Hormonal Mechanisms Provide High Capacity Long Term Regulation of Plasma Calcium and Phosphate Concentrations

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The hormonal mechanisms described here have a large capacity and the ability to make long-term adjustments in calcium and phosphate fluxes, but they do not respond instantaneously. It may take several minutes or hours for the response to occur and adjustments to be made. However, these are the principal mechanisms that regulate plasma calcium and phosphate concentrations.

The Chemistry of Parathyroid Hormone, Calcitonin, and 1,25-Dihydroxycholecalciferol and the Regulation of Their Production. One of the primary regulators of plasma calcium concentrations is parathyroid hormone (PTH). PTH is an 84-amino acid polypeptide produced by the parathyroid glands. Synthetic peptides containing the first 34 amino terminal residues appear to be as active as the native hormone.

There are two pairs of parathyroid glands, located on the dorsal surface of the left and right lobes of the thyroid gland. Because of this close proximity, damage to the parathyroid glands or to their blood supply may occur during surgical removal of the thyroid gland.

The primary physiological stimulus for PTH secretion is a decrease in plasma calcium. Figure 36.4 shows the relationship between serum parathyroid hormone concentration and total plasma calcium concentration. It is actually a decrease in the ionized calcium concentration that triggers an increase in PTH secretion. The net effect of PTH is to in-

Calcium Concentration And Pth

Effect of changes in plasma calcium on parathyroid hormone (PTH) and calcitonin (CT) secretion. (Modified from Arnaud, CD, Littledike T, Tsao HS. Simultaneous measurements of calcitonin and parathyroid hormone in the pig. In: Taylor S, Foster GV, eds. Proceedings of the Symposium on Calcitonin and C Cells. London: Heinemann, 1969, p. 99).

Effect of changes in plasma calcium on parathyroid hormone (PTH) and calcitonin (CT) secretion. (Modified from Arnaud, CD, Littledike T, Tsao HS. Simultaneous measurements of calcitonin and parathyroid hormone in the pig. In: Taylor S, Foster GV, eds. Proceedings of the Symposium on Calcitonin and C Cells. London: Heinemann, 1969, p. 99).

crease the flow of calcium into plasma, and return the plasma calcium concentration toward normal.

Calcitonin (CT) is a 32-amino acid polypeptide. Also known as thyrocalcitonin, CT is produced by parafollicular cells of the thyroid gland (see Fig. 33.1). Unlike PTH, for which only the initial amino terminal segment is required, the full polypeptide is required for CT activity. Salmon calcitonin differs from human calcitonin in 9 of 32 amino acid residues and is 10 times more potent than human CT in its hypocalcemic effect. The higher potency may be due to a greater affinity for receptors and slower degradation by peripheral tissues. CT is often used clinically as a synthetic peptide matching the sequence of salmon calcitonin.

In contrast to PTH, CT secretion is stimulated by an increase in plasma calcium (see Fig. 36.4). Hormones of the GI tract, especially gastrin, also promote CT secretion. Because the net effect of CT is to promote calcium deposition in bone, the stimulation of CT secretion by GI hormones provides an additional mechanism for facilitating the uptake of calcium into bone after the ingestion of a meal.

The third key hormone involved in regulating plasma calcium is vitamin D3 (cholecalciferol). More precisely, a metabolite of vitamin D3 serves as a hormone in calcium homeostasis. The D vitamins, a group of lipid-soluble compounds derived from cholesterol, have long been known to be effective in the prevention of rickets. Research during the past 30 years indicates that vitamin D exerts it effects through a hormonal mechanism.

Figure 36.5 shows the structure of vitamin D3 and the related compound vitamin D2 (ergocalciferol). Ergocalciferol is the form principally found in plants and yeasts and is commonly used to supplement human foods because of its relative availability and low cost. Although it is less potent on a mole-per-mole basis, vitamin D2 undergoes the same metabolic conversion steps and, ultimately, produces the same biological effects as vitamin D3. The physiological actions of vitamin D3 also apply to vitamin D2.

Vitamin D3 can be provided by the diet or formed in the skin by the action of ultraviolet light on a precursor, 7-de-hydrocholesterol, derived from cholesterol (Fig. 36.6). In many countries where food is not systematically supplemented with vitamin D, this pathway provides the major source of vitamin D. Because of the number of variables in

Ergocalciferol Metabolic Pathway

The structures of vitamin D3 and vitamin

D2. Note that they differ only by a double bond between carbons 22 and 23 and a methyl group at position 24.

volved, it is difficult to specify a minimum exposure time. However, exposure to moderately bright sunlight for 30 to 120 min/day usually provides enough vitamin D to satisfy the body's needs without any dietary supplementation.

