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At least 19 recordsLinked to original sources
PubMed1976

Conversion of proparathyroid hormone to parathyroid hormone by a particulate enzyme of the parathyroid gland.

The conversion of proparathyroid hormone (proparathormone) to parathyroid hormone (parathormone) by subcellular fractions of the bovine parathyroid has been investigated. The identification of the conversion product as parathormone was established by its elution postion during ion exchange chromatography and gel filtration, and by partial amino acid sequence analysis of its NH2-terminal region. Total homogenates and derived subcellular fractions (600 X g pellet, 5,000 X g pellet, 20,000 X g pellet, 190,000 X g pellet, and 190,000 X g supernatant) all catalyzed the conversion of exogenous [3H]- or [14C]prohormone. Over 60% of the converting activity was in the particulate fractions; the 190,000 X g particulate fraction contained the highest specific converting activity. The converting activity appeared to be an integral component of the membranes since it could only be partially removed by extraction with Triton X-100. The production of parathormone by the particulate converting enzyme increased with time and the concentration of enzyme protein. The optimum pH range was between 7 and 9, and the enzyme was inactive below pH 6. Conversion by the particulate enzyme was inhibited by benzamidine or chloroquine, but not by pancreatic trypsin inhibitor, indicating its dissimilarity to trypsin. When a mixture of [14C]proparathormone and [3H]parathormone was used as substrate, the particulate enzyme did not metabolize the hormone despite over 70% conversion of the prohormone to hormone and other peptides. There was a close correlation between the subcellular distribution of converting activity and that of newly formed parathormone found in the membrane fraction. These data suggest that the particulate converting activity is that concerned with the formation of parathormone in vivo.

Animals↗
PubMed1978

Role of anions in parathyroid hormone release from dispersed bovine parathyroid cells.

It is known that permeant anions are required for the release of epinephrine from isolated chromaffin granules and of serotonin from intact platelets. We have now investigated the role of anions in the release of a polypeptide hormone, parathyroid hormone, from dispersed bovine parathyroid cells. The release is inhibited 60%-80% by decreasing either [Cl-] or [OH-] and 60%-70% by replacement of NaCl with the impermeant anion isethionate. By contrast, substitution of various monovalent cations in the medium had no effect on the release. Disodium 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate (SITS) and probenecid, which are known to block anion transport in the erythrocyte, also cause a dose-dependent 90%-100% inhibition of release. Moreover, kinetic analysis of inhibition by probenecid suggests that it is competitive with respect to either OH- or Cl-. These results suggest that anions and the anion transport system may play a role in exocytosis of a polypeptide hormone. The proton ionophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone was was also found to block hormone release, and the possibility is discussed of a "chemosmotic" mechanism for exocytosis in this system similar to that previously postulated for chromaffin granules and platelets.

Animals↗
PubMed1977

Mechanism of resistance to the phosphaturic effect of the parathyroid hormone in the hamster.

The effect of parathyroid hormone and calcitonin on the renal excretion of phosphate, calcium, and cyclic AMP was evaluated in the thyroparathyroidectomized hamster, a mammal apparently reisstant to the phosphaturic effect of parathyroid hormone. Parathyroid hormone did not increase phosphate excretion, although it decreased excretion of calcium and increased urinary excretion of cyclic AMP. This lack of a phosphaturic response to parathyroid hormone was not reversed by administration of 25-OH vitamin D or infusions of calcium or phosphate. Calcitonin, another potentially phosphaturic hormone, also vailed to increase phosphate excretion but markedly elevated urinary excretion of cyclic AMP. In hamsters pretreated with infusion of urinary ammonium chloride, which decreased plasma and urinary pH, both parathyroid hormone and calcitonin increased excretion of phosphate as well as that of cyclic AMP. Acetazolamide had no phosphaturic effect in ammonium chloride-loaded hamsters, and it decreased cyclic AMP and calcium excretion. Alkalinization of urine by acetazolamide did not prevent the phosphaturic effect of parathyroid hormone in ammonium chloride-loaded hamsters, but it blocked the increase in urinary cyclic AMP excretion. Parathyroid hormone and calcitonin both stimulated adenylate cyclase in a cell-free system (600-g pellet) from hamster renal cortex, elevated tissue cyclic AMP levels, and activated protein kinase in tissue slices from hamster renal cortex. In acid medium, the increase in cyclic AMP and activation of protein kinase in response to parathyroid hormone was diminished, but addition of acetazolamide restored responsiveness of both parameters to control values. Acetazolamide, on the other hand, did not influence adenylate cyclase or its response to parathyroid hormone or cyclic AMP phosphodiesterase activity. We conclude that the lack of a phosphaturic effect of parathyroid hormone and calcitonin in the hamster depends on steps in the cellular action of these hormones, steps that are sensitive to pH subsequent to cyclic AMP generation and protein kinase activation. In addition, acetazolamide may potentiate the phosphaturic effect of parathyroid hormone by promoting accumulation of cyclic AMP in tissue. Thus, the hamster is a particularly useful model for studies of syndromes in which there is renal resistance to phosphaturic hormones.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1977

