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PubMed1984

Calcium, parathyroid hormone and calcitonin in normal pregnancy and preeclampsia.

Calcium, parathyroid hormone (PTH) and calcitonin (CT) in serum, and the fractional renal excretion of calcium (FECa) were determined in (1) normal pregnant women, (2) patients with preeclampsia, and (3) normal nonpregnant control subjects. Serum calcium, corrected for individual variation in serum protein, was reduced and FECa increased in the normal pregnant group when compared to the nonpregnant control group. In preeclampsia serum calcium did not differ significantly from the normal pregnant group, but FECa was considerably lower and also reduced below the level in the nonpregnant control group. PTH was slightly lower during normal pregnancy than after delivery, but did not deviate significantly from the nonpregnant control group; in preeclampsia PTH did not deviate significantly from the levels in normal pregnancy. CT was the same in the third trimester of pregnancy in both groups. Changes in serum calcium and FECa were not correlated to PTH or CT. It is concluded that both normal pregnancy and preeclampsia are accompanied by considerable alterations in calcium metabolism, that PTH and CT in both groups are mainly unchanged and at nonpregnant level, and that the increase and decrease in renal calcium excretion in normal pregnancy and preeclampsia, respectively, may be attributed to changes in kidney function.

Adolescent↗
PubMed2003

Electronically facilitated transdermal delivery of human parathyroid hormone (1-34).

Electronically facilitated transdermal delivery of human parathyroid hormone (1-34), hPTH (1-34), was investigated in vitro, using dermatomed porcine skin. The effect of iontophoretic current density, electroporative pulse voltages and also electroporation followed by iontophoresis was investigated on the in vitro percutaneous absorption of hPTH (1-34). Iontophoresis at 0.5 mA/cm2 current density significantly enhanced (P<0.05) the flux of hPTH (1-34) in comparison to passive flux. Electroporation pulses of 100, 200 and 300 V significantly increased (P<0.05) the flux of hPTH (1-34) in comparison with the passive as well as iontophoretic flux at 0.5 mA/cm2. The electroporative flux of hPTH (1-34) was found to vary linearly (R2 = 0.97) with the pulse amplitude. The principal barrier of the skin, stratum corneum, was found perturbed following the pulses as evident by light microscopy studies. The application of electroporation pulses followed by iontophoresis further increased the flux by several fold. The flux of hPTH (1-34) with the electroporation pulses of 100 and 300 V followed by iontophoresis at 0.2 mA/cm2 was 10- and 5-fold higher, respectively, in comparison to the flux with corresponding pulses alone. This shows the synergistic effect of iontophoresis in combination with electroporation on skin permeability of hPTH (1-34). The results indicate the possibility of designing controlled transdermal delivery systems for hPTH (1-34) using electroporation followed by iontophoresis.

Administration, Cutaneous↗
PubMed1991

Cyclic parathyroid hormone related protein antagonists: lysine 13 to aspartic acid 17 [i to (i + 4)] side chain to side chain lactamization.

Cyclization of parathyroid hormone related protein (7-34)amide [PTHrP(7-34)NH2] via covalent bond formation between the epsilon-amino of Lys13 and the beta-carboxyl of Asp17 yielded a 20-membered ring lactam. This analogue, [Lys13,Asp17]PTHrP(7-34)NH2, was 5-10-fold more potent than the linear parent peptide (Kb = 15 and 18 nM in PTH receptor binding assays, and Ki = 130 and 17 nM in PTH-stimulated adenylate cyclase assays in bovine renal cortical membrane and in human bone derived B10 cells, respectively). In contrast, a linear analogue in which charges in positions 13 and 17 were eliminated and other stereoisomers of the above-mentioned lactam in which either Lys13 and/or Asp17 were replaced by the corresponding D-amino acids were much less potent with regard to antagonist bioactivity than the parent peptide. The rationale for the design of the lactam as well as the conformational implications for the PTHrP sequence in light of reported models suggested for the 1-34 peptide are described. The potential use of conformationally constrained analogues for elucidating the "bioactive conformation" of antagonists and for the design of substantially simplified molecular structures for antagonists is discussed.

Adenylyl Cyclases↗
PubMedDate not supplied

Reference range for serum parathyroid hormone.

