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.

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 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.