TY - JOUR
T1 - H2O2-induced redox-sensitive coronary vasodilation is mediated by 4-aminopyridine-sensitive K+ channels
AU - Rogers, Paul A.
AU - Dick, Gregory M.
AU - Knudson, Jarrod D.
AU - Focardi, Marta
AU - Bratz, Ian N.
AU - Swafford, Albert N.
AU - Saitoh, Shu Ichi
AU - Tune, Johnathan D.
AU - Chilian, William M.
PY - 2006
Y1 - 2006
N2 - 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+ (KV) 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, 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 H 2O2 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.
AB - 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+ (KV) 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, 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 H 2O2 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.
KW - Coronary circulation
KW - Delayed rectifier potassium channels
KW - Iberiotoxin
KW - Peroxides
KW - Reactive oxygen species
KW - Sulfhydryl compounds
UR - http://www.scopus.com/inward/record.url?scp=33751190977&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00172.2006
DO - 10.1152/ajpheart.00172.2006
M3 - Article
C2 - 16751285
AN - SCOPUS:33751190977
SN - 0363-6135
VL - 291
SP - H2473-H2482
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 5
ER -