Reversible Resistance to the Renal Action of Parathyroid Hormone in Man

1976 ◽  
Vol 51 (1) ◽  
pp. 59-69 ◽  
Author(s):  
S. Tomlinson ◽  
G. N. Hendy ◽  
D. M. Pemberton ◽  
J. L. H. O'Riordan
Keyword(s):  
Parathyroid Hormone ◽  
Cyclic Amp ◽  
Intravenous Injection ◽  
Normal Subjects ◽  
Standard Test ◽  
Initial Increase ◽  
Partial Recovery ◽  
Amino Terminal ◽  
Receptor Sites ◽  
Bovine Parathyroid Hormone

1. Normal subjects showed a highly reproducible, rapid increase in plasma adenosine 3′:5′-cyclic monophosphate (cyclic AMP) after an intravenous injection of 200 MRC units of highly purified bovine parathyroid hormone. 2. No significant increase in plasma cyclic AMP was observed after administration of bovine parathyroid hormone to patients with severe chronic renal failure. 3. Even when renal function was not impaired, some patients with primary hyperparathyroidism, who had high concentrations of endogenous parathyroid hormone, showed resistance to bovine parathyroid hormone and when this was injected intravenously it caused only a small increase in plasma cyclic AMP. This resistance was reversible since there was marked improvement in the response after parathyroidectomy, when endogenous parathyroid hormone concentration had fallen. 4. It was possible to reproduce this resistance to the hormone by intravenous infusion of bovine parathyroid hormone into normal subjects. When the hormone (1000 MRC units) was infused over 2 h, after an initial increase there was a progressive decline in plasma cyclic AMP concentration and a fall in urinary cyclic AMP excretion. The response to a standard test stimulus (200 MRC units of bovine parathyroid hormone given as a rapid intravenous injection) was examined at intervals after 1000 units of bovine parathyroid hormone had been infused. Initially, the response was severely impaired; at 4 h, partial recovery had occurred and, 24 h after the infusion, recovery of the response was complete. The resistance was therefore reversible. Infusion of the amino-terminal peptide, fragment 1–34, gave the same effect as infusion of intact hormone. Region-specific assays for the hormone were used to show that the concentration of immuno-assayable hormone remained high during the infusions. 5. The mechanism of this reversible resistance to parathyroid hormone remains to be elucidated; it seems unlikely that circulating hormone fragments could account for the prolonged impairment in the responsiveness to the intact hormone. It is possible that alteration in the formation, intracellular degradation or, perhaps, release of cyclic AMP from the cells, is the cause. Changes in the characteristics of the hormone receptor sites might also explain the phenomenon.

Cyclic AMP Responses to Parathyroid Hormone and Glucagon during Lithium Treatment

1984 ◽  
Vol 66 (5) ◽  
pp. 557-559 ◽  
Author(s):  
D. G. Waller ◽  
J. D. M. Albano ◽  
J. G. B. Millar ◽  
A. Polak
Keyword(s):  
Parathyroid Hormone ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Intravenous Injection ◽  
Lithium Treatment ◽  
Endocrine Dysfunction ◽  
Urinary Cyclic Amp ◽  
Urine Concentrating Ability ◽  
Bovine Parathyroid Hormone

1. Inhibition of adenylate cyclase has been proposed as a mechanism for hypothyroidism and nephrogenic diabetes insipidus occurring during lithium treatment, but these disorders are rarely found in the same patients. 2. We have measured plasma levels of adenosine 3′:5′-cyclic monophosphate (cyclic AMP) after an intravenous injection of glucagon in eight patients receiving long term lithium treatment and in six control subjects. Urinary cyclic AMP levels after an intravenous injection of bovine parathyroid hormone (PTH) were also measured in the patients. 3. The plasma cyclic AMP response to glucagon in the patient group was significantly lower than that of the controls. No correlation was demonstrated between the plasma cyclic AMP response after glucagon and the urinary cyclic AMP response after PTH. 4. We have previously shown that impairment of the response to PTH correlates with reduced urine concentrating ability during lithium treatment. In contrast, there was no correlation between the responses to PTH and glucagon in individual patients. These results are consistent with the hypothesis that inhibition of adenylate cyclase is an important factor in lithium-induced endocrine dysfunction.

