1. The effect of prostaglandin E(1) (PGE(1)) on gastric secretion was studied in dogs equipped with gastric fundic pouches, either innervated (Pavlov) or denervated (Heidenhain).2. PGE(1) inhibited gastric secretion (volume, acid concentration, acid output, pepsin output) when given either by constant intravenous infusion or by single intravenous injection. The degree of inhibition was dose dependent.3. The antisecretory effect of PGE(1) was demonstrated against gastric stimulants which operate through different mechanisms. Thus, PGE(1) counteracted the secretogogue effect of:(a) histamine dihydrochloride; the ED(50) was 0.5-1.0 mug/kg. min for a submaximal dose, and 1.0-1.5 mug/kg. min for a maximal dose;(b) pentagastrin; the ED(50) was around 0.25 mug/kg. min;(c) food; the ED(50) was 0.5 to 0.75 mug/kg. min;(d) 2-deoxyglucose; the ED(50) was less than 0.1 mug/kg. min.4. Although in some experiments, nausea and vomiting were observed during administration of PGE(1), the antisecretory property of the substance is not related to a vomiting reflex, since(a) an antiemetic, such as atropine, prevented vomiting without interfering with the effect of PGE(1), and(b) profuse vomiting elicited by apomorphine did not reduce gastric secretion stimulated by either histamine or pentagastrin.5. The mechanism by which PGE(1) inhibits gastric secretion is unknown. Studies by others have shown that the compound reduces gastric mucosal blood flow, inhibits acid formation from gastric mucosa when applied in vitro and may change the rate of formation of gastric cyclic AMP. It is likely that PGE(1) interferes with biochemical processes, within parietal and chief cells, which lead to elaboration of gastric juice.6. Unlike most gastric inhibitors, PGE(1) appears to act as a protective shield against most, if not all, gastric stimulants. Since prostaglandins of the E series are naturally occurring substances and are normally present in the stomach, they may play a role in the regulation of gastric secretion.