Abstract
We examined the role of cysteinyl leukotrienes (CysLTs) in the gastric ulcerogenic response to ischemia/reperfusion (I/R) in mice. Experiments were performed in male C57BL/6J mice after 18-h fasting. Under urethane anesthesia, the celiac artery was clamped for 30 min, and then reperfusion was achieved by removing the clamp. The stomach was examined for lesions 60 min thereafter. The severity of I/R-induced gastric damage was reduced by prior administration of pranlukast [CysLT receptor type 1 (CysLT1R) antagonist] as well as 1-[[5′-(3″-methoxy-4″-ethoxycarbonyl-oxyphenyl)-2′,4′-pentadienoyl]aminoethyl]-4-diphenylmethoxypiperidine [TMK688; 5-lipoxygenase (5-LOX) inhibitor]. On the contrary, these lesions were markedly worsened by pretreatment with indomethacin, and this response was abrogated by the coadministration of TMK688 or pranlukast. The gene expression of CysLT1R but not 5-LOX was up-regulated in the stomach after I/R, but both expressions were increased under I/R in the presence of indomethacin. I/R slightly increased the mucosal CysLT content of the stomach, yet this increase was markedly enhanced when the animals were pretreated with indomethacin. The increased CysLT biosynthetic response to indomethacin during I/R was attenuated by TMK688. Indomethacin alone caused a slight increase of CysLT1R expression and markedly up-regulated 5-LOX expression in the stomach. We concluded that I/R up-regulated the expression of CysLT1R in the stomach; CysLTs play a role in the pathogenesis of I/R-induced gastric damage through the activation of CysLT1R; and the aggravation by indomethacin of these lesions may be brought about by the increase of CysLT production and the up-regulation of 5-LOX expression, in addition to the decreased prostaglandin production.
Footnotes
- Received October 9, 2009.
- Accepted December 29, 2009.
This work was supported in part by the Kyoto Pharmaceutical University's “21st Century COE” program [Grant K 26] and the “Open Research” Program [Grant 040019] from the Ministry of Education, Science and Culture of Japan.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.162578.
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ABBREVIATIONS:
- I/R
- ischemia/reperfusion
- PG
- prostaglandin
- COX
- cyclooxygenase
- LT
- leukotriene
- 5-LOX
- 5-lipoxygenase
- CysLT
- cysteinyl leukotriene
- CysLT1R
- CysLT receptor type 1
- TMK688
- 1-[[5′-(3″-methoxy-4″-ethoxycarbonyl-oxyphenyl)-2′,4′-pentadienoyl]aminoethyl]-4-diphenylmethoxypiperidine
- MPO
- Myeloperoxidase
- RT-PCR
- reverse transcription-polymerase chain reaction
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- i.d.
- intraduodenally
- NS-398
- N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide
- TXA2
- thromboxane A2.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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