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J. FOX and A. D. CARE

The effects of hydroxylated derivatives of vitamin D3 and aqueous extracts of Solanum malacoxylon on the intestinal absorption of calcium, phosphate, sodium, potassium and water have been studied in unstressed vitamin D-replete pigs each of which was surgically prepared beforehand with a Thirty–Vella loop of jejunum. The addition, for six 1 h periods of perfusion, of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) or 1α-hydroxycholecalciferol at similar concentrations (3·6–3·75 pmol/ml) to the solution used to perfuse the intestinal loop caused a rapid increase in the absorption of calcium but increased the absorption of phosphate only after a delay of at least 12 h. The absorption of both calcium and phosphate reached a maximum on the day following the addition of the vitamin D derivative to the perfusate. The addition of 25-hydroxycholecalciferol (25-(OH)D3) at a concentration of 3·75 pmol/ml was without effect on absorption except for a small increase in the absorption of phosphate on the following day. However, at higher concentrations (> 250 pmol 25-(OH)D3/ml) the absorptions of calcium and phosphate were both increased rapidly. 24,25-Dihydroxycholecalciferol was without effect on absorption at the concentration tested (3·6 pmol/ml).

Aqueous extracts (1%) of the leaf of S. malacoxylon showed similar effects on absorption to those of 1,25-(OH)2D3. However, there was one point of difference; the absorption of phosphate was stimulated with a similar time course to that of calcium in contrast to its delayed response to 1,25-(OH)2D3.

The absorption rates of water, sodium and potassium were not consistently affected by 1,25-(OH)2D3 or S. malacoxylon. However, the major effects of these derivatives were usually seen on the day following the day of addition to the perfusate. In contrast, 25-(OH)D3 at high concentrations had a marked effect on the absorption of water, sodium and potassium on the day of addition.

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A. D. CARE and T. DUNCAN

As part of their investigation of the source of calcitonin, Copp & Henze (1964) perfused one lobe of the thyroid gland in anaesthetized sheep with hypercalcaemic blood but failed to elicit a systemic hypocalcaemic response. On the other hand, in goats Foster, Baghdiantz, Kumar, Slack, Soliman & Maclntyre (1964) found a marked systemic hypocalcaemia during hypercalcaemic perfusion of a thyroid lobe and two parathyroid glands, but found no such response during hypercalcaemic perfusion of one parathyroid gland only. Care (1965), in young pigs, perfused the thyroid only with high calcium blood and observed a profound fall in the systemic plasma calcium concentration.

The explanation for the contrast in the response to stimulation of thyrocalcitonin secretion may lie in a difference in age and also perhaps in the species. Copp & Henze (1964) used five adult sheep and five younger Suffolk sheep which weighed about 40 kg.; the ages of the

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J. FOX and A. D. CARE

SUMMARY

The intestinal absorption of phosphate has been studied in conscious pigs, each prepared with a Thirty–Vella loop of jejunum. The feeding of diets low in either calcium or phosphorus caused a significant increase in the efficiency of absorption of phosphate from the solution used to perfuse the jejunal loop in both intact and parathyroidectomized (PTX) pigs. An intravenous infusion of parathyroid hormone (0·22 u. kg−1 h−1) into a PTX pig also enhanced the absorption of phosphate. The increase in the absorption of phosphate when the low phosphorus diet was fed was not caused by an increase in the concentration gradient of phosphate ions between the jejunal lumen and blood.

It is concluded that the intestinal absorption of phosphate shows similar changes to those of calcium when diets low in calcium or phosphorus are fed and that parathyroid hormone, although capable of stimulating the absorption of phosphate, is not essential for this adaptation. These effects are probably brought about by changes in the renal production and mucosal uptake of 1,25-dihydroxycholecalciferol, the active metabolite of vitamin D3.

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A. D. CARE, T. DUNCAN and D. WEBSTER

SUMMARY

In pigs, the control of hypercalcaemia was significantly impaired by thyroidectomy.

