The dynamics of parathyroid hormone and calcitonin in surgery with artificial circulation

The use of considerable amounts of gelatinol in hypothermal perfusion determined the occurrence of marked hypercalcemia. The hormonal mechanism (parathyroid hormone and calcitonin) responsible for hypercalcemia compensation proved to be inefficient under hypothermal perfusion. A forced diuresis failed to result in rapid normalization of blood calcium concentrations. The volume of gelatinol used during extracorporeal circulation is not to exceed 500 ml.     

NPS R-568: a type II calcimimetic compound that acts on parathyroid cell calcium receptor of rats to reduce plasma levels of parathyroid hormone and calcium.

Calcimimetics like N-(3-[2-chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine (NPS R-568) potentiate the effects of extracellular Ca(2+) on parathyroid Ca(2+) receptors and inhibit parathyroid hormone (PTH) secretion in vitro. When administered by gavage to normal rats in this study, NPS R-568 caused a rapid, dose-dependent (ED(50), 1.1 +/- 0.7 mg/kg) decrease in PTH levels that was paralleled by a subsequent decrease in plasma Ca(2+) (ED(50), 10.4 +/- 3.7 mg/kg). At higher doses (>/=3.3 mg/kg), PTH was reduced to a minimum level within 15 min, the duration of which was dose dependent. With doses of 10 to 100 mg/kg, the hypocalcemia was rapid in onset (<30 min) and, at 33 to 100 mg/kg, persisted for >24 h. Neither the magnitude nor the kinetics of the hypocalcemic response was affected by total nephrectomy, demonstrating that NPS R-568 does not induce hypocalcemia by acting on renal Ca(2+) receptors to increase Ca(2+) excretion. In contrast, parathyroidectomy (intact thyroid) abolished the hypocalcemic response to NPS R-568, regardless of whether the rats were hypocalcemic or rendered acutely normo- or hypercalcemic by calcium infusion before dosing. These data show that the parathyroid Ca(2+) receptor can be selectively activated in vivo with a small organic compound to decrease plasma levels of PTH and Ca(2+) and thus define the mechanism of action of this compound in vivo. Moreover, the data add pharmacological support to the view that the Ca(2+) receptor is the primary molecular entity regulating systemic Ca(2+) homeostasis.     

Hypocalcemia and parathyroid hormone secretion in critically ill patients

OBJECTIVE: To investigate possible causes of hypocalcemia and to assess parathyroid hormone (PTH) secretion in intensive care unit (ICU) patients. DESIGN: Combined cross-sectional and prospective study. SETTING: ICU in a university hospital. PATIENTS: Thirteen patients with sepsis and 13 patients who underwent major surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Calcium metabolic indices were investigated during the first 24 hrs in the ICU and after 2 days. Eight of the surgical patients and five of the septic patients were subjected to a citrate/calcium infusion on day 1 in the ICU, to study the dynamics of PTH secretion. The blood ionized calcium (Ca2+) concentration was generally low in the septic patients (mean +/- SD, 1.03+/-0.08 mmol/L; reference value, 1.10-1.30) and increased, but not normalized, after 2 days. Hypocalcemia was only occasionally seen in the surgical patients. In the septic patients, urinary excretion of calcium was low; and, in both patient groups, elevated concentrations of two markers of bone resorption, deoxypyridinoline and ICTP (serum carboxy-terminal cross-linked telopeptide of type I collagen), were found. In cases of sepsis, the concentrations of proinflammatory cytokines were high (394+/-536 pg/mL for tumor necrosis factor-alpha and 5676+/-5190 pg/mL for interleukin-6, both normally <10-20). The Ca2+ concentration was inversely related to tumor necrosis factor-alpha and interleukin-6 (r2 = .35-.42; p<.01), as well as to procalcitonin (r2 = .71; p<.01). Despite normocalcemia in the surgical patients, serum PTH concentrations were elevated in both patient groups (97 and 109 ng/L) (reference value, <55 ng/L), both on day 1 and day 3 in the ICU. The citrate/calcium infusion revealed an increased secretory response of PTH to lowered Ca2+ concentrations in both groups of patients (p<.05), when compared with matched healthy controls. CONCLUSION: Hypocalcemia was common in septic ICU patients and was not the result of an increased urinary excretion of calcium or of an attenuated bone resorption, but seemed related to the inflammatory response. An increased PTH secretion was found in both patient groups.     

