Calcimimetic compound NPS R-568 stimulates calcitonin secretion but selectively targets parathyroid gland Ca(2+) receptor in rats.
N-(3-[2-Chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine (NPS R-568) is an orally active compound that activates Ca(2+) receptors on parathyroid cells and rapidly suppresses plasma levels of parathyroid hormone (PTH) and Ca(2+) (ED(50), 1 and 10 mg/kg, respectively). We now show that increased calcitonin secretion contributes to NPS R-568-induced hypocalcemia. In parathyroidectomized thyroid-intact rats in which normocalcemia was restored by PTH infusion, NPS R-568 rapidly reduced plasma Ca(2+) levels, indicating that decreased PTH secretion was not solely responsible for the hypocalcemia seen in normal animals. NPS R-568 decreased plasma Ca(2+) levels in thyroidectomized parathyroid-intact rats, but the rate of onset of hypocalcemia was slower than in controls. In contrast, NPS R-568 had no effect on plasma Ca(2+) levels in PTH-infused, thyroparathyroidectomized rats, providing evidence that increased calcitonin secretion caused the hypocalcemia in PTH-infused parathyroidectomized rats. NPS R-568 rapidly increased plasma calcitonin levels to a peak at 10 to 20 min after oral dosing (ED(50) 40 mg/kg). NPS R-568 did not affect the rate of disappearance of (45)Ca from blood, indicating that hypocalcemia resulted from decreased influx of Ca(2+) into the circulation and not from increased efflux. This suggests that NPS R-568-induced hypocalcemia resulted solely from reduced efflux of Ca(2+) from bone after increased calcitonin and reduced PTH secretion. Thus, NPS R-568 causes hypocalcemia by activating Ca(2+) receptors on C cells and parathyroid cells; however, NPS R-568 is about 40 times more potent in reducing PTH levels than in increasing calcitonin levels. (+info)
Dynamic tests of parathyroid hormone secretion using hemodialysis and calcium infusion cannot be compared.
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)
In vivo effect of endothelin-1 on plasma calcium and parathyroid hormone concentrations.
We have previously reported an in vitro inhibitory effect of endothelin-1 (ET-1) on parathyroid hormone (PTH) secretion. In the present experiment, ET-1 was infused into rabbits to study the in vivo effect of ET-1 on the changes in calcium, magnesium, PTH and calcitonin concentrations. Femoral arteries and veins of anesthetized male rabbits were cannulated to monitor vital signs, blood sampling and infusion of the agents being studied. Infusion of ET-1 (1, 5, 10 and 20 ng/kg per min) induced a dose-dependent decline in plasma ionized calcium concentrations from 6.68+/-0.26 to 5.50+/-0.46 mg/dl (P<0.05) and a decrease in calcitonin concentrations from 48.6+/-6.5 to 32.5+/-4.7 pg/ml. PTH concentrations increased from 58.3+/-10.2 to 159.4+/-22.1 pg/ml. In a separate experiment, calcium gluconate solution was simultaneously infused to keep calcium concentrations steady, thereby proving a calcium 'clamp'. In normal calcium concentration, ET-1 infusion gradually decreased PTH concentrations from 71.4+/-8.6 to 38.0+/-6.2 pg/ml. We further infused sodium citrate solution to decrease the calcium concentration (2.0 mg/dl less) and calcium gluconate solution was infused to keep calcium concentrations steadily less than normal. PTH concentrations were initially stimulated by the induction of hypocalcemia (68.1+/-11.2 to 135.6+/-8.5 pg/ml), but decreased by ET-1 infusion (135.6+/-8.5 to 85.1+/-15.2 pg/ml). Plasma magnesium concentrations did not change significantly throughout the entire study and calcitonin concentrations were not significantly changed during the calcium clamp studies. Serum phosphate and 1,25-(OH)(2) vitamin D(3) concentrations were also measured, but they also did not change significantly. In conclusion, ET-1 exhibited an in vivo acute hypocalcemic action, independent of calcitonin. It also directly decreased PTH secretion if serum calcium concentrations were kept steady. The above findings are consistent with the results of our previous in vitro experiment. (+info)
The management of hyperkalaemia in the emergency department.
