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NADPH OXIDASE‐MEDIATED O 2 −· PRODUCTION AMPLIFIES VASOCONSTRICTOR RESPONSE OF SMALL CORONARY ARTERIES TO M 1 ‐MUSCARINIC RECEPTOR ACTIVATION
Author(s) -
Zhang Andrew Y,
Zhang Guo,
Li Victoria X.,
Teggatz Eric G.,
Li PinLan
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a723-a
Subject(s) - nadph oxidase , chemistry , acetylcholine , agonist , muscarinic acetylcholine receptor , medicine , intracellular , endocrinology , receptor , reactive oxygen species , biochemistry
The present study test the hypothesis that NADPH oxidase (Nox) mediated O 2 −· production amplifies coronary arterial constrictor response to M 1 ‐receptor (M 1 R) agonists. Fluorescence imaging analysis showed that M 1 R agonist, acetylcholine (Ach), simultaneously increased intracellular Ca 2+ and O 2 −· levels in bovine coronary arterial smooth muscle cells (CASMCs) with a maximal increase of 821 + 67 nM in Ca 2+ levels accompanied by 75% in O 2 −· production. However, when cells were transfected with siRNA of p47 phox (a key subunit for Nox activation), Ach‐induced increases in Ca 2+ and O 2 −· were significantly attenuated. Similarly, p47 phox siRNA significantly reduced oxotremorine (OXO)‐induced O 2 −· production in CASMCs by 67%. Functionally, OXO‐induced constrictor response of endothelium‐denuded small bovine coronary arteries was significantly reduced by Nox inhibitor, DPI or O 2 −· scavenger cocktail (tempol + catalase). Moreover, introduction of siRNA for p47 phox , NOX1 and NOX4 into arterial smooth muscle by ultrasound microbubble technology significantly blocked this OXO‐induced contraction. We concluded that Nox‐derived O 2 −· is involved in M 1 R‐mediated intracellular Ca 2+ release in CASMCs and thereby importantly contributes to amplification of vasoconstrictor response of coronary arteries to M 1 R activation (Supported by NIH grants HL057244, HL075316 and AHA predoctoral fellowship 0410061Z).