Amiodarone and N-Desethylamiodarone Enhance Endothelial Nitric Oxide Production in Human Endothelial Cells
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概要
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Amiodarone (AM) is a potent vasodilator and exhibits diverse cardiovascular protective effects in vivo, but their underlying mechanisms remain unsettled. We investigated the effects of AM and N-desethylamiodarone (DEA), the major metabolite of AM, on endothelial nitric oxide (NO) production using cultured human umbilical vein endothelial cells (HUVECs). The release of NO was evaluated as measured by nitrite, a stable metabolite of NO, using the Griess reaction and also measured directly by a NO-selective electrode. The expression of each nitric oxide synthase (NOS) mRNA was examined by reverse transcriptase-polymerase chain reaction (RT-PCR), and the effects of AM on eNOS mRNA expression were studied by quantitative real-time RT-PCR. AM and DEA (1-30 μM) enhanced NO production in a concentration-dependent manner. DEA was capable of producing more NO than AM. L-NAME, a nonselective NOS inhibitor, EGTA, a Ca2+-chelating agent, and nickel, a nonspecific Ca2+ blocker, all inhibited AM-induced NO production. However, LY294002, an Akt pathway inhibitor and SB202190, a MAP kinase inhibitor, did not significantly suppress the production. In RT-PCR analysis, only eNOS mRNA was detected. Treatment with AM for 4 hours did not show a significant increase in the expression of eNOS mRNA. AM lower than 30 μM did not induce apoptosis, net cell loss, or LDH release from cells. The present study provides the first evidence that therapeutic concentrations of AM and DEA enhance eNOS-mediated NO production without any toxic or apoptotic effects. This mechanism may underlie the cardiovascular protective effects of AM and its metabolite observed in a clinical setting.
著者
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Takano Haruhito
Department of Cardiovascular Medicine, the University of Tokyo
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Oonuma Hitoshi
Department Of Ischemic Circulatory Physiology The University Of Tokyo
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Kishida Shinya
Department Of Cardiovascular Medicine The University Of Tokyo
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Morita Toshihiro
Department Of Anesthesiology And Reanimatology Gunma University School Of Medicine
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Ma Ji
Department Of Cardiovascular Medicine University Of Tokyo
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Nagai Ryozo
Department Cardiovascular Medicine The University Of Tokyo Hospital
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Nakajima Toshiaki
Department Of Cardiology Tokyo University
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Iida Haruko
Department of Cardiovascular Medicine, School of Medicine, University of Tokyo
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Imuta Hiroyuki
Department of Ischemic Circulatory Physiology, University of Tokyo
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Oonuma Hitoshi
Department of Ischemic Circulatory Physiology, University of Tokyo
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Jo Taisuke
Department of Respiratory Medicine, University of Tokyo
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