Hypercalcaemic perfusion of the pig thyroid (which contains no parathyroids) in situ produced a systemic hypocalcaemic response which reached its maximum after about 2 hr. perfusion and which persisted for as long as the hypercalcaemic stimulus was applied. Thyroid venous plasma from a gland so perfused, when cross-transfused into a second pig, caused a hypocalcaemic reaction similar to that produced by the intravenous injection of porcine thyrocalcitonin preparations.

Hypermagnesaemia did not appear to influence the release of thyrocalcitonin.

A hypocalcaemic response to hypercalcaemic perfusion of the thyroid, similar to that seen in intact pigs, occurred in parathyroidectomized pigs, provided that the initial plasma calcium level was maintained by suitable calcium supplement to the diet.

Hypocalcaemic perfusion of the thyroid, in either intact or parathyroidectomized pigs, resulted in a rise in the systemic plasma calcium concentration, although this rise was only consistently observed when the systemic plasma calcium level was already low as a result of thyrocalcitonin secretion.

It is suggested that the secretion of thyrocalcitonin is controlled by a negative feedback mechanism operating through the plasma calcium concentration, and that because of the rapidity of its release, action and elimination, relative to parathyroid hormone, thyrocalcitonin acts as a fine regulator of calcium homeostasis.

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J. FOX, A. D. CARE and J. BLAHOS

SUMMARY

The effect of oral administration of betamethasone (25 μg kg−1 day−1) on the duodenal absorption of calcium has been studied in chicks using the ligated loop technique in vivo. The chicks were fed normal calcium, normal phosphorus (NCaNP), low calcium, normal phosphorus (LCaNP) or normal calcium, low phosphorus (NCaLP) diets. Daily oral administration of betamethasone for 2–3 weeks markedly reduced the absorption of calcium in chicks fed the NCaNP diet, but did not significantly affect the adaptation in absorption when the NCaLP or LCaNP diets were fed for the same period of time. In one group of chicks, betamethasone was administered daily for 10 days before the birds were transferred to the NCaLP or LCaNP diets. Adaptation was again unaffected by betamethasone treatment. Administration of betamethasone caused a marked retardation in growth-rate, hypercalcaemia and an increased percentage of ash in the tibiae.

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R. SWAMINATHAN, J. KER and A. D. CARE

SUMMARY

The effect of calcitonin (CT) on small intestinal calcium absorption was studied using Thiry—Vella loops in one intact sheep, one intact pig and three parathyroidectomized pigs. Net calcium absorption rate was measured after recirculating through the loop a known volume of a solution containing calcium and polyethylene glycol 4000. Calcitonin was infused intravenously and its effect on the net calcium absorption rate was measured. When relatively high doses of CT (10 mu./min/kg) were infused for up to 45 h, there was an initial rise in net calcium absorption associated with hypocalcaemia, followed by a marked reduction in calcium absorption. When small doses of CT (0·5 mu./min/kg) were infused for 100 h, the increase in the net absorption rate was not observed or was less marked, but there was a significant reduction in net calcium absorption 2 days after the CT infusion was stopped. A reduction in net calcium absorption rate was seen both in intact and parathyroidectomized animals. In one experiment in which the true absorption rate of calcium from lumen to blood was measured using 47Ca, a reduction in unidirectional transfer of calcium from lumen to blood was seen 2 days after the CT infusion was stopped. The possible mechanism of this action of CT and its significance in calcium homeostasis during the ingestion of a high calcium diet is discussed.

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J. FOX, A. D. CARE and D. H. MARSHALL

SUMMARY

The intestinal absorption of calcium has been studied in conscious, unstressed pigs, using a modification of the double isotope technique. The oral administration of betamethasone (1 mg/day) to four pigs (25–33 kg) for 4 weeks reduced the calcium absorption coefficient, calculated after the intravenous and oral administration of 47Ca2+, by a mean value of 66%. The oral administration of 1α-hydroxycholecalciferol (2 μg/day) in combination with betamethasone (1 mg/day) for a further 4 weeks returned the absorption coefficient to the control value.

