Changes in endothelin-1 gene expression in the gastric mucosa of rats under cold-restraint-stress

To investigate in rats the role of endothelin (ET)-1 gene expression in the development and progression of acute gastric mucosal lesions (AGML) induced by stress, and the effect of BQ-123 (a special ETA receptor antagonist) on the AGML.

A rat model of gastric ulcer induced by cold-restraint-stress (CRS) was used. ET-1 concentrations in the plasma and gastric mucosa were determined by radioimmunoassay (RIA), gastric mucosa blood flow (GMBF) was measured with a laser Doppler flow meter, the ulcer index (UI) was used to estimate the degree of gastric mucosa damage and the expression levels of ET-1 mRNA in the gastric mucosa were measured using dot blot and reverse transcription polymerase chain reaction (RT-PCR). Different doses of BQ-123 were administered via the left femoral vein prior to the stress in order to observe the effects of BQ-123 on the ET-1 concentrations in the plasma and gastric mucosa, the GMBF and the UI.

Compared with the normal controls, the ET-1 concentrations in the plasma and gastric mucosa of the stressed rats were increased significantly (P < 0.05), the GMBF was decreased markedly (P < 0.01), and the UI increased dramatically (P < 0.01). There was a significant positive correlation between the gastric mucosal EF-1 concentration and the UI (r = 0.98, P < 0.01), and a significant negative correlation between the gastric mucosal ET-1 concentration and GMBF (r = -0.89, P < 0.01) and also between the UI and GMBF (r = -0.98, P < 0.01). The expression level of ET-1 mRNA in the gastric mucosa of the stressed rats increased significantly compared with that of the normal controls (P < 0.01), and there was a positive correlation between the expression of ET-1 mRNA and the ET-1 concentration in the gastric mucosa (r = 0.93, P < 0.01). Compared with the untreated animals, the GMBF was increased (P < 0.01) and the UI decreased significantly (P < 0.01) in the BQ-123-treated rats, and the dose of BQ-123 correlated with the degree of change in the GMBF and UI; however, the ET-1 concentrations of either the plasma or the gastric mucosa did not change markedly in the BQ-123-treated animals (P > 0.05).

The present study showed that the level of expression of ET-1 mRNA and the synthesis of ET-1 in the gastric mucosa both increased significantly, which suggests that the increased concentration of endogenous ET-1 may be involved in the development and progression of stress ulcer (acute gastric mucosa lesion). The mechanism of action may be associated with a reduction of GMBF induced by ETAR-mediated vasoconstriction. BQ-123 can dose-dependently attenuate significantly the degree of damage to the gastric mucosa induced by stress, and may have therapeutic benefits for stress ulcer.