Cholecystokinin (CCK) prevents macroscopic injury to the stomach from luminal irritants by an unknown mechanism. The present study was undertaken in conscious rats to ascertain what role gastric mucosal blood flow, sensory neurons, and endogenous somatostatin play in CCK-induced gastric protection. Subcutaneous administration of CCK (10-100 mu g/kg) significantly reduced macroscopic injury to the acid-secreting portion of the stomach caused by 1 ml of orally administered acidified ethanol (150 mM HCl, 50% ethanol) and augmented gastric mucosal blood flow (fluorescent microspheres) in a dose-dependent fashion. However, although the protective response to CCK (100 mu g/kg) was still present at 2 h, the blood flow response had returned to baseline by 45 min. Ablation of capsaicin-sensitive afferent neurons with capsaicin (125 mg/kg sc) did not negate CCK-induced protection. Pretreatment with exogenous somatostatin (1 pmol-1 nmol/kg sc) failed to prevent the damaging effects of acidified ethanol to gastric mucosa. Immunoneutralization of endogenous somatostatin with somatostatin monoclonal antibody (2 mg ip) did not reverse the protective actions of CCK. Thus the data suggest that although CCK may prepare the gastric mucosa to withstand a damaging insult by augmenting gastric mucosal blood flow its protective mechanism is independent of intact sensory neurons and endogenous somatostatin.