The mechanisms of adaptive mucosal cytoprotection by mild irritants were investigated in rats. In an ex vivo chamber preparation, application of 20% ethanol, 5% NaCl or 0.3 M HCl to the posterior side of the mucosa significantly protected that side of the stomach against mucosal damage caused by subsequent exposure to 100% ethanol, with contralateral transmission of protection to the anterior side by 20% ethanol and 0.3 M HCl. Atropine or lidocaine significantly reversed the cytoprotection of 20% ethanol. Bilateral vagotomy partially prevented the antilesion action of 20% ethanol, and completely prevented the action of 0.3 M HCl. However, the three mild irritants did not affect gastric mucosal blood flow, but restored the ion transport mechanism which was depressed by ethanol. It is therefore concluded that the three mild irritants have their own distinctive cytoprotective mechanisms against ethanol ulceration, which is predominantly not mediated by effects on the vascular system of the gastric mucosa.