The stomach plays a key initial role in digestion through its mixing actions, and through the secretion of gastric acid and pepsin, which are important for the activation of key digestive enzymes. The gastric epithelium is remarkably resistant to the deleterious effects of low pH because of the presence of a number of protective elements that prevent acid-induced injury. However, if gastric acid secretion increases to the point that the protective forces are overwhelmed, and/or there is a breakdown or loss in these protective forces, a gastric ulcer can develop.

Gastric acid secretion

Secretion of gastric acid is under control of central and peripheral neurological and hormonal stimuli. Peripherally, the important mediators of gastric acid secretion are acetylcholine, gastrin and histamine. Gastrin is released from G cells in the antral mucosa, and histamine is secreted by enterochromaffin cells in the gastric glands. Gastrin and acetylcholine stimulate the release of histamine from enterochromaffin cells, and the histamine in turn stimulates acid secretion when it binds to H2 receptors on the parietal cells of the gastric glands. The final step in the secretion of gastric acid is the mobilization of a proton pump to the apical surface of the parietal cell so that the pump can exchange a K+ ion for a H+ ion to be secreted into the lumen of the gastric gland. The intragastric pH can become as low as 2, an extremely acidic environment.

The principle protective forces of the gastric mucosa are an adequate blood flow, a mucus/bicarbonate layer, and epithelial cells that are capable of rapidly spreading to cover defects in the mucosa. Locally synthesized prostaglandins, primarily PGE₂, support many of these protective forces. Mucosal blood flow is maintained by adequate concentrations of PGE₂. The anatomy of the mucosal capillary bed promotes delivery of an HCO₃ ^- ion, generated during the production of acid, to the capillaries underlying the surface epithelium where they can be available to neutralize any protons that have diffused back to the epithelial surface. Secretion of mucus is also promoted by PGE₂. The mucus layer itself has within it a pH gradient, with the highest (most basic) pH situated at the epithelial surface. The gastric epithelial cells are capable of altering their shape to become flatter and more spread out to quickly cover any superficial epithelial layer defects, a process known as restitution. Gastric epithelial cells can also, under the right stimuli (growth factors, cytokines, inflammatory mediators), undergo rapid proliferation to fill larger breaches like ulcers in the epithelial barrier.

Gastric ulcer pathogenesis

Gastric ulcers develop when there is an excess of harmful substances, primarily acid and pepsin, or there is a breakdown in a local protective force, or both. Most causes of ulcers in dogs and cats reflect one or both of these pathophysiological processes. Diseases that are known to increase secretion of gastric acid production often do so as a consequence of increases in gastrin or histamine. Examples of the former include renal failure (acute or chronic), and gastrinomas. Mast cell tumors predispose to gastric ulcers as a consequence of increased circulating concentrations of histamine. Studies of dogs with mast cell tumors have documented increased blood histamine concentrations as compared to normal dogs. A recent study of gastric ulcers in cats found systemic mast cell tumors the most common cause of ulcers in that study population.

Gastric ulcers also develop when there are deficiencies in protective forces. Alterations in mucosal blood flow are a common risk factor for the development of gastric ulcers, and can result from many different processes. Administration of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids decrease local prostaglandin production thereby reducing mucosal blood flow, limiting the epithelium's capacity to protect itself from the injurious effects of acid. Recent investigations in other species on the effects of NSAIDs have suggested that this class of drugs can also impair ulcer healing through inhibition of angiogenesis (necessary for granulation tissue formation in the ulcer bed) and epithelial proliferation. Hypovolemia, shock, vascular thrombosis, or other processes that interrupt gastric blood flow (e.g. gastric dilatation/volvulus) also can cause mucosal ulceration. Other diseases associated with ulcers can disrupt normal mucosal architecture, and likely also alter blood flow; examples include gastric neoplasms and inflammatory stomach diseases. Malignant gastric epithelial cells would not be expected to behave like normal epithelial cells thus potentially compromising the process of epithelial restitution, further enhancing the risk of ulcer development. For some of the diseases that are associated with ulcers, for example liver disease and hypoadrenocorticism in dogs, the mechanisms contributing to ulcer formation are not well-characterized, but are still likely to involve aberrations in mucosal protective functions; abnormalities in mucosal blood flow could easily be envisioned with either.