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H₂O₂-induced redox-sensitive coronary vasodilation is mediated by 4-aminopyridine-sensitive K⁺ channels

¹Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and ²Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 16 February 2006 ; accepted in final form 30 May 2006

Hydrogen peroxide (H₂O₂) is a proposed endothelium-derived hyperpolarizing factor and metabolic vasodilator of the coronary circulation, but its mechanisms of action on vascular smooth muscle remain unclear. Voltage-dependent K⁺ (K_V) channels sensitive to 4-aminopyridine (4-AP) contain redox-sensitive thiol groups and may mediate coronary vasodilation to H₂O₂. 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 K⁺ channel antagonists. 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 [GenBank] , a thromboxane A₂ mimetic, and dilated coronary arterioles pressurized to 60 cmH₂O. Denuding the endothelium of coronary arteries and arterioles 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 tetraethylammonium, a nonselective inhibitor of K⁺ channels, and 3 mM 4-AP. Dilation of arterioles by H₂O₂ was antagonized by 0.3 mM 4-AP 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. Furthermore, we suggest 4-AP-sensitive K⁺ channels, or regulating proteins, serve as redox-sensitive elements controlling coronary blood flow.

reactive oxygen species; peroxides; sulfhydryl compounds; iberiotoxin; delayed rectifier potassium channels; coronary circulation

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