|Lynch, Sean - BOSTON UNIV|
|Frei, Balz - BOSTON UNIV|
|Morrow, Jason - VANDERBILT UNIV|
|Roberts, Iii, L. - VANDERBILT UNIT|
|Xu, Aiming - BOSTON UNIV|
|Jackson, Terence - BOSTON UNIV|
|Reyna, Ronald - BOSTON UNIV|
|Vita, Joseph - BOSTON UNIV|
|Keaney, Jr, John - BOSTON UNIV|
Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 14, 1997
Publication Date: N/A
Interpretive Summary: Diets in the U.S. frequently are low in copper; impaired function of heart and blood vessels is a likely result. Arteries from rats deficient in copper were less able to relax than arteries from copper-supplemented animals. This impairment was detected by measuring their response to acetylcholine, a chemical normally produced by animals and people in nerves that control heart rate and blood pressure. It was inferred from measurements made using some experimental drugs that affect this process and from measurements of some enzymes that copper deficiency promotes oxidative damage. This damage inactivates directly an important relaxation mechanism. Further impairment is induced indirectly by the accumulation of oxidized lipids. This work adds to the number of reasons why people should select diets adequate in copper.
Technical Abstract: Nitric oxide (NO) and superoxide are both constitutive products of the endothelium. As NO is readily inactivated by superoxide, the bioactivity of endothelium-derived NO (EDNO) is dependent upon local activity of superoxide dismutase (SOD). We examined the effects of inhibition of copper-zinc SOD (CuZnSOD) in copper-deficient rats. Male weanling Sprague-Dawley rats were fed a Cu-deficient diet and received either no Cu replacement (deficient) or Cu in the drinking water (sufficient). Deficiency was associated with a 68% reduction in CuZnSOD activity and a 58% increase in vascular superoxide as detected by lucigenin chemiluminescence (Both P<0.05). Compared to sufficient animals, arterial relaxation in the thoracic aorta from 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 tand only 1.25-fold less sensitive to authentic NO (all P<0.05). 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 < 0.001). Deficient animals demonstrated a 2.5-fold increase in plasma esterified F2-isoprostanes, a marker of lipid peroxidation, that correlated inversely with arterial relaxation to acetylcholine (R=-0.83; P<0.0009), 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.