Inhibition by (D-Trp12,Tyr34)bPTH(7-34)amide of PTH and PTHrP effects on Pi transport in renal cells

We studied the effect of (D-Trp12,Tyr34)bovine parathyroid hormone-(7-34)amide [(D-Trp12,Tyr34)bPTH(7-34)NH2], a recently described highly potent antagonist of parathyroid hormone (PTH), on the adenosine 3',5'-cyclic monophosphate (cAMP) and the sodium-dependent phosphate transport (NaPiT) responses to bPTH-(1-34) or PTH-related protein [PTHrP(1-34)] in renal epithelial cells. In this system, bPTH and PTHrP increased cAMP production and inhibited NaPiT in a similar manner. (D-Trp12,Tyr34)bPTH(7-34)NH2 did not influence either cAMP or NaPiT, but markedly attenuated the responses to PTH or PTHrP. The effect was concentration dependent, and a maximal inhibition of PTH or PTHrP effects was obtained with a 10(3)- to 10(4)-fold greater concentration of the antagonist. In contrast, the same concentration of the unsubstituted counterpart, (Tyr34)bPTH(7-34)NH2, which abolished the PTH- or PTHrP-induced stimulation of cAMP production, did not affect the inhibition of NaPiT caused by either peptide. Thus (D-Trp12,Tyr34)bPTH(7-34)NH2 inhibited the effects of PTH and PTHrP on both cAMP synthesis and Pi transport in renal cells. Because of the effects of this analogue on a transport function affected by these two Peptides under physiological and pathophysiological conditions, it appears to be a promising antagonist.