Beta-adrenergic stimulation of cyclic AMP content and parathyroid hormone release from isolated bovine parathyroid cells.

The effects of beta-adrenergic agonists and antagonists on cyclic AMP (cAMP) accumulation and parathyroid hormone (PTH) release from isolated bovine parathyroid cells have been determined. Beta-adrenergic agonists markedly stimulate cAMP production and PTH release with an order of potency (-) isoproterenol greater than (-)epinephrine greater than greater than (-) norepinephrine, suggesting a beta2-type adrenergically mediated process. Both effects are blocked by the beta-blocker propranolol with the strict stereospecificity expected for a beta-adrenergic response. Low calcium concentrations also stimulate cAMP accumulation, but the cyclic nucleotide response under these conditions is only 3% of that obtained with isoproterenol, raising the possibility that factors other than cAMP may control low calcium-mediated PTH release. The release of PTH by low calcium is also not blocked by propranolol, confirming the independence of the response to low ambient calcium from the beta-adrenergic receptor. These studies substantiate further the utility of the isolated parathyroid cell preparation for studying secretagogue-mediated alterations in cyclic nucleotides and hormone secretion. Isolated cells also also make feasible the direct identification of beta-adrenergic receptors in parathyroid cell membranes and whole cells.

Adrenergic beta-Agonists↗
PubMed1978

The cleavage and adsorption of parathyroid hormone at high dilution: implications for receptor binding studies.

Like other polypeptide hormones, purified intact parathyroid hormone (1-84)parathyroid hormone is notoriously unstable and is subject to large adsorptive losses in routine laboratory manipulation. The present studies were undertaken with 125I-labeled hormone to quantitate the problem and to develop preventative measures, particularly with concentrations of physiological interest, 1 . 10(-10) M. It was found that spontaneous cleavage of the hormone takes place upon its incubation in air or oxygen. This can be prevented by the presence of mercaptoethanol or by plasma levels of cysteine and ascorbate. Under non-cleavage conditions, adsorption was found to be extensive on all materials tested. This adsorption increased with time up to 2 h, was independent of ionic strength, increased with increasing temperature and was presumed to involve hydrophobic interactions. Under given conditions, adsorption was proportional to concentration (constant percentage). However, at very high concentrations, 1 . 10(-6) M, adsorption was markedly reduced. Adsorption was minimized at low pH (2). Bovine serum albumin reduced adsorption under all conditions when present at concentrations of 2 mg/ml or more. Coating laboratory ware with cetyl alcohol also was helpful. Using optimal conditions, cleavage is prevented and losses are less than 5% at neutral pH, and under 2% at pH 2.

Adsorption↗
PubMed1977

Dopaminergic stimulation of cyclic AMP accumulation and parathyroid hormone release from dispersed bovine parathyroid cells.