Life threatening hyperkalaemia (> 7.0 mmol/l) is commonly associated with acute renal failure. Moderate hyperkalaemia (6.1-6.9 mmol/l) is also common and well tolerated in patients with chronic renal failure. Renal failure is the most common cause of hyperkalaemia although other causes to consider include drugs (potassium sparing diuretics, angiotensin converting enzyme inhibitors), hyperglycaemia, rhabdomyolysis and adrenal insufficiency. Hyperkalaemia affects the cardiac conducting tissue and can cause serious arrhythmias including ventricular fibrillation and asystolic arrest. Therefore it is important to treat hyperkalaemia promptly in the emergency department. This paper evaluates the therapeutic options available for treatment of hyperkalaemia. (+info)
Usefulness of the combination of pre- and intraoperative selective intraarterial calcium injection to detect residual insulinomas.
In a 35-year-old woman diagnosed with insulinoma selective intraarterial calcium injection was positive for proximal gastroduodenal artery and inferior pancreaticoduodenal artery involvement preoperatively. Although non-invasive imaging studies were negative, a mass was detected at the pancreatic uncus by intraoperative ultrasonography. Gastroduodenal artery calcium injection was performed after enucleation of the tumor. Following calcium injection, the insulin level was inappropriately increased and further pancreaticoduodenectomy was performed. After excision, another tumor was detected at the head of the pancreas by histopathological examination. As shown, selective intraarterial calcium injection is useful to localize tumors preoperatively and intraoperatively. (+info)
Hypocalcaemia and hypomagnesaemia due to hydrofluoric acid.
Hydrofluoric acid readily penetrates the skin and mucous membranes, causing deep tissue layer destruction. Dermal exposure can produce hypocalcaemia, hypomagnesaemia, hyperkalaemia, cardiac dysrhythmias and death. We report the case of a 52-year-old man who presented hypocalcaemia and hypomagnesaemia due to occupational dermal contact with hydrofluoric acid. Hypocalcaemia and hypomagnesaemia were corrected by i.v. administration of calcium gluconate and magnesium sulphate. (+info)
Functional atrioventricular block in a preterm infant.
A case of functional second degree atrioventricular block is reported in a preterm infant secondary to early onset hypocalcaemia. An infusion of 10% calcium gluconate rapidly corrected the arrhythmia. (+info)
Effects of elevated calcium on motor and exploratory activities of rats.
The effects of serum and brain calcium concentration on rat behavior were tested by maintaining animals on either distilled water (N = 60) or water containing 1% calcium gluconate (N = 60) for 3 days. Animals that were maintained on high calcium drinking water presented increased serum calcium levels (control = 10.12 +/- 0.46 vs calcium treated = 11.62 +/- 0.51 microg/dl). Increase of brain calcium levels was not statistically significant. In the behavioral experiments each rat was used for only one test. Rats that were maintained on high calcium drinking water showed increased open-field behavior of ambulation (20.68%) and rearing (64.57%). On the hole-board, calcium-supplemented animals showed increased head-dip (67%) and head-dipping (126%), suggesting increased ambulatory and exploratory behavior. The time of social interaction was normal in animals maintained on drinking water containing added calcium. Rats supplemented with calcium and submitted to elevated plus-maze tests showed a normal status of anxiety and elevated locomotor activity. We conclude that elevated levels of calcium enhance motor and exploratory behavior of rats without inducing other behavioral alterations. These data suggest the need for a more detailed analysis of several current proposals for the use of calcium therapy in humans, for example in altered blood pressure states, bone mineral metabolism disorders in the elderly, hypocalcemic states, and athletic activities. (+info)