Blood plasma, calcium concentration

Calcitonin inhibits osteoclasts and decreases blood plasma calcium concentrations (Fig. 10.12). It therefore opposes the action of parathyroid hormone. It is a 32 amino acid hormone secreted by the thyroid C cells. It is related to four bioactive peptides. One is an alternatively spliced product of the calcitonin gene expressed in tissues other than the thyroid (calcitonin gene-related peptide-1, CGRP-1). The other three calcitonin gene-related peptide-2 (CGRP-2), amylin, and adrenomedullin are each encoded by separate genes. 

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. 

Extracellularly, calcium ions circulate in the blood plasma and interstitial fluid (Sect. 3.3.1). In blood plasma, calcium ions are chelated to albumin and citrate. Albumin (mol. wt. 66,700 kDa) is present at 50-60 mg/mL in plasma, corresponding to 0.9 m mol/L. Although plasma albumin has many different sites that can chelate calcium ions in vitro, only one site binds to calcium ions at physiological albumin concentrations and pH. Thus, albumin binds 0.9 mmol/L of free plasma Ca2+. In addition, citrate (Fig. 10.7), a tricarboxylic acid that the liver secretes into plasma, chelates a free calcium ion to two of its three carboxyl groups, replacing two Na+ ions. Citrate has a molar concentration of 0.08 mM in venous blood and therefore binds to an equivalent concentration of free calcium. Because the total calcium ion concentration of venous blood is 1.14 mmol/L (range 0.2), and the free calcium ion concentration is 0.1 mM, it appears that 0.15 mM of the plasma calcium ion concentration is bound to other plasma components. 

Fig. 1. The effect on the systemic plasma calcium concentration of hypercalcemic perfusion of a parathyroid gland in a conscious, thyroidectomized sheep, followed by drainage (D) of the perfused parathyroid venous blood from the animal. The vertical lines represent the standard error. [From Care et al. (C6).]...

It seems to be fully established that the thyroid gland in many animal species contains a substance or substances (thyrocalcitonin) able to lower the plasma calcium concentration, and secreted in response to the passage of hypercalcemic blood through the gland. Potent extracts can be prepared, and are active when injected or infused into normal and parathyroidectomized animals. This substance is quite distinct from thyroid hormone. 

Johnston and Deiss (Jl) injected rats with °Ca a few hours before thyrocalcitonin administration. They found the expected reduction in the plasma calcium concentration, although its specific activity was higher in the thyrocalcitonin-treated group than in the controls this is consistent with an inhibition of release of unlabeled calcium from bone, but could not be explained on the basis of an increased outfiow of labeled calcium into tissue from the plasma. When tracer calcium was administered 10-14 days prior to thyrocalcitonin injection, the hormone produced a decrease in both stable and tracer calcium in the blood plasma, indicating an inhibition of calcium release from bone. In these animals having labeled bone calcium, increases in stable and radioactive plasma calcium resulted from the administration of parathyroid extract alone, although the simultaneous administration of parathyroid extract and thyrocalcitonin resulted in no net change in either stable or radioactive calcium. It was concluded that both hormones probably act on a similar metabolic compartment in bone. 

The extreme stability of the plasma calcium concentration is illustrated by the fact that, when an amount of calcium greater than that normally present in the whole of the extracellular fluids was injected into experimental animals, there was only a transient increase in the plasma calcium concentration, even though only half of the calcium was excreted during the experimental period. Conversely, alternate bleeding of experimental animals and transfusion with calcium-free blood merely causes a hypocalcaemia of short duration. Such experiments show that very efficient mechanisms exist for adding calcium to blood when the level falls and removing it when the level rises. 

The secretion of calcitonin, like that of PTH, is probably governed solely by blood calcium concentration, since there is no evidence for the existence of a trophic hormone that stimulates its release. The dual control system represented by PTH and calcitonin exerts rigorous control over the plasma calcium concentration and is much more efficient than PTH would be acting alone. Calcitonin is somewhat quicker acting than PTH and may be involved in rapid adjustments when the plasma calcium concentration might otherwise overshoot . It has been suggested that while PTH is really the main regulator for plasma, calcitonin is somehow concerned with the balance between bone formation and resorption. 

