The urine cyclic AMP response to parathyroid extract (PTE) administration in normal subjects and patients with parathyroid dysfunction

Tucci, Joe; Perlstein, Robert S.; Kopp, Lowell

doi:10.1016/0026-0495(79)90207-5

Cited by 16 publications

(9 citation statements)

References 26 publications

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“…The majority of these reports (5,6,9,10,(31)(32)(33) Resistance to PTH has been provoked in rats by hypercalcemia (36), hypermagnesemia (37), and hypokalemia (38), and in both rats and chicks by hypocalcemia associated with either vitamin D deficiency or a calcium-deficient diet (27,39). Humans with chronic renal failure (5, 9), vitamin D deficiency (32), and some patients with primary hyperparathyroidism (6)(7)(8)(9) are also refractory to stimulation by exogenous PTH.…”

Section: Resultsmentioning

confidence: 99%

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Rapid development of renal resistance to low doses of synthetic bovine parathyroid hormone fragment 1-34. Dissociation of urinary cyclic adenosine monophosphate, phosphaturic, and calciuric responses.

Law¹,

Heath²

1983

J. Clin. Invest.

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A B S T R A C T The designing of parathyroid hormone (PTH)-renal dose-response studies in human beings is complicated by the possibility of rapid homologous receptor down-regulation, a phenomenon that is clearly shown to occur in vitro. Large amounts of PTH given to human subjects as serial injections or prolonged infusions cause decreased urinary 3',5'-cyclic adenosine monophosphate (cAMP) responses to subsequent PTH doses, but it is uncertain whether lower doses given over shorter periods similarly cause renal tachyphylaxis to PTH action. Thus, in seven water-loaded adults, we infused in ascending order 10, 30, 75, 150, and 300 U of synthetic bovine PTH fragment (bPTH 1-34) per 70 kg body wt over 15 min on widely separated days ("separate day administration"). On another day, each subject received all five 15-min doses in ascending order at 75-min intervals ("single day administration"). Urine collection intervals were control, 0-30 min (including the PTH infusion), and 30-60 min. Peak nephrogenous cAMP (NcAMP, nmol/100 ml glomerular filtrate) response was linearly related to the dose of PTH (separate day study, r = 0.94, P < 0.001; single day study, r = 0.88, P < 0.001). However, the slope of NcAMP responses plotted against PTH dose for the single day study was only 36% of that derived from separate day administration of the same PTH doses (P < 0.001). After only 40 U (10 + 30) of bPTH 1-34/70 kg, the NcAMP response to 75 U was reduced 44%, and the effect of 300 U/70 kg, when given as the last of the sequential single day infusions, was 64% less than the response to 300 U of bPTH 1-34 given alone (P < 0.001). The phosphaturic response (fractional excretion of phosphorus, FEP [percent]) was also linearly related to bPTH 1-34 dose, but combined administration of the PTH infusions on one day increased FEP at each dose identically with the effects of separate day administration. A transient, dose-related, early hypercalciuric response to bPTH 1-34 also occurred, and was of equal magnitude in both protocols. These studies demonstrate that significant blunting of the NcAMP response to bPTH 1-34 occurs rapidly and follows brief exposure to relatively low doses of hormone. In contrast, there is no effect of recent PTH administration on the phosphaturic and early hypercalciuric actions of bPTH 1-34. This seeming dissociation of PTH effects makes unclear the physiologic importance of PTH-induced cAMP tachyphylaxis in the regulation of final PTH actions. In any case, studies of NcAMP responses in which the occurrence of tachyphylaxis would be undesirable should be designed to avoid prolonged or closely spaced administrations of the hormone. INTRODUCTION The acute administration of exogenous parathyroid hormone (PTH)' causes increased urinary excretion of

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Section: Resultsmentioning

confidence: 99%

“…"Resistance" or tachyphylaxis to the effects of PTH follows sustained or repetitive exposure to the hormone in animal studies in vitro (2,3) and in vivo (4). For human beings, chronic endogenous PTH excess (primary or secondary) is associated with reduction of the urinary cAMP response to stimulation by exogenous PTH in some patients (5)(6)(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Rapid development of renal resistance to low doses of synthetic bovine parathyroid hormone fragment 1-34. Dissociation of urinary cyclic adenosine monophosphate, phosphaturic, and calciuric responses.

Law¹,

Heath²

1983

J. Clin. Invest.

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“…They suggested that high levels of endogenous PTH may have reduced renal receptors blunting any effect from exogenous PTH. In this laboratory, the cAMP and phosphaturic responses to an infusion of parathyroid extract (PTE) in normal subjects and in patients with primary hvperparathyroidism and hypoparathyroidism were found to be comparable (Tucci et al 1979), suggesting that the renal cAMP response to a bolus of PTE is not affected by the level of serum calcium, phosphorus, or endogenous PTH. Recently, similar studies were performed in a man suffering from celiac disease, severe osteoma¬ lacia, and secondary hvperparathyroidism. The results of these studies including the measurement of extracellular cyclic nucleotide levels before and after infusions of PTE prior to and subsequent to appropriate therapy form the substance of this report.…”

