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PubMed1986

Comparative study on the cardiac actions of bovine parathyroid hormone (1-34).

The cardiac stimulatory effects of bovine parathyroid hormone (1-34) [bPTH-(1-34)] were studied on isolated atria and ventricular strips from cobra snakes (Naja naja), ducklings (Anas platyrhynchos), pigeons (Columba livia), Japanese quails (Coturnix coturnix japonica), laboratory rats (Rattus norvegicus), and dogs (Canis familiaris). In all atrial preparations, bPTH-(1-34) caused positive chronotropism. This suggests that the chronotropic effect of PTH is ubiquitous among the terrestrial vertebrates. Only the atria of cobra snakes and ducklings gave positive inotropic responses to PTH. No ventricular preparations showed significant response to bPTH-(1-34). This suggests the absence of cardiac stimulatory PTH receptors in the ventricles. Dog papillary muscle, however, showed slight but significant responses to bPTH-(1-34). The reason for this discrepancy between the responses of papillary muscles and the ventricular strips to PTH is unknown.

Animals↗
PubMedDate not supplied

Effect of parathyroid hormone on rat renal calcium/calmodulin-dependent protein kinase II.

Rat parathyroid hormone (PTH) stimulates cAMP-dependent protein kinase and protein kinase C activity in the kidney. However, PTH increases intracellular Calcium in primary cultures of proximal tubular cells. We have investigated the possibility that PTH also stimulates Calcium/calmodulin-dependent protein kinase II (CaM kinase II). We have employed the tandem chromatographic column method, using synthetic peptide as a substrate, to measure the renal CaM kinase II activity. PTH (250 nM) stimulated CaM kinase II activity by about 50% after 15 sec., and activity returned to baseline by 2 min. Calmodulin antagonists significantly impaired the stimulatory action of PTH whereas basal levels of CaM kinase II activity were relatively unaffected. This study demonstrates that PTH does activate CaM kinase II in renal tissue, and suggests another pathway for the actions of PTH in the kidney.

Animals↗
PubMed1978

Modulation of cyclic nucleotides in islated rat glomeruli: role of histamine, carbamylcholine, parathyroid hormone, and angiotensin-II.

Because glomerular functions are modulated by numerous humoral agents, probably acting through cyclic nucleotides, the effects of some polypeptide hormones and biogenic amines on cyclic AMP (cAMP) and cyclic 3',5'-guanosine monophosphate (cGMP) were studied in glomeruli isolated from rat renal cortex. Glomeruli and cortical tubules were prepared by a combination of sieving and density-gradient centrifugation. Under basal conditions, the contents of cAMP and cGMP in glomeruli were significantly higher than in tubules and unfractionated renal cortical tissue.Histamine caused a striking increase in cAMP in glomeruli (+Delta% 675+/-87) and, to a lesser degree, increased cAMP in tubules (+Delta% 103+/-25) or in tissue slices. This stimulation was dose-dependent in the range of 1 muM-1 mM histamine. Metiamide (an H(2)-antagonist), but not pyrilamine (an H(1)-antagonist) blocked the effect of histamine on cAMP, which indicates that histamine causes its effect via interaction with H(2) receptors. Histamine caused less extensive increases in cGMP in both glomeruli and tubules. Carbamylcholine caused a marked increase in cGMP in glomeruli (+Delta 295+/-7) and a much lower increase in tubules (+Delta% 70+/-20); these effects were blocked by atropine. Parathyroid hormone (1 mug/ml) increased cAMP and, to a much lesser degree, also cGMP in glomeruli. In tubules, parathyroid hormone caused much more extensive increases in cAMP than in glomeruli; no changes, or rather a small decline in cGMP, was observed. Angiotensin-II (2 muM) markedly lowered cAMP in glomeruli (-Delta% -45+/-8) and in tubules (-Delta% 33+/-7) but had no effect on cGMP. Bradykinin (20 muM) did not consistently influence either cAMP or cGMP in glomeruli or tubules. Present results demonstrate that cAMP and cGMP metabolism in glomeruli are controlled independently by humoral agents known to alter glomerular functions in vivo. Our findings are consistent with the view that histamine and cholinergic agents generated and (or) released locally in glomeruli or in their vicinity may play important roles as mediators of immunopathological injury of glomeruli, and that these effects are mediated by cAMP and (or) cGMP through interaction with H(2) receptors and muscarinic receptors. Likewise, our results suggest that the effects of angiotensin-II and parathyroid hormone on glomerular dynamics may be mediated by cyclic nucleotides.Thus, we surmise that extrarenal as well as intrarenal humoral agents may play an important role in the pathology and physiology of glomeruli through mediation of either cAMP, cGMP, or both.