OBJECTIVE: To determine whether the reference range for parathyroid hormone (PTH) should be lowered (from 65 pg/mL to a proposed value of 46 pg/mL) with use of the Allegro radioimmunometric assay. METHODS: We examined the reference range for PTH, adjusted for serum 25-hydroxyvitamin D (25-OHD), in 503 healthy African American and white women, who were 20 to 80 years old. We also analyzed other factors that are thought to influence PTH levels. RESULTS: Univariate predictors of PTH were identified, and a multivariate model was developed with use of the variables and PTH. Serum PTH was significantly higher in black study subjects than in white study subjects (P<0.02). Increasing PTH was also significantly correlated with increasing body mass index, age, and serum creatinine and with decreasing dietary calcium intake and serum 25-OHD levels. A stepwise multiple linear regression analysis yielded the following predictors of PTH: body mass index (R2=9.4%), age (R2=1.0%), and serum 25-OHD (R2=0.8%). In our study population, many PTH values were above the proposed new upper limit of 46 pg/mL. CONCLUSION: The upper limit of the reference range for serum PTH should not be changed. Factors to be considered in analysis of serum PTH values in the upper reference range in patients with normocalcemia include obesity, race, 25-OHD levels, advanced age, serum creatinine, and dietary calcium intake.

Adult↗
PubMed1998

20-HETE mediates the effect of parathyroid hormone and protein kinase C on renal phosphate transport.

Parathyroid hormone (PTH) is a major inhibitor of renal proximal tubule (PT) sodium-dependent phosphate (Na+-Pi) cotransport. PTH is thought to exert its effect on Pi transport in the PT via the protein kinase A (PKA) and C (PKC) intracellular signalling pathways. PKC-dependent phosphorylation of phospholipase A2 stimulates arachidonic acid (AA) release, the latter a potent inhibitor of Pi transport. In turn, AA is metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE) in the PT. In addition, 20-HETE production is stimulated by PTH. We therefore explored the possibility that 20-HETE may mediate the PTH/PKC inhibition of renal Na+-Pi cotransport. To this end, we tested the effect of 20-HETE on Na+-Pi cotransport in proximal tubule-like cells. Exposure of opossum kidney (OK) cells for 4 h to 20-HETE (10(-7) M) decreased Na+-dependent uptake of 32Pi (from 0.26 +/- 0.02 to 0.19 +/- 0.01 nmol/mg protein.min) by approximately 25% (P < 0.001). The inhibition was due to a reduction in Vmax. 20-HETE had no significant effect on either the apical amiloride-sensitive and insensitive 22Na uptakes or on basolateral ouabain-sensitive 86Rb uptake, and was specific for Pi. These results indicate that 20-HETE specifically inhibits Na+-dependent Pi transport in OK cells and that it may be a mediator of PTH action in the PT.

Animals↗
PubMed2004

Effects of parathyroid hormone on cancellous bone mass and structure in osteoporosis.

Parathyroid hormone (PTH) is the major hormonal regulator of calcium homeostasis. PTH is a potent stimulator of bone formation and can restore bone to an osteopenic skeleton, when administered intermittently. Osteoblasts are the primary target cells for the anabolic effects of PTH in bone tissue. Anabolic effects of PTH on bone have been demonstrated in animals and humans, by numerous measurement techniques including bone mineral density and bone histomorphometry. Clinically, the most important aspect of treatment for osteoporosis is prevention of fractures. Microstructural alterations, such as loss of trabecular connectivity, have been implicated in increased propensity for fracture. Recent two-dimensional (2D) and three-dimensional (3D) assessments of cancellous bone structure have shown that PTH can re-establish lost trabecular connectivity in animals and humans. These results provide new insight into the positive clinical effects of PTH in osteoporosis. In recent randomized controlled clinical trials of intermittent PTH treatment, PTH decreased incidence of vertebral and non-vertebral fractures in postmenopausal women. Thus, PTH shows strong potential as therapy for osteoporosis. However, 2D and 3D structural analysis of advanced osteopenia in animals has shown that there is a critical limit of trabecular connectivity and bone strength below which PTH cannot completely reverse the condition. Given that PTH treatment fails to completely restore trabecular connectivity and bone strength in animals with advanced osteopenia, early treatment of osteoporosis appears important and efficacious for preventing fractures caused by decreased bone strength resulting from decreased trabecular connectivity.

Animals↗
PubMed1979

Renal handling of calcium: influence of parathyroid hormone and 1,25-dihydroxyvitamin D3.

