on May 22, 2003
Published online before print May 22, 2003, doi: 10.1161/01.ATV.0000078601.79536.6C
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Submitted on February 27, 2003
Accepted on May 13, 2003
Electron Spin Resonance Detection of Hydrogen Peroxide as an Endothelium-Derived Hyperpolarizing Factor in Porcine Coronary Microvessels
Tetsuya Matoba ;
From the Department of Cardiovascular Medicine (T.M., H.S., K.M., H.K., I.K., L.U.-H., Y.M., Y.H., A.T.), Kyushu University Graduate School of Medical Sciences, Fukuoka, and the Department of Microbiology (T.A.), Kumamoto University School of Medicine, Kumamoto, Japan.
* To whom correspondence should be addressed. E-mail: shimo{at}cardiol.med.kyushu-u.ac.jp.
Objective--Endothelium-derived hyperpolarizing factor (EDHF) plays an important role in modulating vascular tone, especially in microvessels, although its nature has yet to be elucidated. This study was designed to examine whether hydrogen peroxide (H2O2) is an EDHF in porcine coronary microvessels with use of an electron spin resonance (ESR) method to directly detect H2O2 production from the endothelium.
Methods and Results--Isometric tension and membrane-potential recordings demonstrated that bradykinin and substance P caused EDHF-mediated relaxations and hyperpolarizations of porcine coronary microvessels in the presence of indomethacin and Nw-nitro-L-arginine. The contribution of H2O2 to the EDHF-mediated responses was demonstrated by the inhibitory effect of catalase and by the relaxing and hyperpolarizing effects of exogenous H2O2. Endothelial production of H2O2 was quantified in bradykinin- or substance P-stimulated intact blood vessels by ESR spectroscopy. Tiron, a superoxide scavenger that facilitates H2O2 formation, enhanced bradykinin-induced production of H2O2, as well as the EDHF-mediated relaxations and hyperpolarizations. By contrast, cytochrome P-450 inhibitors (sulfaphenazole or 17-octadecynoic acid) or a gap junction inhibitor (18
-glycyrrhetinic acid) failed to inhibit the EDHF-mediated relaxations. Involvement of endothelium-derived K+ was not evident in experiments with ouabain plus Ba2+ or exogenous K+.
Conclusion--These results provide ESR evidence that H2O2 is an EDHF in porcine coronary microvessels.
Key words: endothelium • endothelium-derived hyperpolarizing factor • hydrogen peroxide • membrane potential
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