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 Ca2+ /calmodulin and inhibition of Ca2+ overloading in living organisms (Sprague Dawley r...
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| Published in | The Journal of surgical research Vol. 145; no. 1; pp. 49 - 56 |
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| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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New York, NY
Elsevier Inc
01.03.2008
Elsevier |
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| Abstract | 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. |
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| AbstractList | 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. 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. 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. |
| Author | Kamibayashi, Masato, Ph.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 Kobayashi, Hiromichi P., M.D Jinnouchi, Yuji, Ph.D., M.D Ishiuchi, Atsuko, Ph.D Watanabe, Taiji, Ph.D., M.D Nakano, Hiroshi, Ph.D., M.D Kubota, Sunao, Ph.D., M.D Otsubo, Takehito, Ph.D., M.D Oowada, Shigeru, Ph.D., M.D |
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| Cites_doi | 10.1038/nature03434 10.1161/hh2201.100205 10.1074/jbc.272.1.556 10.1016/j.tox.2005.05.008 10.1159/000090612 10.1016/S0891-5849(99)00280-4 10.1016/S0016-5085(99)70241-6 10.1016/0076-6879(90)86093-B 10.1016/S0891-5849(03)00073-X 10.1016/0730-725X(85)90012-8 10.1097/00005344-200405000-00016 10.1016/S0730-725X(99)00122-8 10.1007/s10620-006-8014-y 10.1074/jbc.271.25.15182 10.1016/S0024-3205(99)00011-9 10.1080/10715760600883254 10.1038/nature03317 10.1161/hh0202.103615 10.1016/0006-2952(88)90685-5 10.1016/0006-291X(82)91089-0 |
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| Keywords | 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 |
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| SubjectTerms | 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 |
| Title | 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 |
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