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SUMMARY
A radioimmunoassay for bovine neurophysin is described. The assay has a lower limit of detection of approximately 0·5 ng/ml. Bovine neurophysin extracted and purified from acetone-dried posterior pituitary lobe powder was used for standardization, radio-iodination and immunization of rabbits. Some anti-neurophysin sera were also obtained from human subjects treated with Pitressin. Most of the antisera tested did not readily distinguish between the different neurophysin components isolated from bovine neurohypophysial tissue. The antisera cross-reacted with material extracted from whole pituitaries of a number of mammalian species, including man, pig, sheep, guinea-pig and rat, but not with the pituitary peptides from the cod or dogfish, or the egret. Other pituitary peptides, including oxytocin, vasopressin, corticotrophin, growth hormone and luteinizing hormone, did not interfere with the assay.
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Introduction
Features of hyperparathyroidism have long been associated with malignancy, and with the advent of sufficiently sensitive bioassays, parathyroid hormone (PTH)-like activity was recognised in extracts of tumours from patients suffering from humoral hypercalcaemia of malignancy (HHM) (Stewart et al. 1983). While these extracts exhibited actions on bone and kidney that were very similar to those of PTH, low or undetectable levels of immunoreactive PTH in patients' plasma and in the tumour extracts indicated that the substance was unique (Stewart et al. 1980, Rodan et al. 1983, Stewart et al. 1983, Strewler et al. 1983). Subsequently, parathyroid hormone-related protein (PTHrP) was purified, sequenced and cloned from a human lung cancer cell line derived from a patient with HHM (Moseley et al. 1987, Suva et al. 1987).
This protein, homologous with PTH in the amino-terminal region, acts through a common PTH/PTHrP receptor (Jüppner et al. 1991) to promote bone
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ABSTRACT
Five synthetic analogues of human parathyroid hormone (hPTH), (Tyr34)hPTH(3–34) amide, (5–34) amide, (7–34) amide, (8–34) amide and (9–34) amide, were tested for their ability to antagonize hPTH action specifically in intact cultured cells. Clonal rat osteogenic sarcoma cells were used (UMR 106–06 line) which respond to PTH with an increase in cyclic AMP (cAMP) formation. The most potent antagonists were (Tyr34)hPTH(3–34) amide and (5–34) amide, which inhibited the effect of hPTH(2·4 nmol/l) with half maximally effective concentrations of 0·1 μmol/l. When conditioned medium was used from a human lung cancer cell line producing osteoblast adenylate cyclase-stimulating activity, these two analogues were capable of inhibiting the increase in cAMP production. The specificity of the antagonism was indicated by the inability of the analogues to influence the effects of prostaglandin E2 or of calcitonin, which are alternative stimulators of cAMP production in the osteogenic sarcoma cells. Only (Tyr34)hPTH(3–34) amide showed some PTH-like agonist activity at high concentrations. These analogues should prove valuable in the investigation of PTH actions on target cells and of tumour products which appear to act through the PTH receptor.
J. Endocr. (1986) 108, 261–265
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ABSTRACT
The isolated perfused rat kidney was used to study the effects of amino-terminal fragments of human parathyroid hormone, hPTH(1–34), bovine parathyroid hormone, bPTH(1–84) and of PTH-related proteins, PTHrP(1–34), PTHrP(1–84), PTHrP(1–108) and PTHrP(1–141) on urinary bicarbonate excretion. PTHrP(1–34) (7 nmol/l), bPTH(1–84) (5·5 nmol/l) and hPTH(1–34) (7 nmol/l) had similar effects in increasing bicarbonate excretion with respect to the control. At lower concentrations (0·7 nmol/l) all PTHrP components, but not hPTH(1–34) or bPTH(1–84) increased bicarbonate excretion significantly. Infusions of PTHrP(1–108) and PTHrP(1–141) at 0·7 nmol/l, while associated with a rise in urinary bicarbonate concentration and excretion during the early stages of perfusion, produced a sharp decline in bicarbonate concentration and excretion in the latter part of perfusion. The different peptides produced no significant differences in glomerular filtration rate, fractional excretion of sodium or urine volume. The absence of substantial differences between the effects of hPTH(1–34) and PTHrP(1–34) are as noted in previous studies. The differences between PTHrP(1–108)/PTHrP(1–141) and PTHrP(1–34) demonstrated here are consistent with (1) the clinical manifestations of acidosis in hyperparathyroidism and alkalosis in humoral hypercalcaemia of malignancy, and (2) an independent action of a component of PTHrP beyond amino acids 1–34.
Journal of Endocrinology (1990) 126, 403–408
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SUMMARY
Several aspects of the activation of adenylate cyclase by guanosine 5′-triphosphate (GTP), 5′-guanylylimidodiphosphate (Gpp(NH)p) and bovine parathyroid hormone (bPTH) have been studied in chick kidney plasma membrane preparations. GTP (10−4 mol/l), Gpp(NH)p (10−4 mol/l) and bPTH (10 i.u./ml) activated adenylate cyclase without any significant time lag. However a 2 min delay was observed before the activity of the enzyme increased after the addition of bPTH (−6 → + 34) to incubations.
