Dynamic tests of parathyroid hormone secretion using hemodialysis and calcium infusion cannot be compared.
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BACKGROUND: Extracellular Ca++ concentration [Ca++] and parathormone (PTH) are related by a sigmoidal function. The set point of the control system is the [Ca++] that produces a half-maximal inhibition of PTH secretion. Whether or not this set point is abnormal in patients with chronic renal failure (CRF) and secondary hyperparathyroidism (SHP) is controversial. METHODS: We investigated whether the way [Ca++] is varied [hemodialysis (HD) or calcium gluconate/sodium citrate infusions (INF)] and the way the curve is constructed (four-parameter model or adapted four-parameter, created by Felsenfeld) could influence this set point. We performed dynamic tests of PTH secretion in 12 patients with CRF and SHP during either HD or INF. Both the four-parameter model or adapted four-parameter methods were used, creating four combinations: (a) hypocalcemia and hypercalcemia induced during HD, calculated by Brown's formula (HDB); (b) hypocalcemia and hypercalcemia induced during HD, calculated by Felsenfeld's formula (HDF); (c) hypocalcemia and hypercalcemia induced during infusion, calculated by Brown's formula (INFB); and (d) hypocalcemia and hypercalcemia induced during infusion, calculated by Felsenfeld's formula (INFF). RESULTS: The set points obtained with HDB correlated perfectly with those obtained with HDF (R2 = 0.999). A similar relationship was found between INFB and INFF (R2 = 0.9997). In contrast, there was no correlation between either HDB and INFB (R2 = 0.0157) or HDF and INFF (R2 = 0.0204). CONCLUSIONS: These findings indicate that the calculated [Ca++] set point in patients with CRF and SHP is determined by the way [Ca++] is varied, rather than by the mathematical model used to generate the curves. Further studies are needed to determine the differing physiological mechanisms triggered by HD and INF and the way they influence [Ca++] homeostasis in this setting. (+info)
The relaxant effects of parathyroid hormone(1-34) and parathyroid hormone-related protein(1-34) on ovine reticulo-ruminal smooth muscle in vivo.
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The motility of the reticulo-rumen has been measured in trained, conscious sheep using inflated balloons temporarily introduced to selected regions of that forestomach. The frequency and amplitude of the contractions of the reticulum and both the A and B waves of contraction of the rumen were measured under the same conditions before, during and after the administration of an i.v. bolus of either parathyroid hormone (PTH(1-34)) or PTH-related protein (PTHrP(1-34)) followed by its i.v. infusion. These two peptides are known to share a common receptor in other organs, e.g. the kidney. In this study they both showed an inhibitory effect on reticulo-ruminal motility. The effect of PTHrP(1-34) on the rate of ruminal blood flow was also examined and a significant reduction observed, after a transient increase. The secretion of endogenous PTH(1-34) was stimulated by a 32% reduction in the plasma calcium ion concentration induced by an i.v. infusion of sodium citrate. Associated with this were significant reductions in reticulo-ruminal motility, e.g. the reduction in the mean amplitude of the reticular contractions reflected the reduction in plasma calcium ion concentration. When the PTH(1-34)/PTHrP(1-34) receptor was blocked with [Asn10,Leu11,D-Trp12]PTHrP(7-34) before and during the induction of hypocalcaemia, all but one of the parameters of reticulo-ruminal motility were normalized. Indeed, by the day following the administration of this blocking agent, all these parameters had returned to their normal range. It is concluded that stimulation of the PTH(1-34)/PTHrP(1-34) receptor in reticulo-ruminal smooth muscle reduces the motility of this tissue and may play a role in the depression of motility of the digestive tract which is characteristic of clinical milk fever in the dairy cow. (+info)
Effect of hypocalcaemia on glucose metabolism in hyperketonaemic piglets.
