Cardiac oxidative stress in acute and chronic isoproterenol-infused rats.
OBJECTIVE
Sympathetic nervous system activity in the myocardium is increased in patients with heart failure. However, the in vivo mechanisms responsible for beta-adrenoceptor-mediated cardiac hypertrophy or remodeling remain unclear. This study aimed to clarify the role of reactive oxygen species (ROS) in mitogen-activated protein (MAP) kinase activation and tissue remodeling of the heart of isoproterenol (ISO)-infused rats.


RESULTS
Different doses of ISO (up to 1000 ng/kg/min) were given intravenously to conscious rats for 30 min. Phosphorylated MAP kinase levels (ERK1/2, JNK, p38) and lipid peroxidation were measured in the cardiac left ventricle, revealing the dose-dependent augmentation of MAP kinase phosphorylation and increased lipid peroxidation levels. Simultaneous treatment with 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol), a membrane-permeable radical scavenger, completely eliminated the increases of phosphorylated MAP kinases and their upstream elements (Raf-1, Rac-1, ASK-1) as well as the increases of cardiac lipid peroxidation induced by the highest dose of ISO infusion. In chronically ISO-infused rats (3 mg/kg/day, s.c. for 10 days), cardiac hypertrophy developed with accompanying increases of collagen content, whereas cardiac phosphorylated MAP kinases returned to normal. Tempol treatment prevented increases of collagen accumulation and type I collagen mRNA without any significant reduction of cardiac mass enlargement induced by chronic ISO infusion.


CONCLUSIONS
beta-Adrenoceptor stimulation provokes cardiac oxidative stress. In the acute phase of ISO infusion, ROS are important activators of cardiac MAP kinase cascades; while, in the chronic phase, ROS may participate in cardiac remodeling, especially in respect to wall stiffness, based on fibrogenesis.
Zhang
Guo-Xing
GX
Department of Pharmacology, Kagawa University Medical School, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan.
Kimura
Shoji
S
Nishiyama
Akira
A
Shokoji
Takatomi
T
Rahman
Matlubur
M
Yao
Li
L
Nagai
Yukiko
Y
Fujisawa
Yoshihide
Y
Miyatake
Akira
A
Abe
Youichi
Y
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D024042:Collagen Type I / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D015227:Lipid Peroxidation; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
D000318:Adrenergic beta-Agonists; D000975:Antioxidants; D024042:Collagen Type I; D017362:Cyclic AMP Response Element-Binding Protein; D003497:Cyclic N-Oxides; D013113:Spin Labels; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D007545:Isoproterenol; C001803:tempol