Vitamins D3 and D2 are by themselves relatively inactive. However, they undergo a series of transformations in the liver and kidneys that convert them into powerful calcium-regulatory hormones (see Fig. 36.6). The first step occurs in the liver and involves addition of a hydroxyl group to carbon 25, to form 25-hydroxycholecalciferol (25-OH D3). This reaction is largely unregulated, although certain drugs and liver diseases may affect this step. Next, 25-hydroxycholecalcif-erol is released into the blood, and it undergoes a second hy-droxylation reaction on carbon 1 in the kidney. The product is 1,25-dihydroxycholecalciferol, also known as 1,25-dihy-droxyvitamin D3 or calcitriol, the principal hormonally active form of the vitamin. The biological activity of 1,25-di-hydroxycholecalciferol is approximately 100 to 500 times greater than that of 25-hydroxycholecalciferol. The reaction in the kidney is catalyzed by the enzyme 1a-hydroxylase, which is located in tubule cells.

The final step in 1,25-dihydroxycholecalciferol formation is highly regulated. The activity of 1a-hydroxylase is regulated primarily by PTH, which stimulates its activity. Therefore, if plasma calcium levels fall, PTH secretion increases; in turn, PTH promotes the formation of 1,25-di-hydroxycholecalciferol. In addition, enzyme activity increases in response to a decrease in plasma phosphate. This does not appear to involve any intermediate hormonal signals but apparently involves direct activation of either the enzyme or cells in which the enzyme is located. Both a decrease in plasma calcium, which triggers PTH secretion, and a decrease in circulating phosphate result in the activation of 1a-hydroxylase and an increase in 1,25-dihydroxy-cholecalciferol synthesis.

The Actions of Parathyroid Hormone, Calcitonin, and 1,25-Dihydroxycholecalciferol. Most hormones generally improve the quality of life and the chance for survival when an animal is placed in a physiologically challenging situation. However, PTH is essential for life. The complete absence of PTH causes death from hypocalcemic tetany within just a few days. The condition can be avoided with hormone replacement therapy.

The net effects of PTH on plasma calcium and phosphate and its sites of action are shown in Figure 36.7. PTH causes an increase in plasma calcium concentration while decreasing plasma phosphate. This decrease in phosphate concentration is important with regard to calcium homeostasis. At normal plasma concentrations, calcium and phosphate are at or near chemical saturation levels. If PTH were to increase both calcium and phosphate levels, they would simply crystallize in bone or soft tissues as calcium phosphate, and the necessary increase in plasma calcium concentration would not occur. Thus, the effect of PTH to lower plasma phosphate is an important aspect of its role in regulating plasma calcium.

Parathyroid hormone has several important actions in the kidneys (see Fig. 36.7). It stimulates calcium reabsorption in the thick ascending limb and late distal tubule, decreasing calcium loss in the urine and increasing plasma concentra

Regulation Plasma Calcium
, The conversion pathway of vitamin D3 into 1,25-dihy-droxycholecalciferol [1,25-(OH)2 Dal.

tions. It also inhibits phosphate reabsorption in the proximal tubule, leading to increased urinary phosphate excretion and a decrease in plasma phosphate. Another important effect of PTH is to increase the activity of kidney 1a-hydroxylase, which is involved in forming active vitamin D.

In bone, PTH activates osteoclasts to increase bone resorption and the delivery of calcium from bone into plasma (see Fig. 36.7). In addition to stimulating active osteoclasts, PTH stimulates the maturation of immature osteoclasts into mature, active osteoclasts. PTH also inhibits collagen synthesis by osteoblasts, resulting in decreased bone matrix formation and decreased flow of calcium from plasma into bone mineral. The actions of PTH to promote bone resorption are augmented by 1,25-dihydroxycholecalciferol.

PTH does not appear to have any major direct effects on the GI tract. However, because it increases active vitamin D formation, it ultimately increases the absorption of both calcium and phosphate from the GI tract (see Fig. 36.7).

Calcitonin is important in several lower vertebrates, but despite its many demonstrated biological effects in humans, it appears to play only a minor role in calcium homeostasis. This conclusion mostly stems from two lines of evidence. First, CT loss following surgical removal of the thyroid gland (and, therefore, removal of CT-secreting parafollicu lar cells) does not lead to overt clinical abnormalities of calcium homeostasis. Second, CT hypersecretion, such as from thyroid tumors involving parafollicular cells, does not cause any overt problems. On a daily basis, calcitonin probably only fine-tunes the calcium regulatory system.

The overall action of calcitonin is to decrease both calcium and phosphate concentrations in plasma (Fig. 36.8). The primary target of CT is bone, although some lesser effects also occur in the kidneys. In the kidneys, CT decreases the tubular reabsorption of calcium and phosphate. This leads to an increase in urinary excretion of both calcium and phosphate and, ultimately, to decreased levels of both ions in the plasma. In bones, CT opposes the action of PTH on osteoclasts by inhibiting their activity. This leads to decreased bone resorption and an overall net transfer of calcium from plasma into bone. Calcitonin has little or no direct effect on the GI tract.

The net effect of 1,25-dihydroxycholecalciferol is to increase both calcium and phosphate concentrations in plasma (Fig. 36.9). The activated form of vitamin D primarily influences the GI tract, although it has actions in the kidneys and bones as well.

In the kidneys, 1,25-dihydroxycholecalciferol increases the tubular reabsorption of calcium and phosphate, pro-

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