The influence of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the renal Ca handling was studied in vitamin D-replete rats. The relation between plasma concentration ([Ca]P) and urinary Ca (UCaV/ml GF) was ascertained by clearance techniques over the [Ca]P range of 1.4-3.4 mM varied by infusion of Ca gluconate. Chronic thyroparathyroidectomy (TPTX) decreased the plasma Ca threshold from about 2.3 to 1.5 mM. Between [Ca]P 1.4 and 3.4 mM there was a linear increase in UCaV/ml GF corresponding to 35-50% of the increment in filtered load. In TPTX, PTH (2.5 IU/h i.v.) shifted the Ca threshold from 1.5 to 2.3 mM, without changing the slope of UCaV/ml GF on [Ca]P. The effect of TPTX on the renal Ca handling was not corrected by doses of 1,25(OH)2D3, which increased the intestinal Ca absorption of TPTX rats to normal level. In intact and TPTX rats disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) given at doses which inhibit the production of 1,25(OH)2D3 did not change the tubular Ca handling. Furthermore, 1,25(OH)2D3 had no effect in EHDP-treated TPTX rats. Therefore, tubular Ca handling does not appear to be altered in response to chronic endogenous variation or physiologic supplementation of 1,25(OH)2D3 in vitamin D-replete rats. This is in contrast to the marked alteration observed after TPTX or PTH administration.

Animals↗
PubMed2001

Inducible RGS2 is a cross-talk regulator for parathyroid hormone signaling in rat osteoblast-like UMR106 cells.

Parathyroid hormone (PTH) activates dual signal transduction systems via Galphas and Galphaq proteins. We now report a novel mechanism by which "cross-talk" may occur between the Galphas and Galphaq signaling pathways. RGS2 (Regulator of G protein Signaling 2) mRNA was rapidly and transiently increased only by PTH analogs (PTH1-84, 1-34, 1-31, and PTHrP) that activated the Galphas-mediated cAMP/PKA signaling pathway, whereas activation of the Galphaq-mediated Ca(2+)/PKC signaling pathway by PTH3-34 had no effect on RGS2 expression. Treatment of UMR106 cells with nonPTH activators of the cAMP/PKA signaling pathway such as cholera toxin, forskolin, 8-Br-cAMP, and dibutyryl-cAMP also significantly elevated RGS2 mRNA levels, while activator of the Galphaq pathway PMA did not. Pretreatment using the Galphas signaling pathway inhibitors SQ22536 and H89 significantly blocked PTH-induced RGS2 expression, but the Galphaq signaling pathway inhibitor bisindolylmaleimide I had no effect. Therefore, RGS2 expression is governed solely by the Galphas signaling pathway. Additionally, we demonstrate for the first time that RGS2 binds to both Galphas and Galphaq subunits in their transition state (GDP/AlF(-4)-bound) forms, suggesting that RGS2 has the potential to act as a bridge between the cAMP/PKA and Ca(2+)/PKC pathways, and that it may act as a cross-talk regulator for these two PTH signaling pathways.

Animals↗
PubMed1993

Dopaminergic actions of parathyroid hormone in the rat medial basal hypothalamus in vitro.

Parathyroid hormone (PTH) modulates dopamine (DA) metabolism in the rat medial basal hypothalamus (MBH) in vivo. Direct effects of PTH on MBH DA metabolism were therefore investigated in vitro. Incubation of rat MBHs for 60 min with 10(-7)-10(-5) M human PTH1-34 consistently reduced the tissue DA content and increased the DOPAC (dihydroxyphenylacetic acid) to DA ratio. This ratio was further increased in tissues incubated in 10(-5) M PTH1-34, as a result of an increase in DOPAC content. The tissue content of DOPAC and DA was unaffected by 10(-9) M PTH. The serotonin (5HT) content of the MBH was reduced by 10(-5) M PTH1-34, but concentrations of 5HT, 5-hydroxyindolacetic acid, and norepinephrine were otherwise unaffected by 10(-9)-10(-5) M PTH1-34. Concentrations of DA in the incubation media were reduced after exposure to 10(-6) or 10(-5) M PTH1-34. The uptake of 3H-labelled DA by incubated tissues was also reduced by 10(-6) M PTH1-34, as was the metabolism of 3H-labelled DA into tissue and media DOPAC. Monoamine oxidase (MAO) activities A and B were significantly increased after the incubation of the MBH with 10(-6) or 10(-5) M PTH1-34. These results further demonstrate neuromodulatory actions of PTH on dopaminergic neurons within the rat MBH in vitro, and suggest neural and/or neuroendocrine roles of PTH of central or peripheral origin.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3.

