Protective effect of FR183998, A Na+/H+ exchanger inhibitor, and its inhibition of iNOS induction in hepatic ischemia-reperfusion injury in rats

Morihiko Ishizaki, Masaki Kaibori, Yoichiro Uchida, Takeshi Hijikawa, Hironori Tanaka, Takashi Ozaki, Katsuji Tokuhara, Kosuke Matsui, A. Hon Kwon, Yasuo Kamiyama, Mikio Nishizawa, Tadayoshi Okumura

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Recent evidence indicates that inhibition of the Na+/H + exchanger improves heart and brain injuries induced by l/R. Studies were performed to investigate whether FR183998, a Na+/H+ exchanger inhibitor, has protective effects on hepatic l/R injury in rats. Male Sprague-Dawley rats were subjected to 70% hepatic ischemia by occluding the hepatic artery, portal vein, and bile duct associated with the left and median liver lobes with a microvascular clip for 2 h. FR183998 (1 mg/kg) was administered i.v. 10 min before the hepatic ischemia. Hepatic l/R increased the serum levels of aspartate transaminase, alanine transaminase, and lactate dehydrogenase, which peaked at 9 h after reperfusion. FR183998 reduced these injury markers and recovered liver functions. Histopathologic analysis revealed that FR183998 prevented the incidences of hepatic necrosis, apoptosis, and neutrophil infiltration at 6 and 9 h (P< 0.05). FR183998 reduced the increases in proinflammatory cytokines such as TNF-α (1-6 h), IL-6 (1-12 h), interferon-γ (6-12 h), IL-1β (1-3 h), and cytokine-induced neutrophil chemoattractant 1 (1-3 h), but enhanced the anti-inflammatory cytokine IL-10 (1 h). FR183998 inhibited the hepatic l/R-induced activation of the transcription factor nuclear factor-κB at 1 to 6 h and reduced the induction of iNOS at 6 to 12 h, followed by inhibition of nitric oxide production. Furthermore, FR183998 decreased the expression of the iNOS gene antisense transcript, which is involved in the stability of iNOS messenger RNA, at 9 to 12 h in the liver of hepatic l/R rats. These results demonstrate that FR183998 reduces the induction of proinflammatory cytokines and iNOS at least in part through inhibition of nuclear factor-κB activation and iNOS antisense transcript expression, thereby preventing hepatic l/R injury.

Original languageEnglish
Pages (from-to)311-317
Number of pages7
JournalShock
Volume30
Issue number3
DOIs
Publication statusPublished - 09-2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Fingerprint

Dive into the research topics of 'Protective effect of FR183998, A Na<sup>+</sup>/H<sup>+</sup> exchanger inhibitor, and its inhibition of iNOS induction in hepatic ischemia-reperfusion injury in rats'. Together they form a unique fingerprint.

Cite this