Aims: Endothelin-1 (ET-1), a key mediator of inflammatory processes associated with gastric mucosal injury, is a potent vasoactive peptide produced from a biologically inactive big ET- 1 by the action of endothelin-converting enzyme-1 (ECE-1). In this study, we investigated gastric mucosal expression of ECE-1 during a 16 h course of inflammatory responses associated with gastric mucosal damage caused by indomethacin, and evaluated the effect of pretreatment with an antiulcer agent, sucralfate, on this process. Methods: The experiments were conducted with groups of rats pretreated intragastrically with sucralfate at 200 mg/kg or vehicle, followed 30 min later by an intragastric dose of indomethacin at 60 mg/kg, and at different time (2, 4, 8, and 16 h) intervals, their stomachs were used for macroscopic and biochemical assessments. Results: Examination of gastric mucosa from the control animals revealed that, within 2 h, indomethacin caused multiple hemorrhaging lesions, the extent of which reached a maximum after 4 h and was accompanied by a 4-fold enhancement in the expression of ECE-1 activity, and a marked elevation in ET-1 (4.5-fold), TNF-α (11.3-fold) and apoptosis (29.9-fold). Pretreatment with sucralfate produced within 2 h a 59.7% reduction in the extent of mucosal damage caused by indomethacin, while an 81% reduction in lesion was observed after 16 h. This effect of sucralfate was accompanied by a significant reduction in the mucosal expression of ECE- 1, the activity of which declined by 57.3% within 2 h following sucralfate, while a 38.4% decline in the indomethacin-induced expression of ECE-1 was attained after 16 h. Moreover, the reduction in the severity of damage following pretreatment with sucralfate was reflected at the end of 16-h period in a 47.4% decrease in the mucosal expression of TNF-α, 25.1% decline in ET-1, and a 38.9% decline in apoptosis. Conclusions: The results demonstrate that gastric mucosal injury by indomethacin is associated with up-regulation of ECE-1 expression, which leads to the enhancement of ET-1 production, induction of TNF-α, and triggering of apoptotic events that exacerbate the inflammatory process. Our findings also show that sucralfate protection against gastric mucosal injury caused by indomethacin involves the suppression of the mucosal ECE-1 activity.
All Science Journal Classification (ASJC) codes
- Pharmacology (medical)
- Gastric mucosal damage