Effects of parathyroid hormone and the synthetic 1-34 amino-terminal fragment in rats and dogs.

Since the structural requirements for all known biological activities of parathyroid hormone (PTH(1-84)) are virtually satisfied by the amino-terminal 34 amino acid fragment, PTH(1-34), we investigated whether this fragment could elaborate the overall actions of the intact hormone in the whole animal by comparing the effects of equimolar infusions of each peptide to dogs and rats. Infusion of bovine PTH(1-84) (bPTH(1-84)) at 17 pmol/kg per h for 20 h to three dogs or at 100 and 200 pmol/kg per h to groups of six rats for 5 days produced greater hypercalcaemia (3.02 +/- 0.03, 2.52 +/- 0.07 and 3.24 +/- 0.11 mmol/l respectively) than equimolar infusions of human PTH(1-34) (hPTH(1-34)) (2.61 +/- 0.03, 2.46 +/- 0.05 and 2.71 +/- 0.09 mmol/l respectively). A significant calcium rise was not observed in dogs until after 4 h of PTH infusion. No rise in plasma calcium was apparent in rats, however, until the third day of PTH infusion. Only in parathyroidectomized rats was there a rise in plasma calcium within 24 h of starting an infusion of PTH. The hypercalciuria and plasma phosphate responses in dogs during equimolar infusions of hPTH(1-34) and bPTH(1-84) were not significantly different. However, by day 5 of infusion in rats greater hypercalciuria was produced by bPTH(1-84). Although infusion of hPTH(1-34) and bPTH(1-84) caused rises in urinary cyclic AMP excretion (measured only in the dog) of immediate onset and equal magnitude, bPTH(1-84) tended to produce greater phosphaturia than hPTH(1-34) in both species. If the assumption is correct that the half-lives of hPTH(1-34) and bPTH(1-84) in the circulation are similar and provided that hPTH does not inherently have less biological activity than bPTH, then during equimolar infusions of these peptides into dogs and rats, the greater responses observed with bPTH(1-84) suggest that intact PTH may have a direct action of its own in vivo before being metabolized into smaller biologically active fragments. In additional experiments using parathyroidectomized rats, the infusion rate of bPTH(1-84) required to restore normocalcaemia was 26 pmol/kg per h. Although near-normal calcaemia and intestinal calcium absorption could still be maintained when the infusion rate was increased to 39 pmol/kg per h, hypercalciuria and phosphaturia became apparent.