Effect of parathyroid hormone, calcitonin and growth hormone on cAMP content of growth cartilage in experimental uraemia

Abstract. The response of proximal tibial growth cartilage cAMP content to different hormonal stimuli, i.e. parathyroid hormone, calcitonin and somatotropic hormone was evaluated in rats with bilateral or subtotal nephrectomy. In uraemic rats, basal cAMP content of growth cartilage was unchanged. Administration of 1–34 PTH in vivo or incubation of growth cartilage with 1–34 PTH in vitro caused a significantly smaller increment of cAMP in uraemic rats (40 IU PTH in vivo : 11·4±1·01 pmol cAMP/mg protein; controls 24·0±2·55; P <0·001). This finding implies PTH resistance. Diminished cAMP response in uraemic animals was not changed by pretreatment with 1,25(OH)₂D₃ or parathyroidectomy. The increment of cAMP content of growth cartilage of uraemic animals was significantly ( P <0·01) greater after in vivo administration of 10 IU calcitonin (46·1±4·89 pmol/mg protein; control: 29·0±3·99) or incubation of cartilage with calcitonin in vitro . This finding implies overresponsiveness to calcitonin. Neither in acute nor in chronic uraemia, STH caused a significant change of cartilage cAMP or cGMP content, but STH stimulated ³H-thymidine incorporation into chondrocytes of rats with 5 days uraemia (solvent 2·98±0·51 times 10³ cpm per cartilage; STH 5·08±0·34; P <0·05) and caused significant improvement of longitudinal growth of rats with 20 days uraemia.     

Immunoreactive parathyroid hormone and calcitonin in plasma and ultrafiltrate before and after haemodialysis

The effects of haemodialysis on circulating immunoreactive parathyroid hormone (iPTH) and calcitonin (iCT) were determined in relation to alterations in total (Ca) and ionized (Ca2+) plasma calcium. The hormones were measured in plasma, in dialysate and in ultrafiltrate in eight patients with elevated iPTH concentrations. There was a small, but significant reduction in plasma iPTH during haemodialysis concomitant with an increase in Ca and Ca2+. Only small changes were found in plasma iCT during dialysis. Ultrafiltrate iPTH concentrations were reduced from 46% of plasma values at the beginning of dialysis to 27% of plasma values at the end of 4 h dialysis. Gel chromatography of plasma and ultrafiltrate showed corresponding molecular profiles of intact iPTH and hormone fragments suggesting that none of the PTH peptides were restricted by the dialysis membrane. Clearance of intact iPTH (dialysance) was as expected according to molecular weight. From the PTH clearance we calculated that only 5 to 10 micrograms of intact hormone were removed during dialysis. We therefore conclude that the reduction in plasma iPTH during dialysis is probably related to a relative suppression of PTH secretion rather than due to loss of hormone during dialysis.     

Calcium and phosphorus metabolism parathyroid hormone, calcitonin and bone histology in pseudohypoparathyroidism

Abstract. High blood levels of immunreactive parathyroid hormone and normal levels of calcitonin were detected in a 14-yearoIdgirl suffering from pseudohypoparathyroidism. Antibodies to parathyroid hormone have not been detected. Normalization of the serum calcium concentration suppressed parathyroid hormone and stimulated calcitonin secretion to a reproducible extent. Prolonged administration of parathyroid extract induced an increase ofphosphaturia and subsequently normalized the serum calcium level, while intestinal absorption of calcium did not improve. High values for the exchangeable calcium pool and the bone accretion rate of calcium were found. Histologically the iliac crest bone showed a deficient degree of mineralization and a high osteoclastic activity. Treatment with die hydrotachysterol for over a year did not normalize the respons-of urinary excretion of phosphate and cyclic AMP to administration of parathyroid extract. The data presented are compatible with a relative resistance of the renal tubules, the bone tissue and probably the gut to parathyroid hormone and with the co-existence of a moderate degree of osteomalacia and secondary hyperparathyroidism.     

