Role of bone and kidney in parathyroid hormone-related peptide-induced hypercalcemia in rats.
A protein responsible for the biochemical syndrome similar to primary hyperparathyroidism associated with certain tumors has been recently characterized and its effects at the level of bone and kidney reported. However, the relative role of tubular reabsorption of calcium (Ca) and bone resorption in the pathogenesis of hypercalcemia induced by this factor is still debated. We investigated the effects of a synthetic amino-terminal fragment of parathyroid hormone-related protein [PTHrP-(1-34)] administered chronically by intraperitoneal osmotic minipumps in thyroparathyroidectomized (TPTX) rats. Clearance studies performed on day 6 of treatment after a 24 h fast revealed an increase in renal tubular reabsorption of Ca and a decrease in renal tubular reabsorption of phosphate (Pi), accompanied by an increase in cAMP excretion. PTHrP-(1-34) (90 pmol/h) stimulated bone resorption as evaluated by an increment in fasting urinary Ca excretion. Although the bone resorption inhibitor aminopropylidene diphosphonate fully corrected urinary Ca excretion and reduced plasma Ca from 3.04 +/- 0.07 to 2.44 +/- 0.21 mM (p less than 0.05), this latter value remained considerably higher than in TPTX control rats (1.54 +/- 0.12 mM, p less than 0.01). In contrast, when the agent WR-2721, which is known to decrease the renal tubular reabsorption of Ca by a PTH-independent mechanism, was given, a further drop in plasma Ca and an increase in urinary Ca excretion were observed. These findings are similar to those found in animals implanted with the hypercalcemic Leydig cell tumor.(ABSTRACT TRUNCATED AT 250 WORDS)
Rizzoli
R
R
Department of Medicine, University Hospital, Geneva, Switzerland.
Caverzasio
J
J
Chapuy
M C
MC
Martin
T J
TJ
Bonjour
J P
JP
D004999:Amifostine / Q000494:pharmacology; D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D006934:Hypercalcemia / Q000139:chemically induced / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008274:Magnesium / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D010280:Parathyroid Glands / Q000502:physiology; D010281:Parathyroid Hormone / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity*; D010710:Phosphates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism; D019379:Teriparatide; D013965:Thyroidectomy
D010281:Parathyroid Hormone; D010446:Peptide Fragments; D010710:Phosphates; D019379:Teriparatide; D012964:Sodium; D008274:Magnesium; D004999:Amifostine; D002118:Calcium