VASCULAR SUPEROXIDE-DISMUTASE DEFICIENCY IMPAIRS ENDOTHELIAL VASODILATOR FUNCTION THROUGH DIRECT INACTIVATION OF NITRIC-OXIDE AND INCREASEDLIPID-PEROXIDATION

Nitric oxide (NO) and superoxide are both constitutive products of the endothelium. Because NO is readily inactivated by superoxide, the bio activity of endothelium-derived NO (EDNO) is dependent on local activi ty of superoxide dismutase (SOD). We examined the effects of chronic i nhibition of copper-zinc SOD (CuZnSOD) using a rat model of dietary co pper restriction. Male weanling Sprague-Dawley rats were fed a Cu-defi cient diet and received either no Cu replacement (Cu-deficient) or Cu in the drinking water (Cu-sufficient). Compared with Cu-sufficient ani mals, Cu-deficiency was associated with a 68% reduction in CuZnSOD act ivity and a 58% increase in vascular superoxide as estimated by lucige nin chemiluminescence (both P<.05). Compared with Cu-sufficient animal s, arterial relaxation in the thoracic aorta from Cu-deficient animals was 10-fold less sensitive to acetylcholine, a receptor-dependent EDN O agonist, but only 1.5-fold less sensitive to A23187, a receptor-inde pendent EDNO agonist, and only 1.25-fold less sensitive to authentic N O (all P<.05). In contrast, acute inhibition of CuZnSOD with 10 mM die thyldithiocarbamate produced a more uniform reduction in sensitivity t o acetylcholine (8-fold), A23187 (10-fold), and NO (4-fold; all P<.001 ). Cu-deficient animals demonstrated a 2.5-fold increase in plasma-est erified F-2-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 con clude that chronic inhibition of CuZnSOD inhibits EDNO-mediated arteri al relaxation through two mechanisms, one being direct inactivation of NO and the other being lipid peroxidation that preferentially interru pts receptor-mediated stimulation of EDNO.