caa a22 4500 475833449 CHVBK 20180406123847.0 cr unu---uuuuu 170329e20000301xx s 000 0 eng 10.1023/A:1007890827297 doi (NATIONALLICENCE)springer-10.1023/A:1007890827297 Chronic Treatment with FK506 Increases p70 S6 Kinase Activity Associated with Reduced Nitric Oxide Synthase Activity in Rabbit Hearts [Elektronische Daten] [Tetsuo Minamino, Masafumi Kitakaze, Yasunori Ueda, Hiroshi Asanuma, Philip Papst, Tsunehiko Kuzuya, Naohiro Terada, Masatsugu Hori] FK506, an immunosuppressant, modulates phosphorylation of nitric oxide (NO) synthase, and induces cardiac hypertrophy in clinical settings. Having recently reported that chronic treatment with an inhibitor of NO synthase induces cardiac hypertrophy associated with the activation of 70-kD S6 kinase (p70S6K), which plays an important role in cardiac hypertrophy by regulating protein synthesis, we investigated the effects of chronic administration of FK506 on NO synthase and p70S6K activities in hearts. Twenty rabbits were divided into four groups: untreated rabbits, those treated with low-dose FK506 (0.10 mg/kg), those treated with medium-dose FK506 (0.20 mg/kg), and those treated with high-dose FK506 (0.40 mg/kg). FK506 was administered intravenously twice a day. After 4 weeks of treatment with FK506, calcium-dependent NO synthase activity in myocardium in the high-dose FK506 group was lower (P < 0.05) than in the untreated group. p70S6K activity in myocardium in the high-dose group was higher (P < 0.05) than in the untreated group. There was a significant (P < 0.05) inverse correlation between NO synthase and p70S6K activities in myocardium. However, the endothelial-dependent vasodilation of aortic rings or plasma levels of NO metabolites during experimental protocols did not differ among the groups studied. These findings suggest that chronic treatment of FK506 activates p70S6K and reduces NO synthase activity in rabbit hearts. Reduced NO synthase and/or activated p70S6K activities in hearts might contribute to the cardiac hypertrophy observed in some patients receiving FK506. Kluwer Academic Publishers, 2000 FK506 nationallicence nitric oxide synthase nationallicence p70 S6 kinase nationallicence hypertrophy nationallicence Minamino Tetsuo First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut Kitakaze Masafumi First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut Ueda Yasunori First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut Asanuma Hiroshi First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut Papst Philip Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado, USA aut Kuzuya Tsunehiko First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut Terada Naohiro Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado, USA aut Hori Masatsugu First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut Cardiovascular Drugs and Therapy Kluwer Academic Publishers 14/3(2000-03-01), 329-336 0920-3206 14:3<329 2000 14 10557 https://doi.org/10.1023/A:1007890827297 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1007890827297 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Minamino Tetsuo First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut NATIONALLICENCE 700 1- Kitakaze Masafumi First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut NATIONALLICENCE 700 1- Ueda Yasunori First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut NATIONALLICENCE 700 1- Asanuma Hiroshi First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut NATIONALLICENCE 700 1- Papst Philip Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado, USA aut NATIONALLICENCE 700 1- Kuzuya Tsunehiko First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut NATIONALLICENCE 700 1- Terada Naohiro Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado, USA aut NATIONALLICENCE 700 1- Hori Masatsugu First Department of Medicine, Osaka University School of Medicine, Suita, Osaka, Japan aut NATIONALLICENCE 773 0- Cardiovascular Drugs and Therapy Kluwer Academic Publishers 14/3(2000-03-01), 329-336 0920-3206 14:3<329 2000 14 10557 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer