Histamine and the pathogenesis of duodenal ulcer disease

A key role for histamine in the physiological control of gastric acid secretion was established with the advent of the histamine H2-receptor antagonists which have in vivo been shown to inhibit virtually all forms of basal and stimulated secretion.' These data can be seen to support the common mediator hypothesis championed in the last three decades by Code2 3 and which states that secretory stimulants such as gastrin and acetylcholine do not act directly on the parietal cell, but through mobilisation of histamine from endogenous stores. The histamine in turn acts on the histamine H2-receptor. The presence of histamine stores in the gastric mucosa has clearly been established, although the type of storage cell is species dependent, being predominantly the enterochrommafin-like cell in the rat4 but the mast cell in most other species including dog and man.5 The ability of secretory stimulants to release histamine from these stores by action on specific receptors is, however, unproven6 and is often inferred from changes in histamine content of gastric juice, or venous blood. The possible presence of specific receptors for secretory stimulants on the parietal cell itself is still a matter of controversy, although a recent paper by Soll and coworkers7 indicates specific binding of iodinated gastrin 17 to canine parietal cells. Potentiating interactions between histamine and the other secretory stimulants at the parietal cell level have led to the hypothesis that histamine acts in a permissive role, markedly amplifying the effect of gastrin and acetylcholine on parietal cell receptors. It is the removal of this permissive effect of histamine, which accounts for the inhibitory actions of H2-receptor antagonists. Whatever the exact nature of the underlying mechanisms involved, the ability of histamine H2-antagonists to inhibit gastric acid secretion has given them an important therapeutic role in duodenal ulcer disease. This reflects the fact that although the pathogenesis of duodenal ulcer is still not clear, inappropriate acidification of the duodenum is a fundamental factor.8 The question that now arises is: can the physiological role of histamine in stimulating acid secretion and the importance of acid secretion in the aetiology of duodenal ulcer be connected to provide a pathological role for histamine in the disease? A series of papers published by the Marburg group during the past decade911 and culminating in the paper by Thon et al12 in this issue of Gut have addressed this question. In the past all too frequently studies of the dynamics of mucosal histamine in animals and man have been bedevilled by assays of inadequate sensitivity and specificity and this has led to considerable