doi: 10.1161/hc4901.100382
(Circulation. 2001;104:2967.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Impaired Endothelial Regulation of Ventricular Relaxation in Cardiac Hypertrophy
Role of Reactive Oxygen Species and NADPH Oxidase
From the Department of Cardiology (P.A.M., D.J.G., J.-M.L., A.M.S.) and Cardiovascular Research (C.D., F.J.K.), Guy’s King’s and St Thomas’ Schools of Medicine and Biomedical Sciences, King’s College London, UK.
Correspondence to Professor Ajay M. Shah, Department of Cardiology, GKT School of Medicine, Bessemer Road, London SE5 9PJ, UK. E-mail ajay.shah{at}kcl.ac.uk
Background— Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation. In experimental left ventricular hypertrophy (LVH), this endothelium-dependent LV relaxant response is impaired despite a preserved response to exogenous NO. We investigated the potential role of reactive oxygen species (ROS) in this defect.
Methods and Results— Short-term treatment with the antioxidants vitamin C (10 µmol/L) or deferoxamine (500 µmol/L) restored LV relaxant responses to the NO agonists bradykinin (10 nmol/L) and substance P (100 nmol/L) in isolated ejecting hearts of aortic-banded guinea pigs. Substance P decreased the time to onset of LV relaxation (tdP/dtmin) by -6.8±1.7 ms in the presence of vitamin C and by -8.9±2.2 ms in the presence of deferoxamine compared with -0.8±2.2 ms in the absence of antioxidants (P<0.05 either antioxidant versus control). A similar restoration of relaxant response to substance P was observed in the presence of the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (10 µmol/L), but not with tetrahydrobiopterin or L-arginine. Protein expression of the NADPH oxidase subunits gp91-phox and p67-phox and myocardial NADPH oxidase activity were significantly increased (P<0.05) in the banded group compared with shams.
Conclusions— An increase in ROS, most likely derived at least in part from NADPH oxidase, is responsible for the impaired endothelial regulation of LV relaxation in LVH. These are the first data to potentially link increased NADPH oxidase-derived ROS with a defect in cardiac contractile function in a pathological setting.
Key Words: nitric oxide • hypertrophy • endothelium • free radicals • myocardial contraction
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