The integrity of gastric mucosa is well-balanced by an array of defensive mechanisms which protect the mucosa against external aggressive factors. When excessive stimulation of autonomic nervous system (irritation) is induced, microcirculatory disturbances easily lead to the gastric mucosal damage due to the formation of vasoactive mediators and oxygen radicals. In this review, our discussion has been focused on the co-ordinating function of the autonomic nervous system as well as the microcirculation as an important defense bastion. In this context, Helicobacter pylori represents an important pathogenic factor. In particular, we have discussed the contribution of monochloramine, and active oxidant, which is formed by neutrophils in the presence of ammonia derived from H. pylori to the gastric mucosal injury. Microcirculatory disturbances may be also involved in the pathogenesis of H. pylori-induced mucosal injury. On the basis of these considerations, we should not depend solely on the use of anti-acid secretory drugs for the treatment of gastric mucosal injury, but also should be aware of beneficial effect of mucosal protective drugs which may act on microcirculation and the autonomic nervous system.