreased. Inasmuch as this effect occurs in parathyroidectomized animals, the effect of vitamin D or its metabolites must be direct. Again, the active metabolites are the 25 and 1,25-hydroxy derivatives. A calcium binding protein has been isolated from the kidney cortex, but its role in renal reabsorption is not known. 

The second level involves two kinds of cellular participation resorption of existing bone by osteoclasts and deposition of new bone by osteoblasts. Over short periods these two processes, acting at different sites, approximately balance each other. Acting in conjunction, they not only continuously remodel the surface contour of the bone but also play a major part in the control of calcium and phosphorus metabolism for the whole organism. Coordination at this second level is achieved through hormonal mediation of calcium and phosphate homoeostasis which ensures that the concentrations of these ions in the plasma and tissue fluid remain constant (Chapter 30). 

Because of the close dependence of neuromuscular activity on the concentration of calcium ions in the body fluids, it is essential that this level should be kept constant within very narrow limits. Control of phosphate ion concentration is also important, although rather larger variations can be tolerated for phosphate than for calcium. These levels are controlled mainly by the various dynamic relationships that exist between the dissolved ions in the extracellular fluids and the solid phosphates of bone (page 438). The very rapid exchange reaction involving a small labile reserve of calcium and phosphate ions is purely physicochemical in nature and consequently limited in scope, yet it enables the plasma calcium concentration to be rapidly adjusted, equilibrium being established in about 4 min. 

Attempts to raise the concentrations of calcium and/or phosphate in saliva with a view to decreasing enamel solubility have not been successful. The calcium ion is the most closely regulated of the plasma electrolytes and remains constant in spite of variations in dietary intake. Neither supplementation of the diet of rats with moderate amounts of inorganic phosphate nor infusion of human subjects with sufficient phosphate to bring about a threefold increase in blood levels caused an appreciable change in the phosphate concentration of saliva. Nevertheless, rats fed a phosphate supplement showed a marked reduction in caries, presumably as the result of a local effect. 

SBF is a solution that has inorganic ion concentrations similar to those of human blood plasma but does not contain any cells or protein. A brief summary of SBF, introduced by Cho et al. [17], follows. The ion concentrations of SBF are given in Table 11.1 [17]. The pH of SBF is typically adjusted to 7.25 or 7.40 at 36.5 °C. This fluid is a metastable solution containing calcium and phosphate ions supersaturated with respect to hydroxyapatite. SBF is prepared by successively dissolving the reagent-grade chemicals in ultra-pure water in the order given in Table 11.2 [17]. Each new chemical is added after the previous one has completely dissolved. The temperature... 

There seems to be no metabolic control exerted on hepatic 25-hydroxylase and so all of the available cholecalciferol is converted. Hydroxylation in the kidney however is an important control point being regulated by PTH, and indirectly therefore by calcium and phosphate concentrations. Stimulation of la-hydroxylase by PTH is via a cyclic AMP (cAMP) -dependent mechanism and longer-term regulation of the activity of this enzyme is via induction mediated by other hormones such as oestrogens, cortisol and growth hormone. Typically, the plasma concentration of 1,25 dihydroxy vitamin D is in the range 20-60 ng/1, that is approximately 1000-times lower than that of its precursor. 

The polypeptide parathormone is released from the parathyroid glands when plasma Ca + level falls. It stimulates osteoclasts to increase bone resorption in the kidneys, it promotes calcium reabsorption, while phosphate excretion is enhanced. As blood phosphate concentration diminishes, the tendency of calcium to precipitate as bone mineral decreases. By stimulating the formation of vit D hormone, parathormone has an indirect effect on the enteral uptake of Ca + and phosphate. In parathormone deficiency, vitamin D can be used as a substitute that unlike parathormone, is effective orally. 

PTH is secreted from the parathyroid glands in response to a low plasma concentration of ionized (free) calcium. PTH immediately causes the transfer of labile calcium stores from bone into the bloodstream. PTH increases rates of dietary calcium absorption by the intestine indirectly via the vitamin D3 system activation of enterocyte activity. Within the kidney, PTH directly stimulates calcium reabsorption and a phosphate diuresis. 

The concentration of calcium in the hlood plasma of most mammals and many vertebrates is quite constant al about 2.5 niM 110 milligrams pet 100 milliliters plasma). In the plasma, calcium exists in three forms ill as the tree ion. 12) bound to proteins, and t.l) complexed with organic te.g., citrate) or inorganic ie,g., phnsphatei acids. The tree ion accounts lor about 47.5% of the plasma calcium 46% is bound lo proteins and 6.5% is in complexed form. Of the latter, phosphate and citrate account for half. 

The major location of calcium in the body is in the skeleton, which contains more than 90% of the body calcium as phosphate and carbonate. Bone resorption and formation keeps this calcium in dynamic equilibrium with ionized and complexed calcium in blood, cellular fluids and membranes. Homeostasis is mainly regulated by the parathyroid hormone and vitamin D which lead to increased blood calcium levels, and by a thyroid hormone, calcitonin, which controls the plasma calcium concentration J5 Increasing the concentration of calcitonin decreases the blood calcium level, hence injections of calcitonin are used to treat severe hyperalcaemia arising from hyperparathyroidism, vitamin D intoxication or the injection of too high a level of parathyroid extract. High levels of calcitonin also decrease resorption of calcium from bone. Hypocalcaemia stimulates parathyroid activity, leading to increased release of calcium from bone, reduction in urinary excretion of calcium and increased absorption of calcium from the intestine. Urinary excretion of phosphate is enhanced. 

Tabie 3.4 Plasma Concentrations of Calcidiol, Alkaline Phosphatase, Calcium, and Phosphate as Indices of Nutritional Status... 

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