Decrease in serum immunoreactive parathyroid hormone in rats and in parathyroid hormone secretion in vitro by 1,25-dihydroxycholecalciferol.

The present study determined the effects of 1,25-dihydroxycholecalciferol on serum immunoactive parathyroid hormone and on parathyroid hormone secretion in vitro. Rats injected i.p. with 1,25-dihydroxycholecalciferol, 130 pmol (2 U)/140 g body wt, which is probably a physiologic dose, had a significant 43% decrease in serum immunoreactive parathyroid hormone at 4 h. In addition, this dose of 1,25-dihydroxycholecalciferol inhibited the serum immunoreactive parathyroid hormone response to hypocalcemia induced by phosphate injection. Because the increment in serum immunoreactive parathyroid hormone was less but the decrement in serum calcium more in phosphate plus 1,25-dihydroxycholecalciferol-treated than in phosphate plus vehicle-treated rats, the impaired serum immunoreactive parathyroid hormone response to 1,25-dihydroxycholecalciferol could not be attributed to the change in serum calcium. In studies of parathyroid hormone secretion from bovine parathyroid tissue in vitro, the concentration of 1,25-dihydroxycholecalciferol used for most experiments was 1nM, which is in the range found in rat serum. 1,25-Dihydroxycholecalciferol at 1 or 100 nM significantly inhibited parathyroid hormone secretion when medium calcium concentration was normal (1.5 mM), high (3.0 mM), and low (1.0 mM). Maximum inhibition ranged from 19 to 74%; inhibition was generally seen after 2 h of incubation; and inhibition was sustained or progressive thereafter. Vitamin A, 0.1 muM, caused a marked stimulation of parathyroid hormone secretion. 1,25-Dihydroxycholecalciferol at 1 nM markedly reduced (44%) the effect of vitamin A to stimulate parathyroid hormone secretion. This effect of 1,25-dihydroxycholecalciferol was maximal at 1 h and persisted thereafter. Another steroid, hydrocortisone, 10 muM, did not inhibit parathyroid hormone secretion, suggesting that the 1,25-dihydroxycholecalciferol effect was not a nonspecific inhibitory effect on parathyroid cells. Because other workers have shown that parathyroid hormone directly stimulates 1,25-dihydroxycholecalciferol secretion, our results are consistent with the concept that there is a feedback loop where parathyroid hormone directly stimulates secretion of 1,25-dihydroxycholecalciferol, which in turn directly inhibits secretion of parathyroid hormone.     

Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats

Parathyroid hormone (PTH) is an effective bone anabolic agent, but it must be administered parenterally. An orally active anabolic agent would provide a valuable alternative for treating osteoporosis. NPS 2143 is a novel, selective antagonist (a "calcilytic") of the parathyroid cell Ca(2+) receptor. Daily oral administration of NPS 2143 to osteopenic ovariectomized (OVX) rats caused a sustained increase in plasma PTH levels, provoking a dramatic increase in bone turnover but no net change in bone mineral density. Concurrent oral administration of NPS 2143 and subcutaneous infusion of 17beta-estradiol also resulted in increased bone turnover. However, the antiresorptive action of estrogen decreased the extent of bone resorption stimulated by the elevated PTH levels, leading to an increase in bone mass compared with OVX controls or to either treatment alone. Despite the sustained stimulation to the parathyroid gland, parathyroid cells did not undergo hyperplasia. These data demonstrate that an increase in endogenous PTH secretion, induced by antagonism of the parathyroid cell Ca(2+) receptor with a small molecule, leads to a dramatic increase in bone turnover, and they suggest a novel approach to the treatment of osteoporosis.     

