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


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Duan
Yi Min
YM
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.
Li
Zhao Shen
ZS
Zhan
Xian Bao
XB
Xu
Guo Ming
GM
Tu
Zhen Xing
ZX
Gong
Yan Fang
YF
D000208:Acute Disease; D000818:Animals; D003080:Cold Temperature; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D005753:Gastric Mucosa / Q000098:blood supply / Q000378:metabolism*; D015870:Gene Expression; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D013276:Stomach Ulcer / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D012333:RNA, Messenger; C072247:cyclo(Trp-Asp-Pro-Val-Leu)