A potential mechanism for the impairment of nitric oxide formation caused by prolonged oral exposure to arsenate in rabbits
A potential mechanism for the impairment of nitric oxide formation caused by prolonged oral exposure to arsenate in rabbits
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DOI：
10.1016/s0891-5849(03)00269-7
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发表时间：
2003-07-01
影响因子：
7.4
通讯作者：
Kumagai, Y
中科院分区：
文献类型：
--
作者：
Pi, JB;Horiguchi, S;Kumagai, Y
我们最近发现的证据表明，在中国内蒙古慢性砷中毒病区的居民中，一氧化氮（NO）的形成和诱导氧化应激障碍。为了研究导致这些现象的潜在机制，使用雄性新西兰白色兔进行亚慢性动物实验。连续暴露18周后，兔在饮用水中的5毫克/升的砷酸盐，发生了显着减少全身NO的生产，如显着降低血浆NO代谢产物水平（对照组的76%）和降低血清cGMP水平（对照组的81.4%）的趋势。另一方面，增加氧化应激，如显着增加尿过氧化氢（H2 O2）（对照组的120%），观察砷暴露的兔子。在测量主动脉张力的其他实验中，添加钙离子载体A23187或乙酰胆碱（ACh）诱导了从砷酸盐暴露的家兔制备的主动脉环的短暂血管收缩，但在对照动物制备的主动脉环中没有。在砷暴露家兔的主动脉环中观察到的这种钙依赖性收缩作用被超氧化物（O-2（.-））清除酶Cu，Zn-SOD，以及二亚苯基碘鎓（DPI）或N-G-硝基-L-精氨酸甲酯（L-NAME），它们是一氧化氮合酶（NOS）的抑制剂。然而，环氧合酶抑制剂吲哚美辛或黄嘌呤氧化酶阻断剂别嘌呤醇对这种血管收缩没有影响。这些结果表明，砷酸盐介导的全身NO减少可能与NOS的酶解偶联反应有关，随后增加了活性氧，如O-2（.-），一种内皮衍生的血管收缩因子。此外，（6 R）-5，6，7，8-四氢-L-生物蝶呤（BH 4），一种NOS的辅助因子，在砷暴露的兔子中显著降低至对照组的62%，而心脏L-精氨酸水平没有显著变化。这些结果表明，兔长期暴露于口服砷酸盐可能会损害BH 4在内皮细胞中的生物利用度，从而破坏NO和O-2（.-）之间的平衡。由内皮NOS产生，从而产生增强的自由基，其代价是NO.（C）2003 Elsevier Inc.
We have recently found evidence for impairment of nitric oxide (NO) formation and induction of oxidative stress in residents of an endemic area of chronic arsenic poisoning in Inner Mongolia, China. To investigate the underlying mechanisms responsible for these phenomena, a subchronic animal experiment was conducted using male New Zealand White rabbits. After 18 weeks of continuous exposure of rabbits to 5 mg/l of arsenate in drinking water, a significant decrease in systemic NO production occurred, as shown by significantly reduced plasma NO metabolites levels (76% of control) and a tendency towards decreased serum cGMP levels (81.4% of control). On the other hand, increased oxidative stress, as shown by significantly increased urinary hydrogen peroxide (H2O2) (120% of control), was observed in arsenate-exposed rabbits. In additional experiments measuring aortic tension, the addition of either the calcium ionophore A23187 or acethylcholine (ACh) induced a transient vasoconstriction of aortic rings prepared from arsenate-exposed rabbits, but not in those prepared from control animals. This calcium-dependent contractility action observed in aorta rings from arsenate-exposed rabbits was markedly attenuated by the superoxide (O-2(.-)) scavenging enzyme Cu, Zn-SOD, as well as diphenyleneiodonium (DPI) or N-G-nitro-L-arginine methyl ester (L-NAME), which are inhibitors for nitric oxide synthase (NOS). However, the cyclooxygenase inhibitor indomethacin or the xanthine oxidase blocker allopurinol had no effect on this vasoconstriction. These results suggest that arsenate-mediated reduction of systemic NO may be associated with the enzymatic uncoupling reaction of NOS with a subsequent enhancement of reactive oxygen species such as O-2(.-), an endothelium-derived vasoconstricting factor. Furthermore, hepatic levels of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), a cofactor for NOS, were markedly reduced in arsenate-exposed rabbits to 62% of control, while no significant change occurred in cardiac L-arginine levels. These results suggest that prolonged exposure of rabbits to oral arsenate may impair the bioavailability of BH4 in endothelial cells and, as a consequence, disrupt the balance between NO and O-2(.-) produced from endothelial NOS, such that enhanced free radicals are produced at the expense of NO. (C) 2003 Elsevier Inc.