Dextran-charcoal and dioxane phase separation methods in the radioimmunoassays for parathyroid hormone and calcitonin

Dioxane precipitation and dextran-charcoal adsorption were used to separate free from bound ¹²⁵I-labelled hormone in the radioimmunoassays of calcitonin and parathyroid hormone. Changes in the fraction of bound radioactivity, independent of hormone concentrations, were seen with changes in temperature, plasma concentration, time of standing and amount of dioxane or dextran-charcoal added. Characterization of these variables affecting bound radioactivity, and careful standardization of the conditions of phase separation, indicate that dioxane precipitation is a satisfactory method for the calcitonin immunoassay while dextran-charcoal adsorption provides the most reliable results in the parathyroid hormone immunoassay.     

Early effects of synthetic bovine parathyroid hormone and synthetic salmon calcitonin on urinary excretion of cyclic AMP, phosphate and calcium in man.

Bovine synthetic parathyroid hormone infused intravenously in man increased both the urinary excretion of cyclic AMP and the urinary excretion of phosphate whereas a Salmon synthetic calcitonin infusion increased the urinary excretion of phosphate without change in urinary excretion of cyclic AMP. These data are consistent with the hypothesis that different renal mechanisms are involved in the response to each hormone.     

低钙透析对尿毒症患者甲状旁腺功能的影响

目的探讨低钙透析对慢性肾衰竭维持性血液透析患者甲状旁腺功能的影响.方法前瞻性观察58例维持性血液透析患者在单次高钙透析 (透析液钙1.75mmol/L)、单次低钙透析 (透析液钙 1.25mmol/L)前后及持续低钙透析1个月后(2～3次/周,4小时/次)血钙及甲状旁腺激素水平的变化.结果①单次高钙透析4小时后血钙水平明显升高[(2.18±0.15)mmol/L vs (2.35±0.08)mmol/L],iPTH水平没有明显变化[(191.41±108.19)ng/L vs (190.41±93.50)ng/L].②单次低钙透析4小时后血钙水平没有明显变化[(2.20±0.13)mmol/L vs (2.22±0.17)mmol/L)],但iPTH显著升高[(186.05±106.24)ng/L vs (210.04±113.46)ng/L)].③持续低钙透析1月后血钙水平没有变化[(2.20±0.13)mmol/L vs (2.23±0.11)mmol/L],iPTH有明显升高[(186.05±106.24)ng/L vs (229.98±120.20)ng/L].结论低钙透析会刺激甲状旁腺激素的分泌,加剧尿毒症患者的继发性甲状旁腺功能亢进.     

Renal effects of calcitonin and parathyroid extract in man: Studies in hypoparathyroidism

To clarify the controversial renal action of calcitonin (CT) and a possible interrelationship between CT and parathyroid hormone, eight patients with untreated surgical hypoparathyroidism were studied. Various calcitonins, i.e. extracted porcine, synthetic porcine, synthetic human, and synthetic salmon CT in doses of 150 Medical Research Council U or 1.5 mg were infused over a 3 hr period. Subsequently, six of the same subjects received 500 USP U parathyroid extract (PTE) (Eli Lilly & Co., Indianapolis, Ind.) in 3 hr and later a combination of CT and PTE. In addition, two patients were given an infusion of ammonium phosphate with the aim of producting a phosphaturia of comparable degree as seen after CT and PTE, thus differentiating hormonal from nonhormonal influences on cation excretion. A protocol of serial clearance (C) studies using the patients as their own controls was followed. Serum and urinary inorganic phosphate (P), calcium (Ca), magnesium (Mg), sodium (Na), potassium (K), and creatinine (Cr) were determined and the clearance values calculated.All CT peptides caused a uniform, immediate and significant increase of C(P), C(Na), C(K), C(Ca), and C(Mg), PTE evoked a rise of C(P), C(Na), and C(K), but C(Ca) and C(Mg) were reduced, the Ca and Na figures being not statistically significant. The administration of both CT and PTE resulted in a summation of individual hormone effects on Ca and Mg excretion. Phosphate infusion on the other hand induced an isolated phosphaturia but no concomitant changes of the urinary cations.The hypoparathyroid data demonstrate that calcitonin enhances urinary elimination of P, Na, K, Ca, and Mg independently of parathyroid action, CT and PTE act qualitatively similarly on P, Na, and K excretion, while an antagonism seems to exist for the renal handling of Ca and Mg.