1,25-dihydroxyvitamin D3 [1,25(OH)2D3], plays an important role in the regulation of mineral ion homeostasis. As well as being the major steroid hormone that regulates calcium metabolism, 1,25(OH)2D3 suppresses transcription of the gene encoding parathyroid hormone, a peptide that plays a dominant role in regulating extracellular calcium levels. To identify DNA sequences that may mediate this transcriptional repression, nuclear extracts containing the 1,25(OH)2D3 receptor were examined for binding to sequences in the 5'-flanking region of the human parathyroid hormone gene. A 25-base-pair (bp) oligonucleotide containing the sequences from -125 to -101 from the start of exon I binds nuclear proteins recognized by monoclonal antibodies against the 1,25(OH)2D3 receptor. The sequences in this region contain a single copy of a motif (AGGTTCA) homologous to the motifs repeated in the up-regulatory 1,25(OH)2D3-response elements. When placed upstream to a heterologous viral promoter, the sequences contained in this 25-bp oligonucleotide mediate transcriptional repression in response to 1,25(OH)2D3 in GH4C1 cells but not in ROS 17/2.8 cells. This down-regulatory element, therefore, differs from the up-regulatory 1,25(OH)2D3-response elements both in sequence composition and in the requirement for particular cellular factors other than the 1,25(OH)2D3 receptor for repressing transcription.

Animals↗
PubMed1986

Parathyroid hormone reduces acute ischemic injury of the myocardium.

Synthetic parathyroid hormone (PTH), particularly the molecular fragment containing amino acids one to 34 (1-34), has been shown to produce coronary vasodilation and systemic vasodilation without tachycardia. On this basis, we tested the hypothesis that PTH(1-34) would favorably affect oxygen balance in acutely ischemic myocardium and reduce the extent of injury after coronary occlusion. Experiments were done upon the left anterior descending coronary artery which was ligated through a thoracotomy in anesthetized dogs subjected to ligation of the left anterior descending coronary artery. After 30 minutes of ischemia, the dogs were randomly assigned to either a group which received an intracoronary infusion of 0.008 nanomoles per kilogram of body weight per minute of PTH (1-34) for ten minutes at intervals of 30 minutes or a control group which received intracoronary saline solution. PTH(1-34) increased circumflex artery blood flow 290 +/- 62 per cent (p less than 0.005) and coronary venous return from the ischemic area 190 +/- 12 per cent (p less than 0.005) while reducing mean arterial pressure 12.5 +/- 1.7 per cent (p less than 0.05) without a change in the heart rate. These hemodynamic changes resulted in a 54.3 +/- 3.7 per cent (p less than 0.005) decrease in ischemic myocardial oxygen extraction and a reduction of infarct size (25 +/- 5 per cent of myocardium at risk in treated versus 75 +/- 10 per cent in the control group). It is concluded that PTH given after coronary artery occlusion increases collateral blood flow and oxygen supply to the ischemic myocardium while reducing oxygen requirements. Thus, PTH may offer significant protection for the acutely ischemic myocardium.

Animals↗
PubMed2006

Genistein modulates the effects of parathyroid hormone in human osteoblastic SaOS-2 cells.

Genistein and parathyroid hormone (PTH) are anabolic agents that stimulate bone formation through their direct actions in osteoblastic cells. In the present study, we aimed to determine whether genistein modulates the actions of PTH in human osteoblastic SaOS-2 cells in an oestrogen-depleted condition. The present results showed that genistein (10(-8) to 10(-6) m) induced alkaline phosphatase (ALP) activity and osteoprotegrin (OPG) expression in SaOS-2 cells in a dose-dependent manner. These effects could be completely abolished by co-treatment with oestrogen antagonist ICI 182780 (7alpha-[9-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol). Genistein (at 1 microM) could stimulate the mRNA expression of receptor activator of NF-kappaB ligand (RANKL). As OPG and RANKL are known to modulate osteoclastogenesis, the ability of genistein to modulate OPG and RANKL expression in SaOS-2 cells suggested that it might modulate osteoclastogenesis through its direct actions on osteoblastic cells. PTH (at 10 nM) stimulated ALP activity, induced RANKL mRNA expression and suppressed OPG mRNA expression in SaOS-2 cells, confirming its bi-directional effects on osteoblastic cells. Pre-treatment of SaOS-2 cells with genistein and oestrogen not only enhanced PTH-induced ALP activity, but also attenuated PTH up regulation of RANKL mRNA expression and PTH down regulation of OPG mRNA expression. Taken together, the present study provides the first evidence that genistein could modulate the actions of PTH in human osteoblastic SaOS-2 cells in an oestrogen-depleted condition.

