title: The effect of inorganic arsenic on endothelium-dependent relaxation: role of NADPH oxidase and hydrogen peroxide.
abstract: Chronic arsenic ingestion predisposes to vascular disease, but underlying mechanisms are poorly understood. In the present study we have analyzed the effects of short-term arsenite exposure on vascular function and endothelium-dependent relaxation. Endothelium-dependent relaxations, nitric oxide (NO) and endothelium derived hyperpolarizing factor (EDHF)-type, were studied in rabbit iliac artery and aortic rings using the G protein-coupled receptor agonist acetylcholine (ACh) and by cyclopiazonic acid (CPA), which promotes store-operated Ca(2+) entry by inhibiting the endothelial SERCA pump. Production of reactive oxygen species (ROS) in the endothelium of rabbit aortic valve leaflets and endothelium-denuded RIA and aortic rings was assessed by imaging of dihydroethidium. In the iliac artery, exposure to 100 μM arsenite for 30 min potentiated EDHF-type relaxations evoked by both CPA and ACh. Potentiation was prevented by catalase, the catalase/superoxide dismutase mimetic manganese porphyrin and the NADPH oxidase inhibitor apocynin. By contrast in aortic rings, that exhibited negligible EDHF-type responses, endothelium-dependent NO-mediated relaxations evoked by CPA and ACh were unaffected by arsenite. Arsenite induced apocynin-sensitive increases in ROS production in the aortic valve endothelium, but not in the media and adventitia of the iliac artery and aorta. Our results suggest that arsenite can potentiate EDHF-type relaxations via a mechanism that is dependent on hydrogen peroxide, thus demonstrating that dismutation of the superoxide anion generated by NADPH oxidase can potentially offset loss of NO bioavailability under conditions of reduced eNOS activity. By contrast, selective increases in endothelial ROS production following exposure to arsenite failed to modify relaxations mediated by endogenous NO.
authors: Ionic Cell Signalling Group, Wales Heart Research Institute, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. edwardsdh@cardiff.ac.uk
authors: David H
authors: DH
authors: Edwards
authors: Yiwen
authors: Y
authors: Li
authors: David C
authors: DC
authors: Ellinsworth
authors: Tudor M
authors: TM
authors: Griffith
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D001685:Biological Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007083:Iliac Artery / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D018613:Microscopy, Confocal; D019255:NADPH Oxidases / Q000378:metabolism*; D011817:Rabbits; D017670:Sodium Compounds / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D018053:Arsenites; D001685:Biological Factors; D007211:Indoles; D017670:Sodium Compounds; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; C017947:sodium arsenite; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D000109:Acetylcholine; C000543:cyclopiazonic acid
references: Circ Res. 2011 Mar 4;108(5):566-73
references: 21233456
references: Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H93-100
references: 17040967
references: Biol Trace Elem Res. 2010 Oct;137(1):96-109
references: 19943121
references: Biochem Biophys Res Commun. 2002 Jan 25;290(3):909-13
references: 11798159
references: Trends Cardiovasc Med. 2008 Jan;18(1):15-9
references: 18206804
references: J Biol Chem. 2005 Feb 4;280(5):3875-84
references: 15492012
references: Toxicology. 2002 Dec 27;181-182:211-7
references: 12505313
references: Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1368-76
references: 21415386
references: Eur J Pharmacol. 2000 Mar 31;392(3):163-73
references: 10762670
references: J Clin Invest. 2008 Dec;118(12):3980-9
references: 19033667
references: Blood. 1999 Sep 15;94(6):2102-11
references: 10477740
references: J Cell Biol. 2008 Jun 30;181(7):1129-39
references: 18573911
references: Hypertension. 2008 Feb;51(2):211-7
references: 18086956
references: Am J Physiol Cell Physiol. 2007 Jan;292(1):C413-22
references: 16971501
references: Br J Pharmacol. 1997 Jun;121(4):711-6
references: 9208138
references: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14483-8
references: 9405639
references: Environ Health Perspect. 2003 Apr;111(4):513-7
references: 12676608
references: Circ Res. 2001 May 11;88(9):888-94
references: 11348997
references: Toxicol Sci. 2009 Feb;107(2):312-23
references: 19015167
references: Toxicol Sci. 2008 Apr;102(2):207-18
references: 17947343
references: Free Radic Biol Med. 1999 Dec;27(11-12):1405-12
references: 10641735
references: Free Radic Biol Med. 2003 Jul 1;35(1):102-13
references: 12826260
references: Clin Sci (Lond). 2005 Sep;109(3):217-26
references: 16104842
references: Cardiovasc Toxicol. 2009 Dec;9(4):169-76
references: 19787300
references: Pharmacol Res. 2004 Jun;49(6):551-64
references: 15026033
references: Am J Physiol Lung Cell Mol Physiol. 2001 Mar;280(3):L442-9
references: 11159027
references: J Biol Chem. 2000 May 26;275(21):15749-57
references: 10747906
references: Br J Pharmacol. 2005 Jan;144(1):108-14
references: 15644874
references: Arch Biochem Biophys. 1997 Nov 15;347(2):256-62
references: 9367533
references: Circ Res. 2002 Jun 14;90(11):1205-13
references: 12065324
references: Proc Natl Acad Sci U S A. 2005 May 10;102(19):7008-13
references: 15867155
references: Cardiovasc Res. 2009 Dec 1;84(3):470-8
references: 19592569
references: Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):653-61
references: 19910640
references: Arterioscler Thromb Vasc Biol. 2009 May;29(5):739-45
references: 19213944
references: Free Radic Biol Med. 2008 Nov 1;45(9):1340-51
references: 18760347
references: Eur J Pharmacol. 2012 Jan 15;674(2-3):384-90
references: 22154756
references: Circ Res. 2007 Apr 13;100(7):1016-25
references: 17363703
references: Free Radic Biol Med. 2010 Apr 15;48(8):983-1001
references: 20116425
references: Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1774-81
references: 18669883
references: Hypertension. 2008 Feb;51(2):172-4
references: 18086948
references: Cardiovasc Res. 1987 Aug;21(8):565-8
references: 3502252
references: Cardiovasc Res. 2009 Nov 1;84(2):218-26
references: 19592567
references: J Clin Invest. 2003 Apr;111(8):1201-9
references: 12697739