The early (0–3 min) effects of GTP and Gpp(NH)p upon chick kidney adenylate cyclase activity were antagonized by the addition of the alternative guanyl nucleotide. After 5 min of incubation with kidney plasma membranes, Gpp(NH)p induced a stable state of activation of adenylate cyclase which was not reversible by subsequent addition of GTP. GTP did not induce an irreversible state of enzyme activation. In pre-incubation studies, GTP did not produce a persistent enzyme activation and did not modify the effect of Gpp(NH)p added subsequently at the incubation stage. Gpp(NH)p produced a stable state of activation of adenylate cyclase which was not inhibited by addition of GTP at the incubation stage.
Bovine PTH (2–34) inhibited the effect of bPTH upon adenylate cyclase activity when the native hormone (10 i.u./ml) had been incubated with plasma membranes for up to 8 min before addition of the analogue (5 μg/ml). Incubation of plasma membranes with bPTH (2–34) for as little as 10 s prevented activation of adenylate cyclase by subsequent addition of bPTH. This pattern was confirmed in pre-incubation studies. After pre-incubation of kidney membranes with bPTH and bPTH (2–34), followed by washing, an acid extract of the membranes contained immunoreactive bPTH. Gpp(NH)p produced a greater increase in adenylate cyclase activity in membranes pre-incubated with bPTH or bPTH (2–34) than in membranes pre-incubated with buffer alone, suggesting that the hormone and analogue facilitated the interaction of Gpp(NH)p with adenylate cyclase.
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SUMMARY
In an investigation of the possible role of calcitonin in the metabolism of glycosaminoglycans it was found that the hormone increased the rate of disappearance from serum of [35S]sulphate injected into rats. No excessive deposition of radioactive sulphate was found in bone, kidney, liver or ventricular myocardium of calcitonin-treated rats.
Calcitonin also rapidly lowered serum inorganic sulphate levels. Both effects were prevented by previous nephrectomy, leading to the conclusion that calcitonin acts on the kidney to promote the excretion of inorganic sulphate.
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SUMMARY
Whereas the liver is the major site of accumulation of 125I-labelled porcine calcitonin soon after injection in the rat, both human and salmon calcitonin were rapidly taken up in rat kidney, with relatively insignificant amounts found in the liver.
In-vitro studies of degradation of 125I-labelled calcitonins showed that human calcitonin was readily degraded by most rat tissues but the major activity was found in a kidney microsomal fraction, whereas the liver supernatant was most active towards pig calcitonin. Salmon calcitonin was resistant to breakdown by all tissues and fractions except the kidney microsomal fraction, which rapidly degraded it to trichloroacetic acid-soluble fragments. Liver homogenates from a number of mammalian and non-mammalian species degraded pig calcitonin but had little effect on salmon calcitonin.
The results show that the kidney is the most important organ in the metabolism of human and salmon calcitonin in the rat, while confirming that the liver is mainly responsible for the metabolism of porcine calcitonin.
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SUMMARY
The distribution and localization of 125I-labelled bovine parathyroid hormone was studied by radioautography in adult rats. The principal site of localization was the proximal convoluted tubule of the kidney. Light and variable localization was present in the liver, but no significant amount of label was found in muscle, spleen, bone or articular cartilage. The localization of this labelled compound in the proximal convoluted tubule suggests that this region degrades 125I-labelled parathyroid hormone.
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SUMMARY
When [125I]calcitonin was injected intravenously into rats the major site of accumulation of radioactivity was the liver, whereas [125I]parathyroid hormone was localized chiefly in the kidney.
The distribution of [125I]bovine serum albumin and of Na [125I] was studied for comparison. Although most of the radioactivity of [125I]calcitonin was found in the soluble fractions of liver and kidney, significant binding to liver microsomes occurred. This fraction also bound an appreciable amount of the radioactivity of [125I]parathyroid hormone. The uptake of [125I]calcitonin by liver could be inhibited by the simultaneous injection of unlabelled calcitonin, but not by that of parathyroid hormone, insulin or adrenocorticotrophic hormone.
These results indicate a role for the liver and kidney in the early clearance of calcitonin and parathyroid hormone respectively. It is likely that the liver is the major site of the metabolism of calcitonin in vivo.
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SUMMARY
Adenylate cyclase activity of crude plasma membranes from chick kidney was stimulated by low doses of parathyroid hormone (PTH). Sensitivity to PTH was ten to twenty times greater than that of a similar preparation from rat kidney cortex. Synthetic peptides consisting of the NH2-terminal 34 amino acids of bovine PTH (BPTH) and of human PTH (HPTH) were assayed, as were several analogues of these peptides. Bovine PTH (1–34) and HPTH (1–34) were equivalent in their action on chick kidney but the human peptide had only 20% of the activity of the bovine peptide on rat kidney cortex adenylate cyclase. Bovine proPTH ( −6→ + 34) and (Tyr1)-BPTH (1–34) had less activity than BPTH (1–34). Bovine PTH (2–34) inhibited the response to BPTH (1–34). Neither salmon calcitonin nor vasopressin stimulated adenylate cyclase activity.
