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

• Published in: The Journal of surgical research Vol. 145; no. 1; pp. 49 - 56
• Main Authors: Watanabe, Taiji, Ph.D., M.D, Oowada, Shigeru, Ph.D., M.D, Kobayashi, Hiromichi P., M.D, Kamibayashi, Masato, Ph.D, Ishiuchi, Atsuko, Ph.D, Jinnouchi, Yuji, Ph.D., M.D, Koizumi, Satoshi, Ph.D., M.D, Asano, Takayuki, Ph.D., M.D, Shimamura, Tsukasa, Ph.D., M.D, Asakura, Takeshi, Ph.D., M.D, Nakano, Hiroshi, Ph.D., M.D, Kubota, Sunao, Ph.D., M.D, Otsubo, Takehito, Ph.D., M.D
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.03.2008; Elsevier
• Subjects: Alanine Transaminase - blood; Animals; Biological and medical sciences; Calcium - antagonists & inhibitors; Calmodulin - antagonists & inhibitors; CaM; CV159; Dihydropyridines - pharmacology; Disease Models, Animal; Electron Spin Resonance Spectroscopy; ex vivo EPR; General aspects; hepatic IR injury; in vivo EPR; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Medical sciences; Mitochondria - drug effects; Mitochondria - ultrastructure; Myosin-Light-Chain Kinase - antagonists & inhibitors; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Surgery; Survival Rate; in vivo EPR; CV159; ex vivo EPR; CaM; hepatic IR injury; Evaluation; Toxicity; Liver; Calcium antagonist; Cardiovascular disease; Inorganic element; Medicine; In vivo; Treatment; Ex vivo; Surgery; Lesion
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2006.12.559

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 Ca2+ /calmodulin and inhibition of Ca2+ 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 Ca2+ overloading.