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. 

The final mechanism of action of PTH involves the activation of vitamin D3 through the stimulation of la-hydroxylase in the kidney. In the gastrointestinal tract, vitamin D3 is essential for the absorption of calcium. Enhanced absorption of calcium from dietary sources serves to further increase the concentration of calcium in the blood. Many foods, in particular, dairy products, which are rich in calcium, are fortified with vitamin D. The release of PTH from the parathyroid glands is regulated by plasma calcium levels through negative feedback. A decrease in the level of calcium in the blood stimulates the secretion of PTH and an increase in the calcium level in the blood inhibits it. 

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... 

Calcium-selective electrodes have long been in use for the estimation of calcium concentrations - early applications included their use in complexometric titrations, especially of calcium in the presence of magnesium (42). Subsequently they have found use in a variety of systems, particularly for determining stability constants. Examples include determinations for ligands such as chloride, nitrate, acetate, and malonate (mal) (43), several diazacrown ethers (44,45), and methyl aldofuranosides (46). Other applications have included the estimation of Ca2+ levels in blood plasma (47) and in human hair (where the results compared satisfactorily with those from neutron activation analysis) (48). Ion-selective electrodes based on carboxylic polyether ionophores are mentioned in Section IV.B below. Though calcium-selective electrodes are convenient they are not particularly sensitive, and have slow response times. 

A 60 kg adult contains 1000-1200 g of calcium more than 99% is in the bones and teeth. About 1 g is in the plasma and extracellular fluid and 6-8 g in the tissues, sequestered in calcium storage vesicles. The calcium concentration in the blood is about 2.5 mmol/L, about 50% as the free ion and the rest bound to plasma proteins. 

The cytosolic concentration of free Ca2+ is generally at or below 100 mi, far lower than that in the surrounding medium, whether pond water or blood plasma. The ubiquitous occurrence of inorganic phosphates (Pj and I l ,) at millimolar concentrations in the cytosol necessitates a low cytosolic Ca2+ concentration, because inorganic phosphate combines with calcium to form relatively insoluble calcium phosphates. Calcium ions are pumped out of the cytosol by a P-type ATPase, the plasma membrane Ca2+ pump. Another P-type Ca2+ pump in the endoplasmic reticulum moves Ca2+ into the ER lumen, a compartment separate from the cytosol. In myocytes, Ca2+ is normally sequestered in a specialized form of endoplasmic reticulum called the sarcoplasmic reticulum. The sarcoplasmic and endoplasmic reticulum calcium (SERCA) pumps are closely related in structure and mechanism, and both are inhibited by the tumor-promoting agent thapsigargin, which does not affect the plasma membrane Ca2+ pump. 

When the calcium ion concentration is lowered in the fluids bathing nerve axons ifluids which are in very rapid equilibrium with the blood plasma) the electrical resistance ol the axon membrane is lowered, there is increased movement of sodium ions to ihe inside, and the ability ol ihe nerve to return io iis normal siale fallowing a discharge is slowed. Thus, on the one hand, there is hyperexcitabilily. Bui. the ability lor synaptic transmission is inhihited because the rate of acetylcholine liberation is a function ot ihe calcium ion concentration. The neuromuscular junction is... 

Calcium ions are important in muscle contraction and in regulating heartbeat. If the concentration of calcium ions falls too low, death is inevitable. In a television drama, a patient is brought to hospital after being accidentally splashed with hydrofluoric acid. The acid readily penetrates the skin, and the fluoride ions combine with the calcium ions in the blood. If the patient s volume of blood plasma is 2.8 L, what amount (in mol) of fluoride ions would completely combine with all the calcium ions in the patient s blood ... 

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. 

Q13 Calcium channel blockers decrease the opening of L-type calcium channels in the plasma membrane of vascular smooth muscle cells, and so reduce intracellular calcium concentration and contractile activity. The blood vessels therefore dilate. Calcium channel blockers act mainly on the arterial side of the circulation, and the dihydropyridines, such as nifedipine, are useful coronary arteriolar dilator agents. These agents are usually the treatment of choice for Prinzmetal angina. 

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