Sensory nerve stimulation by intragastric capsaicin (160 microM) prevents ethanol injury to the gastric mucosa and facilitates gastric mucosal blood flow (GMBF). The present study examined whether the capsaicin-induced increase in GMBF accounts for mucosal protection. Gastric perfusion of capsaicin (160 microM) in urethan-anesthetized rats did not change blood pressure but significantly enhanced GMBF as measured by hydrogen gas clearance. The same increase in GMBF was seen when capsaicin was administered together with an injurious concentration of ethanol (25%). GMBF was facilitated by capsaicin in a dose-related manner (10-640 microM), and the dose-dependent vasodilatation was significantly correlated with a dose-dependent reduction of gross damage to the mucosa. Histology showed that capsaicin prevented deep but not superficial mucosal damage. The vasodilator and protective effects of capsaicin resulted from stimulation of sensory neurons and propagation of nerve activity, since they were blocked after ablation of capsaicin-sensitive neurons or local intra-arterial infusion of tetrodotoxin. This and the finding of a limited access of intragastric capsaicin to the gastric wall indicates that the vasodilator and protective effects of capsaicin are mediated by a neural reflex. It is concluded that facilitation of GMBF is the major mechanism of sensory nerve-mediated prevention of gastric mucosal injury.