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W. A. Ratcliffe, S. K. Abbas and A. D. Care

ABSTRACT

In the sheep, goat and pig, radiolabelled parathyroid hormone related protein (PTHRP) and immunoreactive PTHRP(1–34) and (1–86) were rapidly cleared from the circulation. Metabolic clearance rates (MCR) were in the range of 1·25–7·5 ml/min per kg and were slightly slower than that of intact PTH in man (10 ml/min per kg); while the mean MCR of labelled PTHRP(1–86) in fetal sheep and goats was significantly faster than that in their respective mothers (14·4 vs 4·0 ml/min per kg respectively). This may reflect increased metabolism of PTHRP by fetal tissues, e.g. the placenta. Similar rates of clearance of radiolabelled PTHRP(1–141), (1–86) and (1–34) suggest that clearance involves the amino terminus of the molecule.

Journal of Endocrinology (1993) 138, 459–465

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E. M. W. Maunder, A. V. Pillay and A. D. Care

ABSTRACT

The aetiology of the rise in plasma calbindin-D9k (vitamin D-induced calcium-binding protein; CaBP), following insulin-induced hypoglycaemia, was studied in the pig. ACTH led to a rise in plasma concentrations of both CaBP and cortisol. Metyrapone, which blocks cortisol synthesis, abolished the increases in plasma concentrations of CaBP and cortisol normally observed in response to insulin-induced hypoglycaemia. However, there was no significant rise in plasma concentrations of CaBP in response to pharmacological or physiological doses of cortisol.

Injection of clonidine, an α2-adrenergic agonist, led to a rise in plasma concentrations of CaBP, whereas phenylephrine, an α1-adrenergic agonist, tended to exert an inhibitory effect. Also, administration of phentolamine (an α-adrenergic blocker) before injection of insulin abolished the usual increase in plasma concentrations of CaBP, whereas propranolol (a β-adrenergic blocker) enhanced the normal increase in plasma concentrations of CaBP in response to insulin-induced hypoglycaemia. Isoproterenol, a β-adrenergic agonist, was without effect on plasma CaBP. Neither GH nor glucagon appear to be involved in the rise in plasma CaBP following insulin-induced hypoglycaemia. Although atropine abolished the effect of acute hypoglycaemia on plasma CaBP, carbamylcholine was without effect on plasma CaBP concentration. It is concluded that the increases in plasma CaBP induced by either ACTH or α2-adrenergic stimulation may be interrelated since the administration of ACTH can lead to raised plasma concentrations of catecholamines.

J. Endocr. (1987) 115, 121–128

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E. M. W. Maunder, A. V. Pillay and A. D. Care

ABSTRACT

An i.v. injection of calcitriol (1,25-(OH)2D3) had no effect within 2·5 h on plasma concentrations of calbindin-D9k (vitamin D-induced calcium-binding protein; CaBP) in hypocalcaemic pigs with inherited vitamin D-dependent rickets type I or in their normocalcaemic siblings or half-siblings. Three days later the plasma concentration of CaBP had doubled in the hypocalcaemic pigs, but was unaltered in the normocalcaemic siblings and half-siblings. Following daily i.v. injections of 1,25-(OH)2D3 for a further 5 days (days 4–8) plasma concentrations of CaBP increased in both the hypocalcaemic (days 4–8) and normocalcaemic (day 8) pigs, the effect being more rapid and greater in the hypocalcaemic 1,25-(OH)2D3-deficient animals. An i.v. injection of 1,25-(OH)2D3 to pure Yucatan pigs also had no effect on plasma concentrations of CaBP within 1·5 h, but in the following 1 h there was some indication of an increase in plasma CaBP levels.

In contrast to the normal pigs, insulin-induced hypoglycaemia did not lead to a peak in plasma CaBP concentrations in the hypocalcaemic pigs. There was also no change in the plasma concentrations of 1,25-(OH)2D3 associated with the peak in plasma CaBP following insulin-induced hypoglycaemia in normocalcaemic pigs. These results suggest that changes in plasma concentrations of 1,25-(OH)2D3 are not directly involved in mediating the increase in plasma CaBP which follows hypoglycaemia induced by insulin in normal pigs, although 1,25-(OH)2D3 probably plays a permissive role.

J. Endocr. (1987) 115, 129–134