The effects of dopaminergic agonists and antagonists have been studied in dispersed bovine parathyroid cells. Dopaminergic agonists caused a transient 20- to 40-fold increase in cellular cyclic AMP and a 2- to 3-fold increase in parathyroid hormone release. Dose-response relationships were similar for cyclic AMP accumulation and hormone release, whether studied by increasing agonist concentration or by increasing concentration of antagonist with constant agonist. The effects on the dopamine receptor could be differentiated from those of the previously characterized beta-adrenergic receptor by specific inhibitors. These results appear to represent proof with a homogeneous cell population that dopaminergic receptors linked to adenylate cyclase can regulate a secretory process mediated by cyclic AMP. This system should be useful in further studies on dopamine receptors and should provide a valid tool for determining interactions of radiolabeled ligands with such receptors.

Adrenergic beta-Agonists↗
PubMed1976

Immunological comparisons of two synthetic human parathyroid hormone-(1-34) peptides.

The immunological properties of human parathyroid hormone-)1-34) synthesized in accord with the sequence reported by Brewer et al. and the different sequence found by Niall et al. were compared with those of highly purified native human hormone-)1-84). Analyses were performed by radioimmunoassay using 7 anti-bovine parathyroid hormone antisera and bovine parathyroid hormone-)1-34) as tracer. Whereas human parathyroid hormone-(1-34) synthesized in accord with the sequence of Niall et al. was immunologically indistinguishable from native human hormone in all 7 assay systems, striking differences were seen between human parathyroid hormone-(1-34) synthesized in accord with the sequence of Brewer et al. and the native hormone. In none of the 7 assay systems did human parathyroid hormone-(1-34) synthesized in accord with the sequence of Brewer et al. give the same displacement slopes that the reference preparation gave. The observation that immunologic probes easily discriminate between the two different human parathyroid hormone-(1-34) peptides suggests that similar immunologic approaches will be of value in exploring several important issues, particularly those relating to the sequence and conformational properties of human parathyroid hormone and its synthetic peptides and to the question of the existence of isohormonal forms.

Animals↗
PubMed1978

Autoantibodies to parathyroid hormone receptor.

Autoantibodies which block the binding of parathyroid hormone to membrane receptors for the hormone were detected in the sera (especially in the IgG fraction) of 49 out of 50 uraemic patients with secondary hyperparathyroidism (patients with high levels of C-regional parathyroid hormone). These antibodies are species-specific. Their presence in the serum in unaffected by dialysis. Inhibition of binding appears to be related to the rise in C-regional parathyroid-hormone levels and the duration of uraemia. The production of cyclic adenosine monophosphate by parathyroid-hormone-stimulated adenyl cyclase was reduced by the blocking antibodies. The findings show that secondary hyperparathyrodism in uraemia is another example of a receptor-antibody disease, but it is not known whether the antibodies act by modifying the affinity of the receptors for the hormone or by reducing the concentration of receptors available.

Animals↗
PubMed1976

Acquired resistance to parathyroid hormone.

Studies are presented in a patient with pseudohypoparathyroidism who showed a partial response to parathyroid extract. Resistance to the extract was observed after its short-term administration for the gourth time. Serum from the patient contained antibodies of the gamma G globulin class which bound 125I-labelled bovine parathyroid hormone. Prior incubation of parathyroid hormone with the serum prevented the activation in vitro of adenylate cyclase from pork renal cortex. The antibodies were directed primarily toward the C-terminal portion of the molecule. Thus, clinical resistance to parathyroid hormone is attributed to specific antibodies.

Adenylyl Cyclases↗
PubMed1976

Anabolic effect of low doses of a fragment of human parathyroid hormone on the skeleton in postmenopausal osteoporosis.

Parathyroid hormone, injected daily in low dosage, exerted anabolic effects on the human skeleton, just as it does in the rat. Four postmenopausal women with primary osteoporosis were treated for six months with a synthetic fragment of human parathyroid hormone (hP.T.H. 1-34), given as a daily injection of 100 mug. This treatment caused a remarkable acceleration of bone turnover, indicated both by isotopic tracer and histological methods. At this normocalcaemic dose level, the increases in bone formation outweighed increases in resorption. Three of the four patients showed more positive calcium balances, and mean increases in calcium and phosphorus balances were statistically significant for the group as a whole, the changes being principally due to increased intestinal absorption of both elements. Many modifications of the present method of hormone administration are possible which could further increase the preponderance of anabolic effects. These results suggest that low doses of hP.T.H. 1-34, alone or in combination with other agents, may prove useful in the treatment of osteoporosis.

