The role of the new Ca2+ antagonist, CV159, in hepatic I/R injury-the evaluation of hepatic organ reducing activity using in vivo and ex vivo EPR.
We investigated the organ-reducing ability of 1,2-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 6-(5-phenyl-3-pyrazolyloxy) hexyl ester (CV159) that exhibits selective blocking of Ca(2+)/calmodulin and inhibition of Ca(2+) overloading in living organisms (Sprague Dawley rats) using an in vivo and an ex vivo electron paramagnetic imaging technique. Decay rates in CV159-treated rats were significantly higher than those in untreated rats and were almost equal to those in the sham group. Both cytosol and mitochondrial superoxide scavenging activity in CV159-treated rats were significantly higher than those in untreated rats, and cytosol superoxide scavenging activity only was slightly higher than that in the sham group. Faint staining for anti-superoxide dismutase antibody was markedly observed in necrotic lesions in the liver of control group. Alanine aminotransferase level in CV-treated rats were significantly decreased as compared with the levels in untreated rats. Electron microscopy showed a decreased number of damaged mitochondria, whereas mitochondrial damage was significantly reduced in CV-treated animals. We conclude that CV159 retains the organ-reducing activity against radicals in hepatic I/R injury that is mediated by the inhibition of Ca(2+) overloading.
Watanabe
Taiji
T
Department of Gastroenterological Surgery, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Oowada
Shigeru
S
Kobayashi
Hiromichi P
HP
Kamibayashi
Masato
M
Ishiuchi
Atsuko
A
Jinnouchi
Yuji
Y
Koizumi
Satoshi
S
Asano
Takayuki
T
Shimamura
Tsukasa
T
Asakura
Takeshi
T
Nakano
Hiroshi
H
Kubota
Sunao
S
Otsubo
Takehito
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D015996:Survival Rate
D002147:Calmodulin; D004095:Dihydropyridines; D017382:Reactive Oxygen Species; C055634:CV 159; D000410:Alanine Transaminase; D009219:Myosin-Light-Chain Kinase; D002118:Calcium