Abstract
Background/Aim: Eicosanoids are involved in the regulatorymechanism of the gastricmucosal integrity under various conditions. We previously reported that COX-2/PGI2 plays a protective role in the gastric mucosal defense under ischemia/reperfusion (I/R)induced conditions, while indomethacin worsens these lesions, partly mediated by the up-regulation of leukotrienes and their receptors. However, it remains unknown whether thromboxane A2 (TXA2) plays any role in the pathogenesis of I/R-induced gastric injury. In the present study, we examined the role of TXA2 in the ulcerogenic response in the mouse stomach under I/Rinduced conditions. Methods: Under urethane anesthesia, the celiac artery was clamped (ischemia) for 30 min, followed by reperfusion by removal of the clamp. After reperfusion for 60 min, the area (mm2) of macroscopically visible lesions in the stomach was measured. SC-560 (COX-1 inhibitor: 5 mg/kg), rofecoxib (COX-2 inhibitor: 5 mg/kg), ozagrel [TX synthase (TXS) inhibitor: 200 mg/kg] or seratrodast [TXA2 receptor (TP) antagonist: 1-30 mg/kg] was administered PO 60 min before the onset of ischemia. Iloprost (PGI2 analogue: 1 μg/kg) was given IV 5 min before reperfusion. TXB2 and 6-keto-PGF1a contents in the gastric mucosa were measured by enzyme immunoassay. The expression of TP and TXS mRNAs were examined by RT-PCR. Results: I/R produced hemorrhagic lesions in the gastric mucosa, the lesion score being 9.3±2.1 mm2. The severity of I/R-induced gastric lesions was significantly decreased by the pretreatment with ozagrel, seratrodast or iloprost. By contrast, the gastric ulcerogenic response under I/R conditions was markedly worsened by pretreatment with rofecoxib, and this response was abrogated by co-administration of iloprost. The expressions of TP and TXS mRNAs were observed in the normal mouse stomach, and these expressions remained unchanged under I/R-induced conditions. I/R significantly increased both TXB2 and 6-keto-PGF1a contents in the gastric mucosa. The increase of TXB2 content under I/R conditions was significantly attenuated by SC-560 but not rofecoxib, while the increased PGI2 biosynthetic response was totally attenuated by rofecoxib but not SC-560. I/R by itself had no effect on the TXB2/ 6-keto-PGF1a ratio in the gastric mucosa, yet the ratio was markedly increased by rofecoxib and decreased by ozagrel, respectively. Conclusion: These results suggest that 1) COX-1/TXA2 plays a crucial role in the development of I/R-induced gastric lesions, in addition to COX-2/PGI2, and 2) the aggravation by rofecoxib of I/R-induced gastric lesions may be accounted partly for by the imbalance of TXA2/PGI2 ratio in the stomach.
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