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In nine 2- to 3-month-old hyperketonaemic piglets the kinetics of glucose and D-beta-hydroxybutyrate (D-BHB) metabolism were studied during hypo- and normocalcaemia in paired experiments. Hyperketonaemia (1.3 and 2.5 mmol D-BHB (l plasma)-1) was generated by a stepwise increase of DL-BHB infusion. Hypocalcaemia spontaneously developed in five piglets due to an inherited calcitriol deficiency and was induced in four control piglets by a continuous infusion of Na2-EDTA. The method of single isotopic marker injections of glucose and D-BHB was used to calculate replacement rates, rate constants and half-lives of glucose and D-BHB in plasma. When DL-BHB was infused at the same rate into normo- and hypocalcaemic piglets, hypocalcaemia reduced the rate constant of glucose by 20-30% and the replacement rate of glucose by 34%. In the presence of hyperketonaemia, hypocalcaemia increased the rate of replacement of D-BHB by 6-40%. The replacement rate represents the sum of endogenous production and the rate of DL-BHB infusion. This observation shows that the endogenous production of D-BHB was higher during hypocalcaemia than during normocalcaemia. (+info)
Rational design, conformational studies and bioactivity of highly potent conformationally constrained calcitonin analogues.
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Calcitonin is known for its hypocalcaemic effect and the inhibition of bone resorption, and is used therapeutically for the treatment of osteoporosis and Paget's disease. Our studies on the conformational features of human calcitonin (hCt) bioactivity have led to the conformationally constrained hCt analogue cyclo17,21-[Asp17, Lys21]hCt (1), which had a 5-10 times higher in vivo hypocalcaemic potency than hCt [Kapurniotu, A. & Taylor, J.W. (1995) J. Med. Chem. 38, 836-847]. We hypothesized that a stabilized, possibly type I beta turn/beta sheet conformation between residues 17 and 21 could play a crucial role in hCt bioactivity. Here, we designed, synthesized and studied the conformation and bioactivity of 19-member to 17-member ring-size analogues of 1 with the structure cyclo17,21-[Asp17,XX21]hCt with XX = Orn (2), Dab (3) and Dap (4), of the control peptide [Asp17,Orn21]hCt (5), and of the 19-member cyclo17,21-[Glu17,Dab21]hCt (6). Analyses of the far-UV CD spectra indicated increased type I beta turn and antiparallel beta sheet content in the bicyclic analogues compared with hCt. In the in vivo hypocalcaemic assay, cyclo17,21-[Asp17,Orn21]hCt (2) was found to have a 400-fold higher potency than hCt and was fourfold more potent than salmon calcitonin (sCt), which has been the most potent known Ct. Analogue 3 had a 30-fold higher potency than hCt, whereas the highly constrained analogue 4 was as potent as hCt. Bioactivity was not enhanced for the nonbridged compound [Asp17, Orn21]hCt (5), whereas cyclo17,21-[Glu17,Dab21]hCt (6) showed the same bioactivity as 1. This study identifies 2 as exhibiting the highest in vivo potency among currently known Cts, while it differs in only one amino acid residue from hCt, strongly suggesting that the introduced constraint may have served in 'freezing' hCt in a bioactive conformation. Our findings provide evidence for the first time that a beta turn/beta sheet conformation in region 17-21 of hCt and the topological features of the side chain of Asn17 are strongly associated with in vivo bioactivity, and offer a novel lead structure for a hCt-based drug for the treatment of osteoporosis and other bone-disorder-related diseases. (+info)
The PTH-calcium curve and the set point of calcium in primary and secondary hyperparathyroidism.
