The 'gastric mucosal barrier' is a descriptive term for the ability of the gastric epithelium to hold a large (10(5)) H+ concentration gradient from lumen to mucosa under physiological conditions. Compounds which classically have been used to describe the functional integrity of the 'barrier', in addition to very low H+ diffusion from lumen to mucosa, include low diffusion of Na+ and K+ from mucosa to lumen and maintenance of a lumen-negative transmucosal potential difference (PD). Na+ appearance in the luminal fluid is a function of active transport and diffusion. Fixed charges within diffusion channels with pK values greater than or equal to 9, may contribute to maintenance of H+ gradients. Luminal application of aspirin, bile salts, and ethanol increases net cationic flux and reduces PD. When acidified, these luminal agents produce histological and visible damage, yet damage can be produced by parenteral agents without concomitant change in these components. Although no anatomical 'barrier' has been described, it has been suggested that the gel mucus and epithelial phospholipids are constituents. Exogenous administration of a variety of prostanoids attenuate the change in cationic flux and PD produced by those agents in both animals and humans. The role of endogenous prostaglandins in barrier integrity has been questioned since it has been shown that salicylic acid produces permeability changes which are equal to aspirin, yet the former does not inhibit cyclooxygenase while the latter does. The gastric mucosal barrier is physiologically important because, by whatever mechanism, H+ back-diffusion is kept to a minimum under physiological conditions.