A potential mechanism for the impairment of nitric oxide formation caused by prolonged oral exposure to arsenate in rabbits.
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 (H(2)O(2)) (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 (O2(.-)) 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 O2(.-), an endothelium-derived vasoconstricting factor. Furthermore, hepatic levels of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH(4)), 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 BH(4) in endothelial cells and, as a consequence, disrupt the balance between NO and O2(.-) produced from endothelial NOS, such that enhanced free radicals are produced at the expense of NO.
Pi
Jingbo
J
Graduate School Doctoral Program in Medical Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. yk-em-tu@md.tsukuba.ac.jp
Horiguchi
Satomi
S
Sun
Yang
Y
Nikaido
Masatoshi
M
Shimojo
Nobuhiro
N
Hayashi
Toshio
T
Yamauchi
Hiroshi
H
Itoh
Ken
K
Yamamoto
Masayuki
M
Sun
Guifan
G
Waalkes
Michael P
MP
Kumagai
Yoshito
Y
D000109:Acetylcholine / Q000494:pharmacology; D000284:Administration, Oral; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001149:Arsenates / Q000008:administration & dosage / Q000633:toxicity*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000652:urine; D007213:Indomethacin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009520:New Zealand; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D011817:Rabbits; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013723:Teratogens / Q000633:toxicity*; D014665:Vasodilator Agents / Q000494:pharmacology; D014867:Water; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D001149:Arsenates; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007476:Ionophores; D009861:Onium Compounds; D013723:Teratogens; D014665:Vasodilator Agents; D014867:Water; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D000001:Calcimycin; D000493:Allopurinol; C007517:diphenyleneiodonium; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; C003402:sapropterin; D006152:Cyclic GMP; C025657:arsenic acid; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin