Na+/H+ exchanger inhibitor, FR183998, has protective effect in lethal acute liver failure and prevents iNOS induction in rats.

Abstract

BACKGROUND/AIMS:

Selective inhibition of Na(+)/H(+) exchanger (NHE) improves organ dysfunctions including heart ischemia-reperfusion injury. In vivo and in vitro studies were designed to investigate whether NHE inhibitor has a protective effect in lethal acute liver failure, and if so, what are the mechanisms involved.

METHODS:

NHE inhibitor (FR183998) was administered to rats treated with d-galactosamine/lipopolysaccharide (GalN/LPS), or incubated with cultured hepatocytes stimulated by pro-inflammatory cytokine, interleukin (IL)-1beta.

RESULTS:

FR183998 reduced the increases of pro-inflammatory cytokines such as TNF-alpha, interferon-gamma and CINC-1, but enhanced the anti-inflammatory cytokine, IL-10, leading to the prevention of liver injury and increased survival rate in GalN/LPS-treated animals. FR183998 prevented the activation of transcription factor NF-kappaB induced by GalN/LPS. In vivo and in vitro experiments revealed that FR183998 reduced inducible nitric oxide synthase (iNOS) induction and NO production. Further FR183998 decreased levels of iNOS antisense-transcript in GalN/LPS-treated liver and IL-1beta-treated hepatocytes.

CONCLUSIONS:

FR183998 may reduce a variety of inflammatory mediators such as cytokines and NO in part through the inhibition of NF-kappaB activation, resulting in the prevention of fulminant liver failure, and may inhibit iNOS gene expression at steps of iNOS promoter transactivation and its mRNA stabilization through NF-kappaB and iNOS antisense-transcript, respectively.

• Authors: Hironori Tanaka, Yoichiro Uchida, Masaki Kaibori, Takeshi Hijikawa, Morihiko Ishizaki, Masanori Yamada, Kosuke Matsui, Takashi Ozaki, Katsuji Tokuhara, Yasuo Kamiyama, Mikio Nishizawa, Seiji Ito, Tadayoshi Okumura
• Journal: Journal of hepatology (J Hepatol) Vol. 48 Issue 2 Pg. 289-99 (Feb 2008) ISSN: 0168-8278 [Print] Netherlands
• PMID: 18096265 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FR 183998
• Guanidines
• NF-kappa B
• Receptors, Interleukin-1
• Sodium-Hydrogen Exchangers
• Thiophenes
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Nitric Oxide Synthase Type II

Topics

• Animals
• Enzyme Induction (drug effects)
• Guanidines (pharmacology)
• Interleukin-10 (physiology)
• Liver (drug effects, enzymology)
• Liver Failure, Acute (drug therapy)
• Male
• NF-kappa B (antagonists & inhibitors)
• Nitric Oxide Synthase Type II (biosynthesis)
• Rats
• Rats, Sprague-Dawley
• Receptors, Interleukin-1 (antagonists & inhibitors)
• Sodium-Hydrogen Exchangers (antagonists & inhibitors)
• Thiophenes (pharmacology)
• Tumor Necrosis Factor-alpha (physiology)
• Up-Regulation