Immunological evidences for post-translational control of the parathyroid function by ionized calcium in dogs

To outline the role of post-translational events in the control of the parathyroid function in vivo, we have studied the parathyroid function of normal dogs receiving i.v. infusions of CaCl2 and Na2EDTA with intact (I), carboxylterminal (C) and midcarboxylterminal (M) iPTH assays and evaluated the influence of ionized calcium on circulating molecular forms of iPTH via alterations in C/I, M/I and M/C iPTH ratios. Furthermore, the use of the mathematical model fitting the sigmoidal relationship between ionized calcium and iPTH ratios was improved through the generation of more iPTH ratio points in the ascending part of the sigmoid function. Quantitatively, the response to hypocalcemia was highest with M (98.7 +/- 36.8 pmol/l; P < 0.0167 vs. L and P < 0.0001 vs. I) and higher with L (83.1 +/- 26.1 pmol/l; P < 0.0001 vs. I) than with I (12.1 +/- 3.2 pmol/l). Similar results were observed for the non-suppressible fraction of iPTH measured by the three iPTH assays in hypercalcemia. The slope of the sigmoid function was more acute for I than for C or M, while all three secretion set-points were similar at 1.30 mmol/l. Qualitatively, all iPTH ratios increased from hypo- to hypercalcemia, results being more pronounced for the M/I and C/I iPTH ratios (7.66 +/- 2.57 to 73.9 +/- 41.4 and 6.76 +/- 1.93 to 49.8 +/- 27.5) than for the M/C iPTH ratio (1.24 +/- 0.48 to 1.82 +/- 1.16). The slopes of the three ratios were similar as were the set-points, but in this last case, values were higher (1.40 mmol/l) than for secretion set-points. These results indicate that dog parathyroid function is similar to that of man. The lower set-points for secretion and higher ones for regulating M/I and C/I iPTH ratios favor an optimal amount of I in face of decreasing ionized calcium and permit to control the non-suppressible fraction of iPTH secretion via M and C fragments production in face of increasing ionized calcium. These events are important to understand the implication and signification of post-translational events in the parathyroid glands and in peripheral blood in the phenomenon of PTH immunoheterogeneity. They further outline that the tools used here will be useful to study similar phenomenons in individuals in face of diseased parathyroid glands.