Angiotensin II↗
PubMed1988

Increase in serum parathyroid hormone levels after prolonged physical exercise.

Serum concentrations of parathyroid hormone (PTH), calcium, magnesium, phosphate and myoglobin were measured regularly during a 5-d recovery period in 17 men who had participated in a 7-d field exercise maneuver with intense physical activity. Immediately after the exercise, there was an increase in serum PTH levels of the same magnitude as the maximal rise during a hypocalcemic test. The rise in PTH was not related to changes in serum electrolytes, but was significantly correlated to an increase in serum myoglobin, indicating that those who performed the largest amount of work also experienced the greatest stimulus for secretion of PTH. There were no significant changes of the serum total calcium and only a small initial rise of the magnesium concentrations. Serum phosphate levels were greatly reduced and gradually returned during recovery. This study extends previous observations, from short-term investigations, that physical activity stimulates secretion of PTH.

Adolescent↗
PubMed1995

Restoration of severely depleted femoral trabecular bone in ovariectomized rats by parathyroid hormone-(1-34).

It is commonly believed that the parathyroid hormone's (PTH's) main function in bone is to stimulate osteoclastic resorption. However, intermittent injections of small doses of PTH holoprotein, but more often its bioactive hPTH-(1-34) fragment, have been shown to stimulate bone growth in animals and humans through their ability to stimulate adenylyl cyclase and not their ability to independently activate a protein kinases-C stimulating mechanism. This anabolic action suggests that PTH might be an effective therapeutic for osteoporosis. If so, the hormone must be able to restore severely depleted trabecular bone, and the goal of this study was to find out if it can. To do this, we started a multiweek program of daily subcutaneous injections of 0.8 nmoles of hPTH-(1-34)/100 g body weight into rats at 4, 8, or 16 weeks after ovariectomy (OVX) and the increasingly severe selective loss of trabecular bone. These injections strongly stimulated femoral trabecular bone to grow and mineralize at the same rate regardless of how much of it had been lost before the injections were started. Thus, the progressively depleting trabecular bone in the femurs of OVX rats does not lose its anabolic responsiveness to PTH. This finding is another indication of the likelihood of small, adenylyl cyclase-stimulating PTH fragments being effective therapeutics for osteoporosis.

Analysis of Variance↗
PubMed1985

An adenylate cyclase bioassay for parathyroid hormone: some clinical experiences.

An adenylate cyclase bioassay for parathyroid hormone (PTH) was evaluated in peripheral sera of ten normal subjects, 15 patients with various types of hypoparathyroidism, nine patients with malignancy-associated hypercalcaemia and 60 patients with primary or secondary hyperparathyroidism. The lower limit of detectability was 150 pg/ml in terms of synthetic human PTH (1-34). PTH-like bioactivity was not detected in normal subjects, in patients with surgical hypoparathyroidism, in patients with idiopathic hypoparathyroidism or in patients with malignancy-associated hypercalcaemia. Serum from one untreated pseudohypoparathyroid patient consistently contained PTH-like bioactivity. Bioactivity was detected in sera from 50% of patients with primary or secondary hyperparathyroidism. In two patients with secondary hyperparathyroidism calcium infusions suppressed this activity within 5 min. Both in primary and in secondary hyperparathyroidism there was a significant positive correlation between levels of PTH-like bioactivity, PTH immunoreactivity and the histological severity of the disease.

Adenylyl Cyclases↗
PubMed1983

Evaluation of hypocalcemia with a highly sensitive, homologous radioimmunoassay for the midregion of parathyroid hormone.

The diagnosis of hypoparathyroidism by radioimmunoassay of serum parathyroid hormone (PTH) has been hampered by lack of an assay system sensitive enough to allow discrimination between low and normal values. A new assay for human PTH that has improved sensitivity has been developed. It uses an homologous antiserum (against the human hormone) and uses a carboxy-terminal fragment of bovine PTH as tracer to provide an assay monospecific for the midregion of PTH. Immunoreactive PTH (iPTH) was detectable in 25/27 normal children and borderline detectable in the other two. The pediatric normal range was slightly lower than that previously established in adults. Among patients with secondary hyperparathyroidism and normal renal function, iPTH was 3- to 8-fold elevated in those with rickets, and 1.3- to 2.0-fold above normal in those with more acute forms of hypocalcemia. Twelve patients with hypoparathyroidism were studied. iPTH was undetectable in seven with permanent total hypoparathyroidism, and was borderline detectable in five, including four neonates who proved to have transient hypoparathyroidism. In these four patients, iPTH became detectable as the requirements for supplemental calcium decreased. Measurement of iPTH with an adequately sensitive assay may be useful in the diagnosis and management of pediatric hypocalcemia.

