Dissociation of phosphaturia and 25(OH)D-1 alpha-hydroxylase trophism using a novel analogue of parathyroid hormone.
Certain parathyroid hormone (PTH) analogues have been shown to selectively impair some but not all physiological actions of PTH. In this study, transaminated rat (r) PTH [TA-rPTH-(1-34)], a PTH analogue that differs from the rPTH-(1-34) fragment in that the NH2-terminal alanine is converted to pyruvate, was infused into mice to determine its properties in vivo and specifically to determine whether stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity was more dependent on concomitant renal handling of phosphate or on generation of adenosine 3',5'-cyclic monophosphate (cAMP). High-performance liquid chromatography-purified TA-rPTH-(1-34) was infused into C57BL mice at 10 or 30 pmol/h for 24 h. At 30 pmol/h, TA-rPTH-(1-34) was comparable with rPTH-(1-34) in its hypophosphatemic and phosphaturic effects but was less potent than rPTH-(1-34) in raising serum calcium. TA-rPTH-(1-34) was markedly less effective in stimulating renal 1 alpha-hydroxylase than rPTH-(1-34). Stimulation of urinary cAMP excretion occurred after infusion with TA-rPTH-(1-34), but this effect was significantly less than that seen with rPTH-(1-34). These findings indicate that PTH-induced hypophosphatemia and phosphaturia can be uncoupled from PTH stimulation of 1 alpha-hydroxylase. Furthermore, cAMP-related signal transduction appears to be more significant in regulation of 1 alpha-hydroxylase than mechanisms that mediate PTH-sensitive phosphate transport, independent of cAMP.
Carpenter
T O
TO
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510.
McPhee
M D
MD
Bort
R
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Mitnick
M A
MA
Carnes
D L
DL
D000818:Animals; D002118:Calcium / Q000097:blood / Q000652:urine; D053493:Cholestanetriol 26-Monooxygenase; D000242:Cyclic AMP / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010710:Phosphates / Q000652:urine*; D010758:Phosphorus / Q000097:blood / Q000652:urine; D013250:Steroid Hydroxylases / Q000737:chemistry / Q000378:metabolism*
D010281:Parathyroid Hormone; D010710:Phosphates; D010758:Phosphorus; D000242:Cyclic AMP; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse; D002118:Calcium