Superoxide does not mediate the acute vasoconstrictor effects of angiotensin II: a study in human and porcine arteries.
OBJECTIVE
To investigate whether superoxide mediates angiotensin (Ang) II-induced vasoconstriction.


METHODS
Human coronary arteries (HCAs), porcine femoral arteries (PFA) and porcine coronary arteries (PCAs) were mounted in organ baths and concentration-response curves to Ang II, the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) and the NAD(P)H oxidase substrate NADH were constructed in the absence and presence of superoxide inhibiting and activating drugs. Extracellular superoxide was measured using cytochrome c reduction.


RESULTS
Ang II constricted both HCAs and PFAs. In HCAs, the NAD(P)H inhibitors diphenyleneiodonium (DPI) and apocynin, and the xanthine oxidase (XO) inhibitor allopurinol, but not the superoxide dismutase (SOD) mimetic tempol or the SOD inhibitor diethyldithiocarbamate (DETCA), reduced this constriction. Catalase potentiated Ang II in HCAs, indicating a vasodilator role for H2O2. DPI, tempol and SOD did not affect Ang II in PFAs. DPI, apocynin and allopurinol relaxed preconstricted HCAs. Although the relaxant effects of the NO donor SNAP in PCAs was reduced by DETCA, indicating that superoxide-induced constrictions depend on NO inactivation, the apocynin-induced relaxations were NO independent. Moreover, NADH relaxed all vessels, and this effect was blocked by KCl but not DPI or NO removal. Xanthine plus XO also relaxed HCAs and PCAs. Incubation of human or porcine arteries with Ang II or NADH did not result in detectable increases of extracellular superoxide within 1 h.


CONCLUSIONS
Acute vasoconstriction by Ang II is not mediated via superoxide generated through NAD(P)H oxidase and/or XO activation. Such activation, if occurring, rather results in the generation of the vasodilator H2O2.
Schuijt
Martin P
MP
Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
Tom
Beril
B
de Vries
René
R
Saxena
Pramod R
PR
Sluiter
Wim
W
van Kats
Jorge P
JP
Danser
A H
AH
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000098:Acetophenones / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000804:Angiotensin II / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002395:Catecholamines / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D048288:Imidazolines; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009243:NAD / Q000494:pharmacology; D009249:NADP / Q000494:pharmacology; D009599:Nitroprusside / Q000008:administration & dosage; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism / Q000494:pharmacology*; D013552:Swine; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D000098:Acetophenones; D002395:Catecholamines; D003497:Cyclic N-Oxides; D018491:Dopamine Agonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D048288:Imidazolines; D016877:Oxidants; D013113:Spin Labels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009243:NAD; D013481:Superoxides; D000804:Angiotensin II; D009599:Nitroprusside; D009249:NADP; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D026423:S-Nitroso-N-Acetylpenicillamine; C056165:acetovanillone; C011775:(3,4-dihydroxyphenylamino)-2-imidazoline; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; C001803:tempol