Adolescent↗
PubMed2000

Acute regulation of Na+/H+ exchanger NHE3 by parathyroid hormone via NHE3 phosphorylation and dynamin-dependent endocytosis.

Parathyroid hormone (PTH) is a potent inhibitor of mammalian renal proximal tubule Na(+) transport via its action on the apical membrane Na(+)/H(+) exchanger NHE3. In the opossum kidney cell line, inhibition of NHE3 activity was detected from 5 to 45 min after PTH addition. Increase in NHE3 phosphorylation on multiple serines was evident after 5 min of PTH, but decrease in surface NHE3 antigen was not detectable until after 30 min of PTH. The decrease in surface NHE3 antigen was due to increased NHE3 endocytosis. When endocytic trafficking was arrested with a dominant negative dynamin mutant (K44A), the early inhibition (5 min) of NHE3 activity by PTH was not affected, whereas the late inhibition (30 min) and decreased surface NHE3 antigen induced by PTH were abrogated. We conclude that PTH acutely inhibits NHE3 activity in a biphasic fashion by NHE3 phosphorylation followed by dynamin-dependent endocytosis.

Animals↗
PubMed1981

Prolactin and calcitonin responses to parathyroid hormone infusion in hypoparathyroid, pseudohypoparathyroid, and normal subjects.

Since parathyroid hormone (PTH) has been reported to release PRL in normal humans, we studied the effects of exogenous PTH infusion (150 U) on the secretion of PRL, TSH, and calcitonin in 10 normal subjects, 5 with hypoparathyroidism, and 10 with pseudohypoparathyroidism, type I (PHP). PTH produced a rise in serum PRL in the normal subjects from 5.1 +/- 0.8 ng/ml (SE) to 14.9 +/- 3.0 ng/ml (P less than 0.01), while levels similarly rose from 4.0 +/- 0.2 to 8.5 +/- 0.8 ng/ml (P less than 0.01) in the patients with hypoparathyroidism. In 6 PHP patients with deficient PRL responses to TRH, the PRL response to PTH was also blunted (basal, 3.2 +/- 0.81 ng/ml; peak, 4.1 +/- 1.3 ng/ml; P greater than 0.1). Three of 4 PHP patients with normal PRL responses to TRH demonstrated a normal PRL increment in response to PTH infusion. Serum TSH and calcitonin were not changed by PTH infusion in any of the groups. These findings demonstrate that the resistance to PTH seen in PHP does not extend to the pituitary gland.

Adolescent↗
PubMed2001

Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone.

We studied the effects of intermittent administration of parathyroid hormone (PTH(1-34)) on callus formation and mechanical strength of tibial fractures in 27-month-old rats after 3 and 8 weeks of healing. 200 microg PTH(1-34)/kg was administered daily during both periods of healing, and control animals with fractures were given vehicle. At 3 weeks, PTH treatment increased maximum load and external callus volume by 160% and 208%; at 8 weeks, by 270% and 135%. It also enhanced callus bone mineral content (BMC) by 190% and 388% (3 and 8 weeks). From week 3 to week 8, callus BMC increased by 60% in the vehicle-injected animals, and by 169% in the PTH-treated animals. In the contralateral intact tibia, PTH treatment increased BMC by 18% and 21% (3 and 8 weeks). No differences in body weight were found between the vehicle-injected and the PTH-treated animals during the experiment. In conclusion, PTH treatment enhances fracture strength, callus volume and callus BMC after 3 and 8 weeks of healing.

Animals↗
PubMed1981

Parathyroid hormone has a positive inotropic action in the rat.

Parathyroid hormone (PTH: synthetic bovine, amino terminus 1-34 amino acids) demonstrates a positive inotropic action on the isolated papillary muscle of the rat heart. The effect was evident at PTH concentration of 10(-12)M, and the maximum inotropic effect occurred with PTH concentrations greater than 10(-11)M. Biologically inactive PTH (PTH treated with H2O2) was without effect. The inotropic effect of PTH was partially blocked by propranolol and also suppressed in the papillary muscle of the rat pretreated with reserpine. Methoxyverapamil completely blocked the inotropic action of PTH. PTH was without effects on adenylate cyclase activity of the myocardium. Results show the presence of an inotropic action of PTH in vitro and suggest that this action of PTH is partially mediated by releasing the endogenous myocardial norepinephrine which exerts a positive inotropic effect via beta-adrenergic stimulation and by an increase in Ca++ influx across plasma membranes, but independent of adenylate cyclase activation. The inotropic action of PTH may be of significance in normal cardiac function.

