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1 Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
2 Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States
3 Physiology, Louisiana State University Health Sciences Center, New Orleans, United States
4 Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, United States
* To whom correspondence should be addressed. E-mail: parogers{at}bcm.tmc.edu.
Hydrogen peroxide (H2O2) is a proposed endothelium-derived hyperpolarizing factor and metabolic vasodilator of the coronary circulation; however, mechanisms of H2O2 action on vascular smooth muscle remain unclear. Because 4-aminopyridine (4-AP) sensitive KV channels reportedly contain redox sensitive thiol groups, which are likely targets for H2O2, we reasoned these K+ channels may mediate dilation to this reactive oxygen species. This hypothesis was tested by studying the effect of H2O2 on coronary blood flow, isometric tension of arteries, and arteriolar diameter in the presence of specific and nonspecific K+ channel antagonists. We also established that H2O2 produced dilation via thiol oxidation with the thiol reductant dithiothreitol. Infusing H2O2 into the left anterior descending artery of anesthetized dogs increased coronary blood flow in a dose-dependent manner. H2O2 relaxed left circumflex rings contracted with 1 µM U46619, a thromboxane A2 mimetic, and dilated coronary arterioles pressurized to 60 cmH2O. Denuding the endothelium of coronary arteries and arterioles as well as addition of the cyclooxygenase inhibitor, indomethacin, did not affect the ability of H2O2 to cause vasodilation, suggesting a direct smooth muscle mechanism. Arterial and arteriolar relaxation by H2O2 was reversed by 1 mM dithiothreitol, a thiol reductant. H2O2-induced relaxation was abolished in rings contracted with 60 mM K+, and by 10 mM TEA and 3 mM 4-AP. Dilation of arterioles by H2O2 was antagonized by 0.3 mM 4-AP, an inhibitor of voltage-dependent K+ channels, but not 100 nM iberiotoxin, an inhibitor of Ca2+-activated K+ channels. H2O2-induced increases in coronary blood flow were abolished by 3 mM 4-AP. Our data indicate H2O2 increases coronary blood flow by acting directly on vascular smooth muscle. Further, we suggest 4-AP-sensitive K+ channels, or proteins that regulate them, serve as redox-sensitive elements controlling coronary blood flow.
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