The Effects of Exogenous Parathyroid Hormone on Plasma and Urinary Adenosine 3′,5′-Cyclic Monophosphate in Man

1974 ◽  
Vol 47 (5) ◽  
pp. 481-492 ◽  
Author(s):  
S. Tomlinson ◽  
P. M. Barling ◽  
J. D. M. Albano ◽  
B. L. Brown ◽  
J. L. H. O'Riordan
Keyword(s):  
Parathyroid Hormone ◽  
Cyclic Amp ◽  
Bolus Injection ◽  
Normal Subjects ◽  
Peripheral Vein ◽  
Terminal Part ◽  
Cyclic Monophosphate ◽  
Peripheral Plasma ◽  
Bovine Parathyroid Hormone ◽  
Subsequent Disappearance

1. Administration of highly purified bovine parathyroid hormone (BPTH) (200 MRC units) increased the concentration of adenosine 3′,5′-cyclic monophosphate (cyclic AMP) in the peripheral plasma of normal subjects within minutes, whether the hormone was given as a bolus injection or an infusion. 2. The subsequent disappearance of cyclic AMP from the circulation was also rapid (t1/2 = 14 min) and was associated with a prompt decline (t1/2 = 4.6 min) in the concentration of the ammo-terminal part of BPTH, as measured in a region-specific immunoradiometric assay. 3. The concentration of cyclic AMP in plasma from a renal vein was found to increase more rapidly and to reach a greater peak than plasma from a peripheral vein. 4. The administration of BPTH to anephric subjects caused no increase in cyclic AMP. 5. These investigations indicate that parathyroid hormone can act extremely rapidly, with a short half-life, and that the kidney makes a major contribution to the changes in plasma cyclic AMP induced by the hormone. In addition, they form the basis for the development of a simplified Ellsworth—Howard test, using changes in circulating cyclic AMP after BPTH administration as an index of responsiveness to the hormone.

Impairment of Cyclic AMP Response to Bovine Parathyroid Hormone in Patients on Chronic Lithium Therapy with Diminished Renal Urine-Concentrating Ability

1983 ◽  
Vol 64 (6) ◽  
pp. 623-627 ◽  
Author(s):  
D. G. Waller ◽  
J. D. M. Albano ◽  
J. G. B. Millar ◽  
A. Polak
Keyword(s):  
Parathyroid Hormone ◽  
Cyclic Amp ◽  
Intravenous Injection ◽  
Lithium Treatment ◽  
Urine Osmolality ◽  
Control Subjects ◽  
Urinary Cyclic Amp ◽  
Urine Concentrating Ability ◽  
Bovine Parathyroid Hormone

1. Urinary and plasma levels of adenosine 3′:5′-cyclic monophosphate (cyclic AMP) after an intravenous injection of bovine parathyroid hormone (PTH) were measured in 12 patients on long-term lithium treatment and in nine control subjects. The maximum urine osmolality (Umax.) after an intravenous injection of desamino-d-arginine vasopressin (DDAVP) was also measured. 2. in all the control subjects and six of the patients, the Umax. after DDAVP exceeded 700 mosmol/kg. The cyclic AMP responses in these two groups did not differ significantly. 3. in the remaining six patients whose Umax. did not reach 700 mosmol/kg, the cyclic AMP response to PTH was significantly less than that of the controls. 4. A strong correlation was demonstrated in the patients between the urinary cyclic AMP response after PTH and the maximum osmolality after the administration of DDAVP. 5. These observations are consistent with the hypothesis that reduced adenylate cyclase activity contributes to the development of nephrogenic diabetes insipidus in patients on long-term lithium treatment.

