T3 C

11 c T3

Ca2+, as "intracellular transmitter", mediates electromechanical coupling. It stimulates the release of neurotransmitters (synaptic transmitters) and hormones, the secretory activity of exocrine glands and of a number of enzymes (e.g., glycogenolysis, phospholipase A, adeny-lylcyclase, phosphodiesterases). Ca2+ activates some K+ channels, for example, in the heart, where Ca2+-sensitive K+ channels take part in the process of repolarization. Extracellular Ca2+ stabilizes Na+ channels, reduces the permeability of the basement membranes and the tight junctions, and plays a role in blood clotting.

The regulation of the extracellular Ca2+ concentration is, in the first instance, the task of PTH. It is normally released in hypocalcemia and its action increases the plasma concentration of Ca2+ (^A1,A2). PTH stimulates the mobilization of calcium phosphate from bone, decreases the plasma concentration of phosphate by inhibiting its renal reabsorption, and stimulates the formation of calcitriol, which promotes the enteric absorption of Ca2+ and phosphate, and thus aids in the mineralization ofthe bones.

Hypocalcemia (^A1) can be the result of reduced PTH release (hypoparathyroidism) or effect (pseudohypoparathyroidism). In addition, vitamin D deficiency can lead to hypocal-cemia via a diminished formation of calcitriol. In renal failure phosphate elimination by the kidney is reduced, the plasma phosphate level rises, and calcium phosphate is deposited in the body (^ p. 110). One of the consequences is hypocalcemia. Mg2+ deficiency also leads to hypocalcemia, especially if there is no stimulation of PTH release.

Even when the total Ca2+ concentration in blood is normal, the concentration of the effective ionized Ca2+ may be reduced because of increased formation of complexes with proteins (in alkalosis), bicarbonate (in metabolic alkalosis), phosphate (in renal failure, see above), and fatty acids (in acute pancreatitis; ^ p. 126,158) (^ A3).

Hypercalcemia (^ A2) occurs in hyperparathyroidism and vitamin D excess. Malignant tumors with bone metastases lead to an increased mobilization of calcium phosphate from bone and thus to hypercalcemia. Occasionally malignant tumors will, even in the absence of skeletal metastases, produce bone-mobilizing hormones such as osteoclast-acti-vating factor (OAF). Lastly, minerals in bone will be mobilized on acute immobilization associated with atrophy of inactivity. Increased enteric Ca2+ absorption is brought about by an excessive supply of Ca2+ and alkaline substances (milk-alkali syndrome).

The clinically most significant effect of hypocalcemia is an increased excitability of muscles and nerves with the occurrence of involuntary muscle spasms (tetany) and paresthesias (^ A4). The increased excitability is probably due to the lowered threshold of Na+ channels in hypocalcemia. In severe cases epileptic seizures may occur (^ p. 338). Hypocalcemia triggers a lengthening of the action potential in the heart because of the delayed activation of the K+ channels, resulting in prolongation of the ST segment and QT interval in the ECG.

The effects of hypercalcemia (the condition is often asymptomatic) may include gastrointestinal symptoms (peptic ulcers due to stimulation of gastrin release and inhibition of pancreatic HCO3--secretion by the Ca2+ receptor, nausea, vomiting, constipation), polyuria (inhibition of renal reabsorption due to closure of tight junctions and activation of the Ca2+ receptor), increased thirst with polydipsia, and psychogenic disorders (^A5). If present for long, nephrolithiasis may result. If total plasma Ca2+ concentration is above 3.5 mmol/L (so-called hypercalcemia syndrome), coma, cardiac arrhythmias, and renal failure (mainly due to Ca2+ deposition in renal tissue) occur. An important indication of the presence of hyper-calcemia syndrome is precipitation of calcium phosphate in the locally alkaline cornea (through loss of CO2; cataract; "keratitis"). In the ECG the ST segment is shortened in line with accelerated activation of the repolarizing K+ channels. Of great clinical significance in hypercalcemia is the increased sensitivity of the heart to digitalis, as this effect is normally mediated via an increased cytosolic Ca2+ concentration (^ p. 182).

Alkali

Inactivity

Tumor cells a

Calcitriol f i

Interleukin

Ds excess

25-OH-Do

PTH t

Hypercalcemia

Heart:

- Shortening of action potentials

- Increased digitalis sensitivity

Nephrocalcinosis, keratitis

Psychiatric disorders

Polyuria, magnesiuria, constipation, indigestion, nausea gK+ j

Precipitation

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