Sensory neuron-mediated gastric mucosal protection is blocked by cyclooxygenase inhibition.

BACKGROUND: Sensory neurons have been proposed to play a critical role in the protection of the gastric mucosa from a variety of necrotizing agents. The purposes of this study were (1) to investigate the effect of topical capsaicin, a sensory neuron stimulant, on the gastric mucosal injury caused by the topical application of low concentrations of bile acid and (2) to determine whether local neuronal blockade with topical lidocaine or cyclooxygenase blockade with systemic indomethacin has any effect during pretreatment with capsaicin. METHODS: Before injury with topical 5 mmol/L acidified taurocholate (pH 1.2) rat stomachs were pretreated with either vehicle or capsaicin (160 mmol/L), both with and without prior administration of either lidocaine (1%) or indomethacin (5 mg/kg subcutaneously). Injury was assessed by measuring net transmucosal ion fluxes, the appearance of deoxyribonucleic acid into the gastric lumen, and gross and histologic injury scores. RESULTS: Pretreatment with topical capsaicin significantly (p < 0.05) decreased bile acid-induced net luminal ion fluxes and luminal deoxyribonucleic acid accumulation, an effect blocked by both lidocaine and indomethacin. CONCLUSIONS: Thus both local neuronal blockade and cyclooxygenase inhibition block the protective effect of capsaicin, findings corroborated by gross and histologic injury analysis. This study suggests that sensory neurons may mediate gastric mucosal protection from bile acid injury by increasing synthesis of endogenous prostaglandins.

Adaptive cytoprotection of gastric surface epithelial cells against injury by physiologic concentrations of bile acid.

The purpose of this study was to determine whether adaptive cytoprotection of gastric mucosa could be demonstrated with concentrations of bile acid, which is normally found in the human stomach, and whether cyclooxygenase inhibition, in turn, could blunt the response. Surface epithelial cell exfoliation and ion fluxes were used as end points. A transduodenal gastric cannula was placed, and the pylorus/gastroesophageal junction was ligated in adult male Sprague-Dawley rats that had been anesthetized. In experiment 1 (N = 30), rat stomachs were exposed for 15 minutes to 5 ml of either a neutral test solution (160 mmol/L NaCl, pH 7) or 1 mmol/L acidified taurocholate (ATC) (100 mmol/L HCl, 60 mmol/L NaCl, 1 mmol/L taurocholic acid; pH 1.2). All rats were subsequently exposed for 15 minutes to 5 mmol/L ATC during which time mucosal injury was assessed by measuring net flux of H+, Na+, and K+, volume, and DNA efflux. In experiment 2 (N = 35), all stomachs were pretreated for 15 minutes with 1 mmol/L ATC before mucosal injury with 5 mmol/L ATC (15 minutes). Eighteen rats were pretreated with indomethacin (5 mg/kg) subcutaneously 75 minutes before the experiment was begun, and the same parameters were measured. Pretreatment of rat gastric mucosa with 1 mmol/L ATC significantly attenuated the mucosal injury that was seen with subsequent exposure to 5 mmol/L ATC, resulting in significantly (p less than 0.05) less luminal H+ loss (-16 +/- 4 vs -32 +/- 4 mEq/15 min) and DNA efflux (181 +/- 21 vs 270 +/- 25 micrograms/15 min) than the nonadapted group. Indomethacin pretreatment significantly attenuated the adaptive protective response, resulting in greater loss of H+ (-29 +/- 4 vs -18 +/- 3) and DNA efflux (190 +/- 35 vs 110 +/- 18, both p less than 0.05) after exposure to 5 mmol/L ATC. These studies demonstrate that adaptive cytoprotection of gastric mucosa occurs with physiologic concentrations of an irritant that is normally present in the stomach. Indomethacin blunts this effect, which suggests that adaptive cytoprotection in this setting may be mediated by production of endogenous prostaglandins.