Absorption↗
PubMed1976

Effects of parathyroid hormone on H+ and NH+4 excretion in toad urinary bladder.

The urinary bladder of Bufo marinus excretes H+ and NH+4, and the H+ excretion is increased after the animal is placed in metabolic acidosis. The present study was done to determine if parathyroid hormone could stimulate the bladder to increase the excretion of H+ and/or NH+4. Parathyroid hormone added to the serosal solution in a final concentration of 10 mug/ml was found to increase H+ excretion by 50 per cent above the control hemibladders, while there was no effect on NH+4 excretion. Parathyroid hormone had no effect on H+ excretion when added to the mucosal solution. We also performed experiments utilizing theophylline and dibutyryl cyclic AMP which mimicked those of the parathyroid hormone experiments. A dose-response analysis was performed and the results indicate that 1 mug/ml of parathyroid hormone was the minimal effective dose. These results suggest that parathyroid hormone can stimulate H+ excretion in the toad urinary bladder and this effect seems to be mediated by cyclic AMP. In addition, it was found that parathyroid hormone has no effect on NH+4 excretion.

Ammonia↗
PubMed1976

A radioimmunoassay for bovine parathyroid hormone.

A radioimmunoassay for bovine parathyroid hormone (bPTH) has been developed. An antibody was raised in a goat against 1-84 b PTH which was directed against the carboxy-terminal part of the molecule (no cross-reactivity with synthetic 1-34 b PTH fragment). 1-84 b PTH was labelled with 125I using the chloramine-T method. The tubes were incubated at 4 degrees C for 6 days in an equilibrium system with 25% protein concentration. Separation was performed using plasma-coated charcoal. Jugular venous plasma PTH levels were shown to be increased in hypocalcemic parturient cows.

Animals↗
PubMed1976

Failure of parathyroid hormone and cyclic AMP to inhibit renal carbonic anhydrase.

It has been suggested that the parathyroid hormone and cyclic AMP produce their bicarbonaturic effects through inhibition of renal carbonic anhydrase. In the present study, the incubation of renal carbonic anhydrase with parathyroid hormone or cyclic AMP in presence of ATP, Mg++ and K+ ions, did not produce any inhibition of the enzyme when the pH of the solution was maintained above 7. It is concluded, that parathyroid hormone and cyclic AMP produce urinary bicarbonate excretion by a mechanism independent of carbonic anhydrase inhibition.

Animals↗
PubMed1976

A simplified assessment of response to parathyroid hormone in hypoparathyroid patients.

Hightly purified bovine parathyroid hormone (B.P.T.H) was given by injection and/or infusion to six normal volunteers and to patients with surgical hypoparathyroidism (five cases), idiopathic hyparathyroidism (five cases), or poeudo-hypoparathyroidism (six cases). Infusion and injection of B.P.T.H. produced very similar patterns of response in plasma adenosine 3' 5' cyclic monophosphate (cyclic A.M.P.) In all six normal volunteers and in the patients with surgical (five cases) or idiopathic (four cases) hypoparathyroidism who had injections of B.P.T.H., plasma-cA.M.P. had risen significantly within 5 min and the peak response was genereally observed 10 min after injection of hormone. In the five pseudohypoparathyroid patients who received injections of B.P.T.H., plasma-c?A.M.P. concentration increased only slightly or not at all after the hormone was administered. Unlike the traditional test for the investigation of hypocalcaemia, the test described here does not require collections of urine samples.

Adolescent↗
PubMed1977

Effect of parathyroid hormone on urinary acidification.

The effect of parathyroid hormone (PTH) administration on urinary acidification was studied in intact and thyroparathyroidectomized dogs. PTH administration resulted in a significant increase in urine pH and HCO3 excretion. In dogs with maximally acid urine caused by Na2SO4 infusion PTH administration also led to a significant increase in urine pH and to a decrease in ammonium excretion. To examine the effect of PTH on H+ secretion in the distal nephron we measured the urine-blood (U-B) PCO2 gradient in dogs with maximally alkaline urine (urine pH greater than 7.8) before and after PTH administration. After infusion of the hormone, HCO3 excretion increased significantly but the U-B PCO2 gradient remained unchanged. The effects of PTH infusion on urinary acidification in animals with distal renal tubular acidosis caused by LiCl administration were also studied. PTH administration to these dogs increased HCO3 excretion to the same level seen in normal dogs. These data suggest that PTH does not inhibit distal H+ secretion but increases HCO3 excretion by depressing proximal HCO3 reabsorption.