Animals↗
PubMed1998

Simple approach to reducing proteolysis during secretory production of human parathyroid hormone in Saccharomyces cerevisiae.

A gene coding for human parathyroid hormone (hPTH) was synthesized and cloned into a yeast expression and secretion vector containing the mating factor alpha pre-pro leader sequence and the galactose-inducible promoter, GAL10. The intact hPTH(1-84) was found to be secreted into the culture medium. As observed in the previous reports on the secretory production of hPTH in yeast, however, the proteolytic cleavage occurred as the culture proceeded, resulting in a significant loss of the intact hPTH. Attempts were therefore made to reduce the extent of proteolysis by simply controlling the culture conditions. The proteolytic cleavage was significantly reduced by the addition of an excess amount of l-arginine (>/=0.2M) to the culture medium, which resulted in a marked improvement in the yield of intact hPTH. To examine whether l-arginine affects the activities of intracellular proteases such as KEX2 endoproteinase or extracellular proteases, the proteolysis experiments were performed by incubating the commercial intact hPTH in a yeast host culture supernatant. The results demonstrated that l-arginine at high concentrations reduced the rate of hPTH proteolysis by inhibiting extracellular proteases.

Arginine↗
PubMed1995

Expression of parathyroid hormone receptors in MDCK and LLC-PK1 cells.

Parathyroid hormone (PTH) inhibits renal proximal tubular phosphate (Pi) and bicarbonate reabsorption by regulating the activity of apical Na/Pi cotransport and Na/H exchange. Two renal epithelial cell lines ["proximal tubular", LLC-PK1; "distal tubular", Madin-Darby canine kidney, (MDCK) cells] were stably transfected with complementary deoxyribonucleic acids (cDNAs) encoding a cloned PTH receptor in order to examine the polarity of transfected receptor function and whether or not intrinsic Pi transport is regulated by the transfected PTH receptor. The receptors are functionally coupled to the stimulation of adenosine 3':5' cyclic monophosphate (cAMP) production at both cell surfaces in LLC-PK1 cells, whereas this response is primarily limited to the basolateral surface in MDCK cells. Immunocytochemistry suggests an apical and basolateral localization of the transfected PTH receptor in LLC-PK1 cells and only a basolateral localization in MDCK cells. PTH activation of the transfected receptors is not coupled to the regulation of intrinsic Pi transport in either LLC-PK1 or MDCK cells.

Adenylyl Cyclases↗
PubMed1992

Serum intact parathyroid hormone concentration measured by a two-site immunoradiometric assay in normal subjects and patients with various parathyroid disorders.

Serum intact parathyroid hormone (PTH) concentration was measured by a two-site immunoradiometric assay (IRMA) in normal subjects and patients with various parathyroid disorders. Serum intact PTH levels were all within the detection limit of the IRMA in normal subjects, and there was a significant negative correlation between serum calcium (Ca) and intact PTH levels. Although 3 out of 26 patients (11.5%) with primary hyperparathyroidism had a normal serum intact PTH concentration, these patients could be readily discriminated from normal subjects by plotting serum intact PTH against the serum Ca concentration. In contrast, serum intact PTH was undetectable in 16 out of 17 patients (94.1%) with idiopathic hypoparathyroidism. Patients with pseudohypoparathyroidism (PHP) type I, mostly under treatment with active vitamin D, exhibited wide distribution of serum intact PTH concentration, and appeared to belong to two distinct subgroups. One group of patients demonstrated a similar relationship between serum intact PTH and Ca levels to normal subjects. The other exhibited much higher serum intact PTH levels despite a normal serum Ca concentration, and no obvious relationship could be observed between the two parameters. These results demonstrate that an inverse relationship between serum Ca and intact PTH can be demonstrated in normal subjects with normocalcemia, that most of the parathyroid disorders can be diagnosed by measuring serum Ca and the intact PTH concentrations simultaneously, and that patients with PHP can be divided into two subgroups: one with a normal relationship between serum Ca and intact PTH, and the other with a high serum PTH level in the face of normocalcemia.

Adolescent↗
PubMed1991

Attenuated rise of 1,25 (OH)2 vitamin D3 in response to parathyroid hormone in patients with incipient renal failure.