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BACKGROUND: The regulation of PTH secretion by calcium is altered in patients with primary hyperparathyroidism (HPT). A similar abnormality may occur in secondary HPT, but comparisons of PTH secretion in normal subjects and those with secondary HPT have given contrasting results. Differences in baseline serum ionized calcium (ICa) may partly account for these conflicting results. The aim of the present study was to evaluate whether the regulation of PTH secretion by calcium differs from normal in patients with primary and secondary HPT and to determine whether serum calcium concentration per se can affect the set point of calcium and the PTH-calcium relationship. METHODS: The PTH-ICa relationship and the set point of ICa were evaluated in 19 patients with primary HPT (1-HPT), 16 normocalcaemic patients with secondary HPT (2-HPT; PTH 344+/-191 pg/ml), 19 hypercalcaemic patients with secondary HPT (3-HPT; PTH 806+/-254 pg/ml) and 14 healthy volunteers, by inducing hypocalcaemia and hypercalcaemia in order to maximally stimulate or inhibit PTH secretion. In five 1-HPT patients the PTH-ICa curve was restudied after normalization of serum ICa by pamidronate. Parathyroid gland volume was determined by measuring gland size at parathyroidectomy or by means of high-resolution color Doppler ultrasonography. RESULTS: In 1-HPT patients the PTH-ICa curve, constructed using maximal PTH secretion induced by hypocalcaemia as 100%, was shifted to the right, the set point of ICa was increased, and the slope of the curve was reduced when compared to normal subjects. After normalization of baseline serum ICa by pamidronate, a shift of the PTH-ICa curve towards normal and a reduction in the set point of ICa was observed. However, basal PTH and maximal PTH secretion induced by hypocalcaemia increased, minimal PTH secretion induced by hypercalcaemia remained increased and the slope of the curve did not change significantly. The alterations in the PTH-ICa relationship in hypercalcaemic patients with secondary HPT were similar to those found in 1-HPT patients. In normocalcaemic patients with secondary HPT baseline PTH, maximal and minimal PTH secretion and parathyroid gland size were reduced compared to 3-HPT patients. Compared to normal subjects, 2-HPT patients showed greater calcium-induced minimal PTH secretion. The increase in non-suppressible PTH secretion resulted in a rightward shift of the PTH-ICa curve and an increase in the set point of ICa. A strong correlation was found, in both primary and secondary HPT, between the set point of ICa and baseline serum ICa, and between parathyroid gland size and baseline PTH, maximal PTH and minimal PTH. Multivariate regression analysis showed that baseline serum ICa was the main determinant of the set point of ICa in both primary and secondary HPT. CONCLUSIONS: (i) The regulation of PTH secretion by calcium is abnormal in secondary as well as in primary HPT. (ii) Parathyroid gland enlargement in secondary HPT is associated with reduced sensitivity to serum ICa and resistance of parathyroid gland to calcium-mediated PTH suppression, resulting ultimately in PTH hypersecretion, despite hypercalcaemia. (iii) The set point of calcium is strongly dependent on baseline serum calcium, and the PTH-ICa relationship can be affected by variations in serum ICa concentrations. Thus, when the set point of calcium and the PTH-ICa relationship are evaluated, possible differences in baseline serum ICa concentration among the patients should be taken into account. (+info)
Experimental hypocalcemia induced by hemodialysis in goats.
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To evaluate whether hemodialysis with a dialysate containing no calcium (Ca-free HD) can induce hypocalcemia and restore the clinical signs and blood biochemical changes in naturally occurred hypocalcemic disorder in ruminants, the clinical signs and the changes in plasma electrolytes and minerals concentrations were observed in goats during 6-hr hemodialysis. The four goats received hemodialysis with the dialysate containing calcium (Ca HD), and 10 days later they had Ca-free HD. The plasma ionized Ca (Ca++) and total Ca (TCa) concentrations were not affected by Ca HD, whereas the levels significantly decreased during whole period of Ca-free HD. The Ca++ and TCa concentrations were 0.69+/-0.06 mmol/l and 5.9+/-0.3 mg/dl at 6 hr of Ca-free HD, respectively. The clinical signs observed during Ca-free HD seemed to resemble to those in naturally occurred hypocalcemic cases that were reported previously. Therefore, Ca-free HD was suggested to be one of the possible methods to induce experimental hypocalcemia in ruminants. (+info)
Fractures due to hypocalcemic convulsion.
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We report on two cases of patients in whom hypocalcemic seizures during hemodialysis led to right scapular body fracture in one and bilateral femoral neck fractures in the other. (+info)
Cross-sectional study of the association of abomasal displacement or volvulus with serum electrolyte and mineral concentrations in dairy cows.
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The objective of this study was to evaluate serum mineral and electrolyte concentrations at the time of on-farm diagnosis of left displaced abomasum, right displaced abomasum, or abomasal volvulus in dairy cows. Data were collected from 104 affected cows and 96 control cows matched with cases, based on herd, parity, and stage of lactation. Cows with abomasal displacement or volvulus had significantly lower calcium, phosphorous, magnesium, potassium, and chloride concentrations and increased anion gap at the time of diagnosis compared with control cows from the same herds. The percentages of cases and controls with total serum calcium concentrations below the lower limit of the laboratory reference range (2.08 mmol/L [8.3 mg/dL]) were 70% and 23%, respectively. Based on the large percentage of cases with hypocalcemia, administering calcium salts at the time of treatment of field cases of abomasal displacement or volvulus may be beneficial. (+info)