Secondary hyperparathyroidism in chronic renal failure is stimulated by dietary phosphate (Pi) loading and ameliorated by dietary Pi restriction. We investigated the rapidity of the response of serum PTH to changes in dietary Pi. Uremic rats adapted to a high Pi diet (HPD) were trained to feed during a 2-hour feeding period each morning. Following a switch to a meal of low Pi diet (LPD), plasma PTH fell by 80% within the 2-hour feeding period with no change in plasma Ca but a 1 mg/dl fall in plasma P. In uremic rats adapted to the HPD, gavage with the LPD reduced PTH by 60% within 15 minutes; plasma P fell by 3.0 mg/dl with no change in total plasma Ca. In contrast, HPD gavage increased PTH by 80% within 15 minutes with no change in plasma P or Ca, suggesting that the response may be independent of altered plasma Pi. Duodenal infusion of sodium Pi increased PTH 2-fold within 10 minutes, with no change in ionized Ca but an increase in plasma P, whereas duodenal infusion of sodium chloride had no effect on any of these parameters. PTH clearance was not altered by duodenal phosphate infusion. Intravenous infusion of sodium phosphate also increased PTH within 10 minutes with no change in plasma ionized calcium, whereas intravenous sodium chloride had no effect. On the other hand, duodenal infusion of phosphonoformate, a nonabsorbable phosphate analog, increased PTH 4-fold within 5 minutes, but did not change plasma phosphate or ionized calcium. Taken together, these findings indicate that oral Pi increases PTH release more rapidly than previously reported in parathyroid culture models, and that the PTH response may be from both plasma phosphate and an additional signal arising from the gastrointestinal tract.