Acute gastric ulceration induced by haemorrhagic shock is associated with profound intramucosal acidification due to diffusion of luminal H+ into the mucosa. High-HCO3- metabolic alkalosis protects the mucosa against this ulceration, whereas low-HCO3- respiratory alkalosis does not, suggesting that lack of systemic and intramucosal HCO3-, rather than tissue acidosis per se, renders the mucosa susceptible to ulceration. In normal mucosa, disruption of the mucosal barrier by taurocholate, ethanol or acetylsalicylic acid leads to efflux of alkali (HCO3-) from the mucosa, with generation of an alkaline buffer layer at the epithelial surface to protect the mucosa from further damage. In ischaemic mucosa no such protective alkaline layer is formed, and exposure to luminal acid leads to severe acidification of and damage to the mucosa. The efflux of alkali may be driven by capillary hydrostatic pressure, since no such protective alkaline efflux occurs in vitro, but rather exposure to luminal acid and barrier-breaking agents results in intracellular acidification. The potential pathogenetic role of a disrupted intramucosal acid-base balance, as well as the protective effect of systemic and intramucosal HCO3- in acute gastric stress ulceration is further substantiated by the in vitro findings that perfusion conditions simulating in vivo ulcerogenic conditions provoke intracellular acidosis, and serosal HCO3- significantly contributes to the maintenance of normal intracellular pH in surface epithelial cells exposed to luminal acid.