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confidence: 90%

Extracellular cyclic AMP levels in osteomalacia

Castro¹,

Tucci²

1980

Acta Endocrinologica

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Plasma and urinary cyclic AMP were measured in a 62-year-old man with severe osteomalacia due to a gluten-induced enteropathy. Before therapy, plasma cyclic AMP was normal and both urinary and nephrogenous cyclic AMP were markedly increased. A calcium infusion acutely diminished the elevated iPTH and urinary cyclic AMP levels. Following a bolus infusion of PTE, there was no phosphaturia despite a somewhat exaggerated increase in cyclic AMP excretion. With appropriate therapy, serum calcium, phosphorus, alkaline phosphatase, iPTH and 25-OHD3 and urinary and nephrogenous cyclic AMP gradually returned to normal.The response to PTE infusion after normalization of serum electrolytes, iPTH, and 25-OHD3 levels was similar to that seen before therapy.These results demonstrate that non-azotaemic malabsorptive osteomalacia is associated with elevations in urinary and nephrogenous cyclic AMP which gradually fall to normal with therapy. In contrast to studies in the vitamin D deficient rat, the maximal urinary cyclic AMP response to PTE is not diminished in the human with malabsorptive osteomalacia. The lack of a phosphaturic response to PTE depite a normal increase in urinary cyclic AMP excretion, as seen in our patient, is similar to that described in some patients with pseudohypoparathyroidism, suggesting that the response is not specific for the latter disorder. Finally, the data suggest that endogenous PTH does not modulate its renal receptors, at least in terms of cyclic AMP generation.It is generally accepted that vitamin D plavs a major role in the action of parathyroid hormone (PTH) in bone, whereas in the kidnev, PTH can exert its usual effects in the absence of vitamin D (Rasmussen et al. 1963;Arnaud et al. 1966). In keeping with the critical effects of vitamin D on calcium metabolism, a deficiency in this substance is typi¬ cally associated with skeletal resistance to PTH (Steendijk 1964) and the development of hyperparathvroidism (Arnaud et al. 1972;Joffe et al. 1972). Evidence of an increase in PTH secretion is supported bv recent studies in which children with rickets had significant elevations in urinary cyclic AMP (cAMP) excretion (Sovik et al. 1976;Vainsel et al. 1976). Forte et al. (1976) found that in vitamin D deficient rats the administration of PTH was associated with a diminished response in terms of phosphate and cAMP excretion and renal cell adenylate cyclase activity. They suggested that high levels of endogenous PTH may have reduced renal receptors blunting any effect from exogenous PTH. In this laboratory, the cAMP and phosphaturic responses to an infusion of parathyroid extract (PTE) in normal subjects and in patients with primary hvperparathyroidism and hypoparathyroidism were found to be comparable (Tucci et al. 1979), suggesting that the renal cAMP response to a bolus of PTE is not affected by the level of serum calcium, phosphorus, or endogenous PTH. Recently, similar studies were performed in a man suffering from celiac disease, severe osteoma¬ lacia, and secondary hvperparathyroidism. T...

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“…Hyperparathyroid states in man are often associated with renal and skeletal resistance to the action of exogenous parathyroid hormone (PTH)l (1)(2)(3)(4)(5). The renal resistance is manifested by blunting of the phosphaturic and urinary cyclic (c)AMP responses to exogenous PTH, and appears to be related to the level of endogenous PTH (2).…”

Section: Introductionmentioning

confidence: 99%

Canine renal receptors for parathyroid hormone. Down-regulation in vivo by exogenous parathyroid hormone.

Mahoney¹,

Nissenson²

1983

J. Clin. Invest.

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A B S T R A C T Chronic elevation of circulating parathyroid hormone (PTH) is associated with decreased target cell responsiveness to PTH. To study the subcellular mechanism of this phenomenon we evaluated PTH receptors and adenylate cyclase activity in renal cortical membranes prepared before and after infusion of bovine parathyroid gland extract (PTE) into thyroparathyroidectomized dogs. PTE infusion resulted in a 53% decrease in the number of high-affinity receptors (P < 0.01) associated with a 66% decrease in PTH-stimulated adenylate cyclase (P < 0.01) relative to paired base-line values. Both the equilibrium constant of dissociation (KD) for PTH binding and the concentration of PTH that caused half-maximal stimulation of adenylate cyclase were in the range of 1 to 4 nM, and were unaffected by the PTE infusion. Responsiveness of the renal adenylate cyclase to sodium fluoride was 88% of base-line values. Infusion of the PTE vehicle alone did not affect PTH receptor number or blunt the adenylate cyclase response to PTH.Pretreatment of the membranes made after PTE infusion with guanosine triphosphate (GTP), which is known to produce dissociation of receptor-bound PTH, failed to restore either receptor number or PTH-stimulated adenylate cyclase. This finding was not due to a lack of efficacy of the GTP pretreatment, because identical GTP pretreatment restored PTH incubation with PTH in vitro. Thus, simple residual occupancy of PTH receptors by the infused hormone did not appear to account for the observed receptor loss.The results of this study suggest that target cell resistance to PTH in patients with hyperparathyroidism might occur, at least in part, due to down-regulation of PTH receptors by circulating hormone.

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The urine cyclic AMP response to parathyroid extract (PTE) administration in normal subjects and patients with parathyroid dysfunction

Cited by 16 publications

References 26 publications

Rapid development of renal resistance to low doses of synthetic bovine parathyroid hormone fragment 1-34. Dissociation of urinary cyclic adenosine monophosphate, phosphaturic, and calciuric responses.

Rapid development of renal resistance to low doses of synthetic bovine parathyroid hormone fragment 1-34. Dissociation of urinary cyclic adenosine monophosphate, phosphaturic, and calciuric responses.

Extracellular cyclic AMP levels in osteomalacia

Canine renal receptors for parathyroid hormone. Down-regulation in vivo by exogenous parathyroid hormone.

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