Acid-Base Equilibrium↗
PubMed1975

New aspects of radioimmunochemical measurement of human parathyroid hormone using the labelled antibody technique.

Two forms of heterogeneity of parathyroid hormone (PTH) have given rise to conflicting results: one due to the heterogeneity of the secreted species from the gland and their peripheral metabolism and the other representing the immunochemical heterogeneity of the available antibodies. We have developed sequence specific assays using the technique of labelled antibodies. Therefore, results of assays measuring the C-terminal part and the (1-34)-N-terminal part of the molecule could be compared to those of an assay for hormone bearing both N- and C-terminal antigenic determinants. This assay is supposed to detect predominantly (1-84)-intact hormone. The immunoradiometric assay of (1-34)-PTH has a sensitivity of 0.04 ng/ml. This technique avoids the critical iodination of the hormone fragment containing no tyrosine. There is the expected overlap between normal subjects and patients with primary and secondary hyperparathyroidism. The most important finding are results from patients undergoing neck catheterization. We demonstrated nonuniform secretion of different species of PTH by parathyroid adenomata and normal glands. This supports the hypothesis of cleavage of the (1-84)-molecule in the gland.

Antigen-Antibody Reactions↗
PubMed1978

Neuroendocrine modulation of calcitonin and parathyroid hormone in man.

Recent evidence suggests that of calcitonin (CT) and parathyroid hormone (PTH) is controlled by factors other than the ambient serum calcium concentration. We studied the effects of infusions of four neuroendocrine modulators upon CT and PTH levels: isoproterenol (beta-adrenergic agonist), methoxamine (alpha adrenergic agonist), prostaglandin E2, and somatostatin. Isoproterenol was a consistent secretagogue for both hormones. Maximal CT increments during isoproterenol infusion in normal subjects were 13 +/- 2 pg/ml (mean +/- SEM, n = 6, P less than 0.001; basal, 26 +/- 5). Maximal increments in PTH were 113 +/- 22 pg/ml (P less than 0.01, n = 6; basal, 430 +/- 11). Infusions of methoxamine increased CT by 13 +/- 5 pg/ml (n = 5, P less than 0.05; basal, 43 +/- 13), but had no effect on PTH. The means of the maximal CT increments during isoproterenol (21 +/- 8 pg/ml) and methoxamine infusion (28 +/- 11 pg/ml) were not statistically different from those achieved by acute elevations of serum calcium levels within the physiological range (41 +/- 23 pg/ml). Infusions of somatostatin and prostaglandin E2 had no or only transient effects on basal or stimulated CT or PTH levels. Our data suggest that adrenergic input modulates CT and PTH secretion in humans independently of changes in serum calcium.

Adult↗
PubMed1978

Effects of alpha-adrenergic stimulation and blockade of plasma parathyroid hormone concentrations in cows.

Experiments were designed to investigate responses of immunoreactive parathyroid hormone (PTH) during alpha-adrenergic stimulation and blockade in cows. Alpha-adrenergic agonists (methoxamine, phenylephrine and noradrenaline, the beta-adrenergic action of which was blocked by propranolol) did not change PTH and free fatty acid levels, whereas they characteristically increased the blood pressure and decreased the heart rate. In contrast, alpha-adrenergic blockade by phentolamine progressively increased PTH levels. The elevated PTH concentrations, associated with increased plasma noradrenaline and free fatty acid levels, rising heart rate and decreasing blood pressure, indicated that all these changes can be related to a beta-adrenergic stimulatory mechanism. Beta-adrenergic stimulation was presumably responsible for the initial elevation of PTH concentrations, whereas, during the later phase of the phentolamine infusions, a concomitant hypocalcaemia probably also produced a stimulatory effect.

Adrenergic alpha-Agonists↗