The relationship between circulating levels of PTH and the concentration and rate of change of ionized calcium (CaI) was studied in normal humans by measuring intact PTH during stepwise changes in CaI. Six normal subjects received two different citrate infusion protocols that produced stepwise decreases in CaI; one infusion produced a rapid decrement in calcium, and a second infusion produced a slower approach to the same (approximately 0.05 mmol/L) decline in calcium for each of four steps. The rapid decline in CaI resulted in a more marked increase in levels of PTH, which subsequently fell to levels similar to those with the slower infusion. For similar absolute changes in calcium, the mean maximal increment in PTH levels was significantly greater with the rapid infusion (36.4 +/- 3.1 ng/L) than with the slower infusion (19.4 +/- 2.1 ng/L; P = 0.001). Six additional subjects received infusions of citrate and calcium in a stepwise manner to induce either decreases or increases in CaI, followed by a return to baseline. During induced hypocalcemia, when calcium was changing slowly or not at all (i.e. at the plateau of each calcium change) PTH levels were not affected by the direction of change in calcium and appeared to be dependent upon the calcium concentration per se. At elevated levels of CaI, the PTH response to a stepwise decrease in calcium was blunted over that seen when CaI declined to or below baseline. Thus, the relationship between CaI and levels of PTH is dependent not only on the concentration but also on the rate of change in calcium, particularly during induced hypocalcemia; different rates of change in calcium result in different inverse sigmoidal relationships between PTH and CaI. When calcium is changing slowly or not at all, however, PTH levels appear to be dependent on the calcium concentration per se and are not affected by the previous direction or rate of change. Therefore, the role of the extracellular calcium concentration in the control of PTH secretion is part of more complex and dynamic regulatory mechanisms.