Alkaline Phosphatase↗
PubMed1985

Relationship among parathyroid hormone, cAMP, and calcium on proximal tubule sodium transport.

Parathyroid hormone (PTH), through the generation of cAMP, inhibits the transport of sodium, bicarbonate, and water in the proximal convoluted tubule. The present studies were designed to determine whether the response to PTH or dibutyryl cAMP by proximal renal tubules requires an influx of calcium into the cells or an alteration in the cytosolic concentration of calcium. O2 consumption was determined in an enriched suspension of rabbit proximal convoluted tubules, and the ouabain-sensitive component of O2 consumption was taken as a measure of sodium transport. PTH (1 IU/ml) inhibited the ouabain-sensitive component of O2 consumption from 14.2 +/- 1.6 to 8.9 +/- 1.1 nmol O2 X min-1 X mg protein-1 (P less than 0.005). Dibutyryl cAMP (10(-4) M) inhibited ouabain-sensitive O2 consumption from 12.0 +/- 1.1 to 8.4 +/- 0.8 nmol O2 X min-1 X mg protein-1 (P less than 0.005). In the presence of lanthanum (5-50 microM) or verapamil (20-200 microM), PTH inhibited ouabain-sensitive O2 consumption by 21.3 +/- 3.4% (P less than 0.025) and 33.9 +/- 5.5% (P less than 0.025), respectively. Dibutyryl cAMP inhibited the ouabain-sensitive O2 consumption by 22.6 +/- 7.1% (P less than 0.025) in the presence of lanthanum and 35.4 +/- 3.1% (P less than 0.01) in the presence of verapamil. To more directly assess the cytosolic concentration of calcium, the fluorescent intensity of quin 2-loaded tubules was determined. As compared with timed controls, exposure to PTH resulted in a lower cytosolic concentration of calcium over the 10 min of incubation. Dibutyryl cAMP had a similar effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoquinolines↗
PubMedDate not supplied

Influence of sevelamer hydrochloride on serum concentration of whole (1-84) and N-terminally truncated (7-84) parathyroid hormone fragments in hemodialysis uremic patients.

Phosphate retention stimulates parathyroid hormone (PTH) secretion in uremic patients. Sevelamer hydrochloride is an aluminium- and calcium-free phosphate binder used in the treatment of secondary hyperparathyroidism in uremic patients. The influence of the phosphate lowering effect on serum levels of whole PTH-1-84 and N-terminally truncated PTH-7-84 has not been studied. Seventeen hemodialysis (HD) patients (nine male, eight female) with chronic renal failure and serum phosphorus concentrations, despite calcium carbonate treatment, >2.0 mmol/L were enrolled in this study. Patients did not receive aluminium containing binders. Blood samples for serum concentration assessments of calcium, phosphorus, PTH-1-84 and N-terminally truncated PTH-7-84, carboxyterminal cross-linked collagen fragments (Ctx), total (AP) and bone specific alkaline phosphatase activity (BAP) were drawn twice: before and after 5-week sevelamer administration (in addition to calcium carbonate). Sevelamer treatment was followed by a significant reduction in serum phosphorus level (from 2.46 +/- 0.09 to 2.07 +/- 0.10 mmol/L; p=0.009), PTH-1-84 level (from 396 +/- 75 to 298 +/- 64 pg/mL; p=0.03) and PTH-1-84/PTH-7-84 ratio (from 1.78 +/- 0.18 to 1.55 +/- 0.19; p=0.01), while serum PTH-7-84 levels declined only slightly (from 220 +/- 35 to 183 +/- 25 pg/mL; p=0.11). Serum calcium, Ctx concentrations, AP and BAP activity did not change markedly. There was a significant positive correlation between changes of phosphorus and PTH-1-84 (tau=0.48; p=0.007) or PTH-7-84 concentration (tau=0.43; p=0.02). A 5-week sevelamer treatment suppressed both PTH-1-84 (change statistically significant) and PTH-7-84 (change statistically non-significant) serum concentration in HD uremic patients seemingly related to changes in phosphatemia.

