The influence of different physiological stimuli on plasma concentrations of the acid-stimulating hormone gastrin and on the tissue concentrations of its precursor, progastrin. were examined in the conscious rat. Plasma concentrations were measured by radioimmunoassay using antibody specific for the C-terminus of biologically active (amidated) gastrins, and tissue concentrations of progastrin were measured after size exclusion chromatography by radioimmunoassay using antibody specific for the C-terminus of rat progastrin. Plasma and antral tissue were taken from control rats fed ad libitum, from rats fasted for 48 h, and from fasted or fed rats treated with the proton pump inhibitor omeprazole to reduce acid-induced inhibition of gastrin release. Plasma gastrin concentrations were depressed 4-fold by fasting and this was reversed by treatment with omeprazole; in rats fed ad libitum and treated with omeprazole plasma gastrin was elevated 8-fold. Fasting did not significantly change the plasma clearance of gastrin, indicating that changes in endogenous circulating levels are attributable to altered secretion rather than metabolism. Tissue progastrin concentrations were depressed 3-fold in fasted rats compared with rats fed ad libitum. Treatment of fasted rats with omeprazole produced a 2-fold increase in tissue progastrin; but in spite of the substantial elevation of plasma gastrin in fed rats treated with omeprazole, tissue progastrin was elevated by only about 50%. Sulphation at Tyr103 of progastrin was not changed by fasting or omeprazole. An estimate of the conversion of progastrin to amidated gastrin was determined as the tissue progastrin clearance, i.e. the weight of antral mucosa in which progastrin is converted to amidated gastrin and secreted per minute to maintain plasma concentrations. Conversion rates were increased 7-fold in fed omeprazole-treated rats compared with controls; in fasted rats treated with omeprazole the rate of conversion was depressed 50% compared with controls. It is concluded that changes in the lumen of the stomach are able to influence the processes by which progastrin is converted to its active amidated products.