Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa

Abstract

A major clinical problem encountered in the use of non-steroid anti-inflammatory drugs has been the high incidence of gastrointestinal irritation. The mechanisms underlying damage to the gastric mucosa evoked by these drugs are complex. The normal resistance of the gastric mucosa to the back-diffusion of gastric acid from the lumen into the mucosal tissue can be disrupted by topical administration of aspirin as well as several irritants such as ethanol, bile salts and detergents; this results in gastric mucosal damage¹. Such an action, however, cannot be the sole mechanism because many non-steroid anti-inflammatory drugs cause gastrointestinal damage when administered parenterally^2,3. It has been proposed that a reduction in prostaglandin biosynthesis by aspirin-like drugs⁴ in the gastric mucosa leads to a fall in local blood flow which, in turn, gives rise to areas of focal ischaemia ultimately developing into erosions⁵. However, a combination of the direct topical irritant actions and inhibition of prostaglandin formation can lead to a marked potentiation of gastric damage³. Such a situation is likely to be encountered in the clinical use of these compounds following oral administration. We have investigated the relationship between gastric damage and inhibition of cyclooxygenase in the gastric mucosa following oral administration of anti-inflammatory compounds. For these studies, we have measured the ex vivo formation of prostacyclin (PGI₂), the major cyclooxygenase product in the rat gastric mucosa which, like other prostaglandins such as PGE₂, has gastro-protective actions⁶. In the inflammatory exudate induced by carrageenin, PGE₂ predominates and has pro-inflammatory actions⁷. We have, therefore, investigated whether selective inhibition of prostaglandin production, assayed as PGE₂-like activity, in the inflammatory exudate can be achieved in vivo. We report here that it can.