Quantitative evaluation of anticalciuretic effects of synthetic parathyroid hormonelike peptides

The PTH-like peptide (PTHLP) responsible for hypercalcemia in many patients with humoral hypercalcemia of malignancy (HHM) acts on PTH receptors in bone and kidney, and large doses of PTHLPs have been shown to reduce urinary calcium excretion. However, PTHLPs have not been assessed quantitatively for effects on renal calcium excretion at concentrations (5-100 pM) now known to be found in the serum of patients with HHM. We perfused isolated rat kidneys with synthetic [tyr-36] PTHLP-(1-36)amide [PTHLP-(1-36)], PTHLP-(1-74), and synthetic bovine PTH-(1-34). The ratio of calcium to sodium clearances (CCa/CNa), a measure of distal tubular calcium transport, was reduced to the same extent by PTH, PTHLP-(1-36), and PTHLP-(1-74) (54.3 +/- 3.9, 52.9 +/- 3.9, and 52.7 +/- 1.3% reductions from control), respectively) at maximal doses (35-50 pM and higher), with half-maximal effects at 10, 18, and 32 pM, respectively. PTH, PTHLP-(1-36), and PTHLP-(1-74) all increased fractional phosphate excretion over control (p less than 0.05 each). All three peptides were natriuretic, at least doubling fractional Na excretion (p less than 0.05 or less). Urinary cAMP excretion was increased by all three. None had any effect on GFR or renal vascular resistance. These results indicate that clinically relevant concentrations of PTHLPs are anticalciuretic and natriuretic, with maximal effects similar to those of PTH. Differences in anticalciuretic potencies are small but may explain differences among patients, depending on the size(s) and concentrations of the native circulating form(s) of the peptide.