ACTH and adrenal aerobic glycolysis. I: Effects of O-nitrophenylsulphenyl and other ACTH analogues, vasoactive intestinal peptide and human parathyroid hormone(1–34) on lactic acid, steroid and cyclic AMP production by mouse adrenocortical cells

1987 ◽  
Vol 115 (1) ◽  
pp. 61-69 ◽  
Author(s):  
J. Hinson ◽  
M. K. Birmingham
Keyword(s):  
Parathyroid Hormone ◽  
Cyclic Amp ◽  
Vasoactive Intestinal Peptide ◽  
Aerobic Glycolysis ◽  
Fold Increase ◽  
Terminal Segment ◽  
Human Parathyroid Hormone ◽  
Experimental Conditions ◽  
Adrenal Cells ◽  
Amino Terminal

ABSTRACT The structural requirements in the ACTH molecule for evocation of the glycolytic response in suspensions of mouse adrenal cells were investigated by examining the effects of analogues containing modifications at positions 8,9 and 10 and of peptides containing homologies with the amino-terminal segment of ACTH. Introduction of a nitrophenylsulphenyl (NPS) group into the tryptophan moiety at position 9 of ACTH(1–24) greatly reduced both the potency and the capacity for maximal glycolytic response. It also virtually abolished cyclic AMP formation. In contrast, the capacity for a maximal steroidogenic response remained unimpaired in the NPS derivative, although steroidogenic potency was reduced to 0·4% of that of ACTH(1–24). Replacement of the tryptophan moiety with phenylalanine had intermediate inhibitory effects on glycolysis and steroid output; replacement with alanine virtually abolished both these responses. Replacement of arginine in position 8 with lysine in the Phe9 analogue caused a fifty-fold increase in glycolytic potency, but rendered it steroidogenically inactive. Cyclic AMP production was abolished in the Ala9 analogue and greatly impaired in the Phe9 and Lys8,Phe9 analogues. Replacement of the glycine moiety in position 10 with l-alanine, d-alanine, β-alanine or α-aminoisobutyric acid had little or no effect on steroidogenic or glycolytic capacity, although potency was reduced with all substitutions excepting l-alanine. Vasoactive intestinal peptide, which contains homologies with positions 3, 7, 15 and 16 of ACTH, proved completely inactive in dispersed mouse adrenal cells under our experimental conditions, in contrast to human parathyroid hormone(1–34) (hPTH (1–34)) which contains homologies with positions 3, 4, 5, 9 and 11 and was steroidogenic at the lowest concentration tested (0·1 nmol/l), eliciting an eleven-fold increase in steroid production, a response which might be physiologically relevant. It induced near maximal steroidogenesis at a concentration of 10 nmol/l, without affecting cyclic AMP production, and stimulated glycolysis at concentrations above 10 nmol/l, accompanied by a slight rise in cyclic AMP levels. The examples of dissociation between glycolysis and steroidogenesis suggest that different receptors may mediate the two responses. The examples of increased steroidogenesis unaccompanied by a rise in cyclic AMP accord with the concept that cyclic AMP is not an obligatory second messenger for the steroidogenic response. J. Endocr. (1987) 115, 61–69

THE IMMUNOCHEMICAL SPECIFICITY OF ANTISERA TO BOVINE PARATHYROID HORMONE: AN APPROACH TO REGION-SPECIFIC RADIOIMMUNOASSAY

1973 ◽  
Vol 56 (3) ◽  
pp. 493-501 ◽  
Author(s):  
T. M. MURRAY ◽  
H. T. KEUTMANN
Keyword(s):  
Parathyroid Hormone ◽  
Human Plasma ◽  
The Other ◽  
Amino Terminal ◽  
Specific Radioimmunoassay ◽  
Carboxyl Terminal ◽  
Bovine Parathyroid Hormone

SUMMARY Six different antisera to bovine parathyroid hormone were characterized immunochemically by comparing their reactivity towards amino-terminal (1–29) and carboxyl-terminal (53–84) fragments of the hormone molecule. Three of the antisera were primarily amino-terminally directed. One antiserum contained antibody populations to at least three discrete sites; two other antisera each contained two antibodies directed against each end region of the hormone. By saturating one of these antisera with one or the other of the end fragments of the hormone, specific immunoassays for the amino-terminal and carboxyl-terminal regions of the molecule were developed. Such techniques may be applied to improving the specificity of the radioimmunoassay for parathyroid hormone by eliminating interference from carboxyl-terminal hormonal fragments which circulate in human plasma.

