Chronic treatment with FK506 increases p70 S6 kinase activity associated with reduced nitric oxide synthase activity in rabbit hearts.
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.
Department of Internal Medicine and Therapeutics, Osaka University, Graduate School of Medicine, Japan.
T
T
Minamino
M
M
Kitakaze
Y
Y
Ueda
H
H
Asanuma
P J
PJ
Papst
T
T
Kuzuya
N
N
Terada
M
M
Hori
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D011817:Rabbits; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D007166:Immunosuppressive Agents; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D019893:Ribosomal Protein S6 Kinases; D000109:Acetylcholine; D016559:Tacrolimus