Alkaline Phosphatase↗
PubMed1988

1,25 dihydroxyvitamin D3 alone or in combination with parathyroid hormone does not increase bone mass in young rats.

Parathyroid hormone (PTH) alone is known to increase bone mass, but clinical studies of osteoporotic men suggest that when 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) is given in combination with PTH, the effect on bone growth is enhanced. To determine if 1,25(OH)2D3 alone would stimulate bone growth, young male rats were given daily subcutaneous injections of either vehicle or 2.5, 5, 10, or 20 ng 1,25(OH)2D3 per 100 g body weight for 30 days. To determine if 1,25(OH)2D3 would augment the PTH anabolic response, rats were given daily subcutaneous injections of either vehicle for 12 days; or 4 micrograms/100 g hPTH alone or in combination with 5 ng/100 g 1,25(OH)2D3; or 8 micrograms/100 g hPTH alone or in combination with 5 ng/100 g 1,25(OH)2D3. Calcium (Ca), dry weight (DW), and hydroxyproline (Hyp) of the distal femur; the rate of mineralization in the metaphysis of the proximal tibia; and serum calcium and phosphate were measured. Low normocalcemic doses of 1,25(OH)2D3 did not significantly stimulate bone growth. 1,25(OH)2D3 did not augment the PTH-stimulated anabolic effect in young male rats. Low doses (2.5 and 5 ng) of 1,25(OH)2D3 were not hypercalcemic, and there was no increase in total bone calcium or dry weight although the 5 ng dose increased trabecular bone calcium. 1,25(OH)2D3 at 10 and 20 ng increased trabecular bone DW and Hyp, but mineralization was impaired and rats were hypercalcemic. 1,25(OH)2D3 in combination with PTH did not augment the PTH stimulation of bone growth as trabecular and cortical bone Ca, DW, and HYP were not increased in rats given both hPTH and 1,25(OH)2D3 compared with values for rats treated with hPTH alone.

Animals↗
PubMed1997

Single-dose subcutaneous administration of recombinant human parathyroid hormone [rhPTH(1-84)] in healthy postmenopausal volunteers.

BACKGROUND: Parathyroid hormone [PTH(1-84)] is intended for treatment of osteoporosis because it stimulates new bone formation of normal structure and composition. Recently, recombinant human PTH(1-84) [rhPTH(1-84)] has become available for therapeutic evaluation. OBJECTIVES: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of rhPTH(1-84) after single-dose subcutaneous administration of rhPTH(1-84) or placebo to 32 healthy postmenopausal volunteers (dose range, 0.02 to 5.0 micrograms.kg-1). RESULTS: In the lower dose range (0.02 to 2.0 micrograms.kg-1), serum ionized and total calcium concentrations increased dose dependently, with approximately 0.15 mmol/L for dose levels > 0.2 microgram.kg-1 and > 1.5 micrograms.kg-1, respectively, unlike the higher dose range (2.0 to 5.0 micrograms.kg-1), for which concentration-time profiles clearly exhibited a biphasic pattern. Urine evaluation revealed an increase in both calcium/ creatinine and phosphate/creatinine ratios, the former appearing in the 12- to 24-hour and 24- to 36-hour collections for doses > 2.5 micrograms.kg-1 and the latter in the 0- to 12-hour collection for doses > or = 1.5 micrograms.kg-1. Urinary deoxypyridinoline excretion was used as a biochemical marker of bone resorption, but no consistent changes were found. Urinary cyclic adenosine monophosphate excretion, which is an indirect measure of PTH(1-84) action on the kidney, showed a clear increase in the 0- to 12-hour urine collection for doses > or = 1.5 micrograms.kg-1. As for ionized and total calcium, serum concentration-time curves of PTH(1-84) exhibited a double-peak profile, the first peak appearing about 5 to 10 minutes after administration and the second peak occurring about 1 1/2 to 2 hours after administration. Serum terminal half-life of PTH(1-84) was approximately 2 1/2 hours. CONCLUSION: Up to a dose of 5.0 micrograms.kg-1, rhPTH(1-84) was safe and well tolerated by healthy postmenopausal volunteers.

