© 1997 American Heart Association, Inc.
Articles |
Vascular Superoxide Dismutase Deficiency Impairs Endothelial Vasodilator Function Through Direct Inactivation of Nitric Oxide and Increased Lipid Peroxidation
From the Evans Memorial Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts (S.M.L., B.F., A.X., T.J., R.R., J.A.V., J.F.K.), the Departments of Pharmacology and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee (J.D.M., L.J.R.), and the United States Department of Agriculture, Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota (L.M.K.).
Correspondence to John F. Keaney, Jr., Whitaker Cardiovascular Institute, Boston University School of Medicine, 80 East Concord Street, Room W507, Boston, Massachusetts, 02118. E-mail jkeaney{at}acs.bu.edu
Abstract Nitric oxide (NO) and superoxide are both constitutive products of the endothelium. Because NO is readily inactivated by superoxide, the bioactivity of endothelium-derived NO (EDNO) is dependent on local activity of superoxide dismutase (SOD). We examined the effects of chronic inhibition of copper-zinc SOD (CuZnSOD) using a rat model of dietary copper restriction. Male weanling Sprague-Dawley rats were fed a Cu-deficient diet and received either no Cu replacement (Cu-deficient) or Cu in the drinking water (Cu-sufficient). Compared with Cu-sufficient animals, Cu-deficiency was associated with a 68% reduction in CuZnSOD activity and a 58% increase in vascular superoxide as estimated by lucigenin chemiluminescence (both P<.05). Compared with Cu-sufficient animals, arterial relaxation in the thoracic aorta from Cu-deficient animals was 10-fold less sensitive to acetylcholine, a receptor-dependent EDNO agonist, but only 1.5-fold less sensitive to A23187, a receptor-independent EDNO agonist, and only 1.25-fold less sensitive to authentic NO (all P<.05). In contrast, acute inhibition of CuZnSOD with 10 mM diethyldithiocarbamate produced a more uniform reduction in sensitivity to acetylcholine (8-fold), A23187 (10-fold), and NO (4-fold; all P<.001). Cu-deficient animals demonstrated a 2.5-fold increase in plasma-esterified F2-isoprostanes, a stable marker of lipid peroxidation, that correlated inversely with arterial relaxation to acetylcholine (R=-.83; P<.0009) but not A23187 or authentic NO. From these findings, we conclude that chronic inhibition of CuZnSOD inhibits EDNO-mediated arterial relaxation through two mechanisms, one being direct inactivation of NO and the other being lipid peroxidation that preferentially interrupts receptor-mediated stimulation of EDNO.
Key Words: superoxide • nitric oxide • oxidation
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