REGION-SPECIFIC IMMUNOASSAYS FOR PARATHYROID HORMONE

1975 ◽  
Vol 66 (3) ◽  
pp. 307-318 ◽  
Author(s):  
P. M. BARLING ◽  
G. N. HENDY ◽  
M. C. EVANS ◽  
J. L. H. O'RIORDAN
Keyword(s):  
Parathyroid Hormone ◽  
Antigenic Site ◽  
Amino Terminal ◽  
Specific Radioimmunoassay ◽  
Lower Reactivity ◽  
Intact Molecule ◽  
Carboxy Terminal ◽  
Amino Terminal Fragment ◽  
Selection Of ◽  
Bovine Parathyroid Hormone

SUMMARY Immunoassays specific for limited regions of bovine parathyroid hormone were developed in four ways. With the heterogeneous antisera produced by immunizing with intact bovine parathyroid hormone (BPTH 1–84), the specificity of radioimmunoassays could be enhanced by presaturating either with an amino-terminal (BPTH 1–34) or carboxy-terminal (BPTH 53–84) fragment. Then, the antibodies which had not been neutralized reacted exclusively with the opposite end of the molecule, even using [125I]BPTH 1–84 as tracer. With some antisera, the appropriate fragment and intact hormone reacted identically. However, with other antisera, the fragment reacted less well than the intact hormone, possibly because these antisera contain antibodies reacting with the middle of the molecule. Using the labelled fragment ([125I]BPTH 1–34) as tracer, with heterogeneous antisera, radioimmunoassays specific for the amino-terminal region were obtained. With one antiserum, BPTH 1–34 reacted identically with the intact hormone, but with another antiserum, the fragment was more reactive than the intact molecule. A region-specific radioimmunoassay was also developed using antibodies produced by immunization with a fragment of the hormone. An antiserum raised against BPTH 1–34 had high affinity for the amino-terminal fragment, but reacted less well with the intact hormone. Immunoradiometric assays, specific for the amino- or carboxy-terminal regions, were developed by using immunoadsorbents consisting of a fragment (either BPTH 1–34 or BPTH 53–84) coupled to cellulose. These were used to fractionate 125I-labelled antibodies. With some of these selected antibodies, the appropriate fragment was of lower reactivity than the intact hormone. This may have been due to the presence of an incomplete antigenic site on the fragment, or to conformational differences between the fragment and the corresponding region of the intact hormone. With other selected antibodies the fragment and the intact molecule reacted identically. Careful selection of antisera and of technique is necessary to obtain an assay in which a fragment and the intact hormone behave identically.

scholarly journals Parathyroid hormone inhibits B cell proliferation: implications in chronic renal failure.

1990 ◽  
Vol 1 (3) ◽  
pp. 236-244
Author(s):  
J M Alexiewicz ◽  
M Klinger ◽  
T O Pitts ◽  
Z Gaciong ◽  
M Linker-Israeli ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Renal Failure ◽  
Parathyroid Hormone ◽  
Chronic Renal Failure ◽  
B Cells ◽  
B Cell ◽  
Normal Subjects ◽  
Dependent Manner ◽  
Dialysis Patients ◽  
Amino Terminal

B cell proliferation is impaired in patients with chronic renal failure, but the mechanisms underlying this defect are not known. Lymphocytes have receptors for parathyroid hormone, and it is possible that the state of secondary hyperparathyroidism of renal failure is responsible for the B cell defect. Our studies were designed to (a) examine T cell-independent B cell proliferation [3H)thymidine incorporation) induced by Staphylococcus aureus Cowan 1 after 5 days of culture, (b) evaluate the effect of parathyroid hormone on S. aureus Cowan I-induced B cell proliferation, and (c) investigate the mechanisms through which parathyroid hormone may exert its effect on B cell proliferation. Lymphocytes were obtained from 37 normal subjects and 21 dialysis patients. S. aureus Cowan I induced significant stimulation (P less than 0.01) of the proliferation of B cells from both groups, but the effect was smaller on B cells from dialysis patients (10.0 x 10(3) +/- 1.4 x 10(3) cpm) than on those from normal subjects (21.8 x 10(3) +/- 2.0 x 10(3) cpm). Both the intact molecule of parathyroid hormone (1-84 PTH) and its amino-terminal fragment (1-34 PTH) caused significant inhibition of proliferation of B cells from normal subjects in a dose-dependent manner, with the effect being significantly greater (P less than 0.01) with an equimolar concentration of 1-84 PTH than that of 1-34 PTH. Inactivation of 1-84 PTH by oxidation abolished most of its inhibitory effect on B cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

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