Despite elevated parathyroid hormone (PTH) levels, low normal or diminished serum 1,25(OH)2D3 concentrations are found in patients with incipient renal failure. To further assess (indirectly) the reserve capacity of renal production of 1,25(OH)2D3 we studied 9 patients with incipient or moderate renal failure (inulin clearance 31-68ml/min/1.73 m2) and 9 controls, using a novel stimulation test. We measured 1,25 (OH)2D3 levels, free 1,25(OH)2D3 index, cAMP excretion, calciuria and phosphaturia before and after infusion of 2 x 400 U of human (h) PTH (1-38). Baseline 1,25(OH)2D3 levels were not significantly different in patients (42.5 pg/ml, 21.6-51.1) compared with controls (45.0 pg/ml, 37.4-67.3). After infusion of hPTH(1-38), however, median increase in 1,25(OH)2D3 was only +25% versus +86% in controls, despite a greater proportional increase in cAMP/GF ratio. The data suggest subnormal stimulation of renal 1,25(OH)2D3 production in response to exogenous PTH in most patients with incipient renal failure. This may reflect partial exhaustion of biosynthetic reserve capacity.

Adult↗
PubMed1991

Oral administration of 24,25(OH)2D3 suppresses the serum parathyroid hormone levels of dialysis patients.

We measured the serum parathyroid hormone (PTH) levels in 20 patients treated with continuous ambulatory peritoneal dialysis before and after oral treatment with 24,25-dihydroxyvitamin D3- 24,25(OH)2D3. This metabolite was given in addition to existing treatment with 1 alpha-OH-D3 and calcium carbonate. Administration of 24,25(OH)2D3 led to a significant decrease in PTH levels (intact molecule) from 382 +/- (SE) 65 to 245 +/- 54 pg/ml in 9 patients whose initial levels were extremely high (p = 0.01). No side effects were observed. On the average, calcium values were unchanged and within the normal range throughout the study period; however, a few episodes of mild asymptomatic hypercalcemia occurred which responded quickly to reduction of the calcium carbonate dosage. The present study suggests that oral administration of 24,25(OH)2D3 combined with 1 alpha-OH-D3 is safe and capable of suppressing the raised serum PTH levels of end-stage renal disease patients without the danger of significant hypercalcemia.

24,25-Dihydroxyvitamin D 3↗
PubMed1996

Stimulation of the growth of femoral trabecular bone in ovariectomized rats by the novel parathyroid hormone fragment, hPTH-(1-31)NH2 (Ostabolin).

The human parathyroid hormone, hPTH-(1-84), and its hPTH-(1-34) fragment are promising anabolic agents for treating osteoporosis because they can strongly stimulate the production of biomechanically effective cortical and trabecular bone in osteopenic ovariectomized (OVX) rats and trabecular bone in osteoporotic postmenopausal humans. The ideal PTH fragment for treating osteoporosis would be the smallest and functionally simplest fragment that activates only one signal mechanism and still strongly stimulates trabecular bone growth. A new PTH fragment, hPTH-(1-31)NH2, which only stimulates adenylyl cyclase instead of stimulating both adenylyl cyclase and phospholipase-C as do hPTH-(1-84) and hPTH-(1-34), is this minimum, high-potency anabolic fragment. hPTH-(1-31)NH2 (which we have named Ostabolin) can greatly thicken trabeculae and increase the dry weight and calcium content of trabecular bone in the distal femurs of osteopenic, young, sexually mature OVX Sprague-Dawley rats when injected subcutaneously each day for 6 weeks at doses between 0.4 and 1.6 nmole/100 g of body weight.

Animals↗
PubMed1981

Malignancy-associated hypercalcemia: evaluation with a cytochemical bioassay for parathyroid hormone.

Employing a cytochemical assay initially developed for measuring parathyroid hormone (PTH), bioactivity was assessed in 33 patients with malignancies. Initial studies in vitro were consistent with a role for cAMP as a second messenger in the bioassay. Cytochemical bioactivity was increased in the peripheral plasma of 10 of 16 hypercalcemic patients with elevated nephrogenous cAMP excretion, and mean levels were 10-fold higher in these patients than in 17 normocalcemic or hypercalcemic patients with normal or suppressed nephrogenous cAmP excretion, respectively. Plasma bioactivity, serum calcium, and nephrogenous cAMP excretion all fell to normal in 1 patient after tumor resection, and cytochemical bioactivity was demonstrable in the tissue culture medium in which the neoplasm was maintained. Gel chromatographic analysis revealed that a major component of plasma bioactivity eluted before rather than with PTH-(1-84) in patients with malignancy in contrast with that in patients with primary hyperparathyroidism. The studies, therefore, demonstrate the capacity of the cytochemical bioassay to measure increased activity in patients with malignancy, hypercalcemia, and elevated nephrogenous cAMP excretion; suggest that the material responsible for the activity differs from PTH-(1-84); and provide a sensitive detector system for further analysis of this material and its role in the pathogenesis of this disease.

Animals↗