Protective effect of FR183998, a Na+/H+ exchanger inhibitor, and its inhibition of iNOS induction in hepatic ischemia-reperfusion injury in rats.
Recent evidence indicates that inhibition of the Na+/H+ exchanger improves heart and brain injuries induced by I/R. Studies were performed to investigate whether FR183998, a Na/H exchanger inhibitor, has protective effects on hepatic I/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 I/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-alpha (1-6 h), IL-6 (1-12 h), interferon-gamma (6-12 h), IL-1beta (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 I/R-induced activation of the transcription factor nuclear factor-kappaB 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 I/R rats. These results demonstrate that FR183998 reduces the induction of proinflammatory cytokines and iNOS at least in part through inhibition of nuclear factor-kappaB activation and iNOS antisense transcript expression, thereby preventing hepatic I/R injury.
Ishizaki
Morihiko
M
Department of Surgery, Kansai Medical University, Moriguchi, Osaka, Japan.
Kaibori
Masaki
M
Uchida
Yoichiro
Y
Hijikawa
Takeshi
T
Tanaka
Hironori
H
Ozaki
Takashi
T
Tokuhara
Katsuji
K
Matsui
Kosuke
K
Kwon
A-Hon
AH
Kamiyama
Yasuo
Y
Nishizawa
Mikio
M
Okumura
Tadayoshi
T
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000737:chemistry; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; C449400:FR 183998; D006146:Guanidines; D007378:Interleukins; D017923:Sodium-Hydrogen Exchangers; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II