title: H2O2-induced redox-sensitive coronary vasodilation is mediated by 4-aminopyridine-sensitive K+ channels.
abstract: Hydrogen peroxide (H(2)O(2)) 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 H(2)O(2). This hypothesis was tested by studying the effect of H(2)O(2) on coronary blood flow, isometric tension of arteries, and arteriolar diameter in the presence of K(+) channel antagonists. Infusing H(2)O(2) into the left anterior descending artery of anesthetized dogs increased coronary blood flow in a dose-dependent manner. H(2)O(2) relaxed left circumflex rings contracted with 1 muM U46619, a thromboxane A(2) mimetic, and dilated coronary arterioles pressurized to 60 cmH(2)O. Denuding the endothelium of coronary arteries and arterioles did not affect the ability of H(2)O(2) to cause vasodilation, suggesting a direct smooth muscle mechanism. Arterial and arteriolar relaxation by H(2)O(2) was reversed by 1 mM dithiothreitol, a thiol reductant. H(2)O(2)-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 H(2)O(2) was antagonized by 0.3 mM 4-AP but not 100 nM iberiotoxin, an inhibitor of Ca(2+)-activated K(+) channels. H(2)O(2)-induced increases in coronary blood flow were abolished by 3 mM 4-AP. Our data indicate H(2)O(2) 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.
authors.affiliation: Dept. of Physiology, Louisiana State Univ. Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, USA. proger@lsuhsc.edu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rogers
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dick
authors.forename: Jarrod D
authors.initials: JD
authors.lastname: Knudson
authors.forename: Marta
authors.initials: M
authors.lastname: Focardi
authors.forename: Ian N
authors.initials: IN
authors.lastname: Bratz
authors.forename: Albert N
authors.initials: AN
authors.lastname: Swafford
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Saitoh
authors.forename: Johnathan D
authors.initials: JD
authors.lastname: Tune
authors.forename: William M
authors.initials: WM
authors.lastname: Chilian
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010084:Oxidation-Reduction; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014665:Vasodilator Agents; D006861:Hydrogen Peroxide; D015761:4-Aminopyridine