Evaluation of a parathyroid hormone antagonist in an in vivo multiparameter bioassay.
The antagonist properties of a bovine parathyroid hormone analogue ([Tyr34]bPTH-(7-34] amide were quantitatively assessed in vivo in a multiparameter assay to estimate the potency of the antagonist against the major actions of PTH. The analogue inhibited PTH-stimulated urinary excretion of phosphate and adenosine 3',5'-cyclic monophosphate in vitamin D-deficient thyroparathyroidectomized rats in a dose-dependent manner. At a molar dose ratio as low as 5:1 of antagonist to PTH, partial inhibition occurred. PTH stimulates the activity of 25-hydroxyvitamin D3-1 alpha-hydroxylase in renal proximal tubules. When coinfused with PTH, this analogue completely inhibited PTH-stimulated 1 alpha-hydroxylase activity at a molar dose ratio of 25:1 of antagonist to PTH and partially inhibited the activity at a molar dose ratio of 10:1. The analogue revealed no PTH-like agonist activity for stimulation of the 1 alpha-hydroxylase. Taken together, these studies indicate that [Tyr34]bPTH-(7-34) amide is a potent antagonist of several of the parameters of PTH action in vivo and demonstrate the feasibility of designing a PTH antagonist that can interact simultaneously with all the PTH receptors responsible for the hormone's major actions in vivo.
D000818:Animals; D053493:Cholestanetriol 26-Monooxygenase; D000242:Cyclic AMP / Q000652:urine; D004305:Dose-Response Relationship, Drug; D008297:Male; D008722:Methods; D010280:Parathyroid Glands / Q000502:physiology; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010710:Phosphates / Q000652:urine; D010758:Phosphorus / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D013250:Steroid Hydroxylases / Q000378:metabolism; D013965:Thyroidectomy
D010281:Parathyroid Hormone; D010446:Peptide Fragments; D010710:Phosphates; D010758:Phosphorus; C038040:parathyroid hormone (7-34)amide, Tyr(34)-; D000242:Cyclic AMP; D013250:Steroid Hydroxylases; D053493:Cholestanetriol 26-Monooxygenase