Na+/H+ exchanger inhibitor, FR183998, has protective effect in lethal acute liver failure and prevents iNOS induction in rats.
OBJECTIVE
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.
Tanaka
Hironori
H
Department of Surgery, Kansai Medical University, Moriguchi, Osaka, Japan.
Uchida
Yoichiro
Y
Kaibori
Masaki
M
Hijikawa
Takeshi
T
Ishizaki
Morihiko
M
Yamada
Masanori
M
Matsui
Kosuke
K
Ozaki
Takashi
T
Tokuhara
Katsuji
K
Kamiyama
Yasuo
Y
Nishizawa
Mikio
M
Ito
Seiji
S
Okumura
Tadayoshi
T
D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D016753:Interleukin-10 / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D017114:Liver Failure, Acute / Q000188:drug therapy*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation
C449400:FR 183998; D006146:Guanidines; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D017923:Sodium-Hydrogen Exchangers; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D052247:Nitric Oxide Synthase Type II