Previous studies in stressed animals have shown a subjective decrease in shock-related gastric submucosal edema formation associated with the administration of H2-receptor antagonist cimetidine. The object of this study was to quantify the difference as well as to examine indices which could lead to an understanding of H2-receptor control. Fasted, stressed rats pretreated with cimetidine had significantly less edema formation than the control rats in all areas of the gastrointestinal tract, with the greatest difference seen in the stomach. Addition of intragastric hydrochloric acid did not alter cimetidine's edema-lowering capacity in the stomach. Analysis of multiple serum samples consistently showed that a stress-related decrease in vascular volume occurred, as evidenced by significant increases in hematocrit and BUN. Although cimetidine was not associated with changes in vascular volume, there was a significant (10%) increase in serum albumin in both stressed and nonstressed animals that received the drug. These data suggest an additional mechanism by which cimetidine may protect against gastric mucosal injury.