Indirect calcium-level-increasing

Indirect calcium level-increasing actions of PTH on the gut are mediated through the vitamin 0 system. Following synthesis in the skin and hydroxylation by the liver, 25(OH)Vit03 is converted... 

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

Parathyroid hormone is a single-chain polypeptide of 84 amino acids which is produced in the parathyroid glands. It increases serum calcium and decreases serum phosphate. In bone it promotes resorption of calcium. It indirectly increases osteoclastic activity by promoting the action of osteoblasts. It has been shown that in low doses PTH may even increase bone formation without stimulating bone resorption. In the kidney PTH increases resorption of calcium and it increases excretion of phosphate. An other important activity in the kidney is the enhanced synthesis of 1,25-dihydroxyvitamin D. An increased serum calcium level inhibits PTH secretion and increased serum phosphate decreases free serum calcium and thus stimulates PTH secretion. 

Parathyroid hormone (PTH) is an 84-amino acid peptide secreted by the parathyroid glands, and is the principal regulator of extracellular calcium levels [44, 45]. The effects of PTH on extracellular calcium are mediated directly or indirectly through effects on bone, kidney, and intestine. A decrease in extracellular calcium causes an increase in PTH secretion. As a consequence, the rise in PTH levels causes increased bone resorption and the release of calcium from bone, decreased calcium excretion by the kidney, and increased intestinal calcium absorption. The therapeutic application of PTH has centered on the bone effects as an anabolic treatment for osteoporosis. PTH increases the activity of both osteoblasts (which form bone) and osteoclasts (which mediate bone resorption). The desirable anabolic effects of PTH on osteoblasts appear to be highly dependent on dose schedule and the duration of daily exposure. 

The contractile machinery of the myocardial cell is essentially the same as in striated muscle. The force of contraction of the cardiac muscle is directly related to the concentration of free (unbound) cytosolic calcium. Therefore agents that increase these calcium levels (or increase the sensitivity of the contractile machinery to calcium) result in an increase in the force of contraction (inotropic effect). [Note The inotropic agents increase the contractility of the heart by directly or indirectly altering the mechanisms that control the concentration of intracellular calcium.]... 

The account given above is only the briefest summary of the explosion of work on the mechanisms of effect of sulphur mustard that has been published during the past ten or so years. It is clear that Papirmeister s hypothesis linking DNA repair by poly(ADP-ribose) polymerase with a reduction in NAD+ and activation of the hexose monophosphate shunt and subsequent activation of proteases is still plausible. However, so is the apoptosis theory linking as it does with increases in intracellular calcium levels. It has also been shown that sulphur mustard can affect, directly or indirectly, components of the epidermal-basal lamina linkage system and this may explain the blistering effect of this chemical. However, some questions remain ... 

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. 

Many pathological conditions, including ischemia/reperfusion, inflammation, and sepsis may induce tissues to simultaneously produce both superoxide and nitric oxide. For example, ischemia allows intracellular calcium to accumulate in endothelium (Fig. 20). If the tissue is reperfused, the readmission of oxygen will allow nitric oxide as well as superoxide to be produced (Beckman, 1990). For each 10-fold increase in the concentration of nitric oxide and superoxide, the rate of peroxynitrite formation will increase by 100-fold. Sepsis causes the induction of a second nitric oxide synthase in many tissues, which can produce a thousand times more nitric oxide than the normal levels of the constitutive enzyme (Moncada et al., 1991). Nitric oxide and indirectly peroxynitrite have been implicated in several important disease states. Blockade of nitric oxide synthesis with N-methyl or N-nitroarginine reduces glutamate-induced neuronal degeneration in primary cortical cultures (Dawson et al., 1991). Nitroarginine also decreases cortical infarct volume by 70% in mice subjected to middle cerebral artery occlusion (Nowicki et al., 1991). Myocardial injury from a combined hy-... 

The high calcium works directly and indirectly by reducing PTH secretion. The high phosphate works directly and indirectly by increasing FGF23 levels. Since l,25(OH)2D raises serum calcium and phosphate, whereas 24,25(OH)2D has less effect,... 

Regulation of 25-hydroxycholecalciferol 1-hydroxylase 1,25-diOH D3 is the most potent vitamin D metabolite. Its formation is tightly i regulated by the level of plasma phosphate and calcium ions (Figure 28.24). 25-Hydroxycholecalciferol1 -hydroxylase activity is I increased directly by low plasma phosphate or indirectly by bw I plasma calcium, which triggers the release of parathyroid hormone I... 

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. 

Thus, a complex relationship exists among serum Ca + and phosphate, PTH, and vitamin D and its metabolites. Release of PTH in response to low serum Ca + directly mobilizes calcium from bone and increases synthesis of 1, 25-(0H)2D, which in turn mobilizes skeletal Ca + and causes increased intestinal calcium absorption. These effects raise the serum Ca level sufficiently to reduce PTH secretion. The effect of PTH on the kidneys occurs within minutes, whereas the effects of PTH on bone and (indirectly) on intestine take hours and days, respectively. An increase in serum phosphate acts in a way qualitatively similar to that of hypocalcemia to release PTH, increase excretion of phosphate in the proximal tubules, and decrease intestinal phosphate absorption. These events are mediated predominantly by the decrease in serum calcium that accompanies a rise in phosphate concentration. In addition, phosphate may inhibit 25-(OH)D-la-hydroxylase. 

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