Two receptor-specific inhibitors of gastric secreTion—the new H2 antagonist, ranitidine, and the muscarinic antagonist, atropine—were used to study basal hypersecretion in duodenal ulcers. The two drugs and saline placebo were administered in graded bolus doses to 10 duodenal ulcer patients who had unusually high basal gastric acid secretion (basal acid output, 12–31 mmol/h, mean 18.7 ± 1.4; peak acid output, 52 ± 4 mmol/h). In each subject we measured volume, H+, Cl−, pepsin, and serum gastrin serially. Both drugs were potent inhibitors of secretion; atropine equally suppressed the output of all constituents without changing concentrations significantly (pH, 1.8–2.2). Ranitidine reduced [H+] to 0 (pH > 7.4) and pepsin concentrations by 75%, but left a substantial alkaline volume (30% of pretreatment) of an undetermined source. Kinetic analysis of the dose-response curves showed marked sensitivity of acid secretion to atropine (calculated maximum inhibition 98%, dose causing 50% inhibition 1.4 nmol/kg). Ranitidine inhibited acid 100% with ID50 38 nmol/kg. Pepsin was less sensitive to both inhibitors (ID50 2.2 nmol/kg and 124 nmol/kg, respectively). Atropine also differed from ranitidine in elevating serum gastrin dose-responsively up to 80+ pg/ml, median effective dose 3 nmol/kg, while ranitidine and saline had no effect on serum gastrin up to 120 min after the last dose. Because all the constituents responded equally to atropine, but not to ranitidine, and because atropine was effective at very low doses (pA2 8.9), we conclude that basal hypersecretion in duodenal ulcer patients is largely dependent upon a cholinergic pathway. We also report the pharmacokinetics from measured blood levels of ranitidine. Serum concentrations of ranitidine giving 50% of inhibition were: acid 50 nM, chloride 95 nM, volume 116 nM, and pepsin 150 nM. These values closely matched the expected serum concentrations from calculated doses causing 50% inhibition. Ranitidine disappeared from the plasma in two phases. Observed blood values decayed first with a t½ of 36 min independent of dose. A second phase representing elimination had t½ of 95–200 min related to the blood level of ranitidine. When corrected for the second slope, the first had a t½ of 19 min. Volume of initial distribution was 57% of body weight; in the elimination phase, volume of distribution was 150% of body weight. Chloride, volume, and pepsin secretion began to recover from maximum inhibition at blood levels of ranitidine of ~250 μg/L and preceded recovery of acid by some 40–60 min. Because half-life of elimination is positively related to starting blood level, a higher dose would be expected to give a longer period of effective blood concentration. This fact may have important therapeutic implications.