Adult↗
PubMed1996

Effects of parathyroid hormone on hepatocyte pHi and Na(+)-H+ exchanger activity.

Parathyroid hormone (PTH) induces a rise in cytosolic calcium--[Ca2+]i--in many cells. A rise in [Ca2+]i activates the Na(+)-H+ antiport, but PTH inhibits the Na(+)-H+ exchanger in kidney cells. Since PTH induces a rise in [Ca2+]i of hepatocytes, we examined the effect of PTH on their Na(+)-H+ antiport and intracellular pH(pHi). PTH caused an initial activation of Na(+)-H+ exchanger, and this stimulation is amiloride sensitive. The activation of the Na(+)-H+ exchanger was followed by progressive inhibition. This inhibitory effect was dose dependent and occurred over a wide range of external sodium concentrations. PTH also caused a progressive rise in hepatocyte pHi which became apparent after the initial activation of the Na(+)-H+ antiport. This alkalinization of hepatocytes occurred when the cells were placed in sodium or potassium media. These actions of PTH were mimicked by dibutyryl cyclic AMP and 12-o-tetradecanoylphorbol-13-acetate(TPA) and were abolished by H-89 (an inhibitor of protein kinase A), staurosporine (an inhibitor of protein kinase C), and the calcium channel blockers verapamil or nifedipine. The data are consistent with the formulation that PTH, through the activation of the cAMP-protein kinase A pathway, protein kinase C, and calcium channels inhibitable by verapamil or nifedipine, induces a rise in [Ca2+]i of hepatocytes. The latter event causes an initial activation of Na(+)-H+ antiport which is followed by a rise in pHi. Also, PTH may facilitate a Ca2+/2H+ exchange across the hepatocyte membrane and causes an initial and persistent rise in pHi, since the rise in pHi occurred under conditions where Na(+)-H+ antiport is inactive (potassium media). In addition, PTH either directly or through activation of second messenger(s) leads to an increased ammonia content of hepatocytes which could maintain a high pHi. Consequently, the Na(+)-H+ antiport is inhibited in an effort to restore the pHi back to normal.

Ammonia↗
PubMed1997

Insulin-like growth factor-I mediates osteoclast-like cell formation stimulated by parathyroid hormone.

There have been several lines of evidence that parathyroid hormone (PTH) stimulates production of insulinlike growth factor I (IGF-I) in bone and that IGF-I stimulates osteoclast formation. Thus, the present study was performed to clarify the possible role of IGF-I in PTH-stimulated osteoclastlike cell formation and the role of PTH-responsive dual signal transduction systems (cyclic [c] AMP-dependent protein kinase [PKA] and calcium/protein kinase C [PKC]) in its mechanism. Treatment with anti-IGF-I antibody (1-10 micrograms/ml) partially but significantly blocked hPTH-(1-34)-stimulated osteoclastlike cell formation in unfractionated mouse bone cell cultures, although it did not affect osteoclastlike cell formation stimulated by 1,25-dihydroxyvitamin D3. Rp-cAMP5 (10(-4) M), a direct PKA inhibitor, as well as two types of PKC inhibitors, H-7 (10 microM) and staurosporine (3 nM), and dantrolene (10(-5) M), an inhibitor of calcium mobilization from intracellular calcium stores, all significantly blocked PTH-stimulated osteoclastlike cell formation. Anti-IGF-I antibody (3 micrograms/ml) significantly blocked osteoclastlike cell formation stimulated by 10(-4) M dbcAMP, 10(-4) M Sp-cAMPS, a direct PKA activator, and 10(-5) M forskolin in mouse bone cell cultures. Dibutyryl cAMP, forskolin, and hPTH-(1-34) significantly stimulated mRNA expression of both IGF-I and IGF-binding protein 5 (IGFBP-5) in these cultures, but neither 10(-7) M PMA, a PKC activator, nor 10(-7) M A23187 did. Moreover, anti-IGF-I antibody significantly blocked osteoclastlike cell formation stimulated by the conditioned medium from MC3T3-E1 cells pretreated with 10(-8) PTH-(1-34), which induced IGF-I and IGFBP-5 mRNA expression in these cells. In conclusion, the present study indicates that IGF-I mediates osteoclastlike cell formation stimulated by PTH and that the PKA pathway is involved in its mechanism. However, IGF-I does not seem to be the sole effector molecule to be active in this system.

Animals↗