Mechanisms Underlying Gastric Mucosal Damage Induced by Indomethacin and Bile‐salts, and the Actions of Prostaglandins

Abstract

1 The mechanisms by which the bile salt, sodium taurocholate, potentiates the formation of gastric mucosal erosions induced by indomethacin has been investigated in the rat. 2 Systemic administration of indomethacin lowered resting mucosal blood flow but had no effect on the acid back‐diffusion across the mucosa. 3 Gastric perfusion of taurocholate in acid solution increased acid back‐diffusion and lowered the potential difference. This was accompanied by an increase in mucosal blood flow, which may represent a protective mechanism in the mucosa. 4 Administration of indomethacin during acid‐taurocholate perfusion reduced this elevated mucosal blood flow without any further change in acid back‐diffusion. 5 The results suggest that although a decrease in mucosal blood flow or an increase in acid back‐diffusion can lead to a low incidence of erosions, a combination of both produces extensive mucosal damage. 6 The (15S)‐methyl analogue of prostaglandin E2 reduced erosion formation induced by indomethacin and acid‐taurocholate administration. 7 It is suggested that this protective action of the prostaglandin analogue may be linked to changes in gastric mucosal permeability and in mucosal blood flow.

Desensitization of Capsaicin-Sensitive Sensory Neurons in Rat Stomachs on Chronic Treatment with Sodium Taurocholate

“…The present results clearly confirmed the well-known fact (20,21) that a single topical application of TC to rat stomachs reduced PD followed by increases in luminal pH and GMBF. It has been shown that such GMBF responses in the stomach after damage are mediated by capsaicin-sensitive neurons as well as endogenous prostaglandins (PGs) (22).…”

“…Other investigators (1,2) and our group (3) used 5 mM TC in previous studies, but the concentration of TC was increased to 10 mM in this study to ensure the production of the possible dysfunction of capsaicin neurons within a short period. In some experiments, ablation of capsaicin-sensitive neurons was performed by s.c. injection of capsaicin once daily for 3 consecutive days (20,30 and 50 mg/kg) 2 weeks before the experiments (capsaicin pretreatment) (15). Capsaicin injections were given under ether anesthesia, and the rats were pretreated with terbutaline (0.1 mg/kg, i.m.)…”

The potentiation of taurocholate‐induced rat gastric erosions following parenteral administration of cyclo‐oxygenase inhibitors

“…In a study on the mechanisms underlying gastric damage in the rat, the increase in acid-back diffusion in the presence of acidified-taurocholate, failed to induce extensive damage, the accompanying rise in mucosal blood flow being thought to prevent acid accumulation within the mucosal tissue (Whittle, 1977). This protective hyperaemic response may be mediated in part by local prostaglandin production since it could be attenuated by concurrent administration of indomethacin (Whittle, 1977), an inhibitor of prostaglandin biosynthesis (Vane, 1971).…”

“…This protective hyperaemic response may be mediated in part by local prostaglandin production since it could be attenuated by concurrent administration of indomethacin (Whittle, 1977), an inhibitor of prostaglandin biosynthesis (Vane, 1971). Such a reduction in the prostaglandin-mediated component of hyperaemia would be expected to reduce the ability of the mucosa to dispose of the acid diffusing back into the tissue, leading eventually to acid accumulation, a fall in tissue pH and subsequent necrosis.…”

“…In a study in rats on the underlying mechanisms, it was proposed that a decrease in mucosal blood flow by indomethacin resulting from prostaglandin synthesis inhibition (Vane, 1971) and the increase in acid back diffusion induced by the topical irritant sodium taurocholate interact to produce this extensive gastric damage (Whittle, 1977). In the present study, the potentiation of bile salt-induced damage by aspirin and other antiinflammatory agents has been correlated with the ability of these drugs to inhibit the production of gastric mucosal prostacyclin ex vivo.…”