Ischemic preconditioning is considered as the most powerful gastroprotective intervention against mucosal lesions and ulcerations but the mechanism of this phenomenon has been little examined. In this study we tested the effects of inactivation of sensory nerves in new rat model combining acute gastric erosions with subsequent ulcers induced by ischemia-reperfusion (I/R). I/R lesions were produced in rats by clamping the celiac artery for 0.5 h followed by 3 h of reperfusion in rats with intact or inactivated sensory nerves by pretreatment with capsaicin for two weeks before the I/R. The animals were killed at 0 and 3 h and 3 days after I/R and the area of gastric lesions was determined planimetrically, the gastric blood flow (GBF) by H2-gas clearance technique and the plasma levels of gastrin by RIA. Gastric mucosal content of calcitonin gene related peptide (CGRP) was assessed by RIA. Following I/R, gastric erosive lesions occurred after 3 h and these erosive lesions then progressed into gastric ulcers within 3 days in all rats. Sensory-inactivation with capsaicin caused several fold increase in the area of early (at 3 h) acute lesions and later (at 3 d) gastric ulcers induced by I/R. This enhancement of acute and then chronic gastric lesions was accompanied by a significant fall in GBF, an elevation of plasma gastrin and a decrease in mucosal expression of CGRP. Ischemic preconditioning markedly reduced acute lesions and chronic ulcerations induced by I/R and attenuated the changes in plasma gastrin and mucosal CGRP contents but these effects were significantly more pronounced in rats with intact sensory nerves but less in capsaicin-inactivated animals. We conclude that: 1) The I/R resulted in the formation of early acute gastric lesions followed 3 days later by chronic gastric ulcers and this gastric injury was accompanied by an impairment of gastric microcirculation, hypergastrinemia and suppression the gastric mucosal CGRP; 2) Gastric ischemic-preconditioning significantly attenuated both acute mucosal damage and chronic ulcers induced by I/R and this was accompanied by a rise in gastric blood flow; 3) The inactivation of sensory nerves with capsaicin enhanced the formation of I/R-induced acute and chronic gastric lesions and strongly attenuated the gastroprotection afforded by I/R possibly due to the decline in mucosal blood flow and the fall in expression of integrity peptides such as CGRP and 4) The excessive release of gastrin may limit the extent of mucosal lesions observed during progression of gastric erosions into ulcers induced by I/R.