Clinical/Translational Research H2O2-Induced Dilation in Human Coronary Arterioles: Role of Protein Kinase G Dimerization and Large-Conductance Ca -Activated K Channel Activation

Rationale: Hydrogen peroxide (H2O2) serves as a key endothelium-derived hyperpolarizing factor mediating flowinduced dilation in human coronary arterioles (HCAs). The precise mechanisms by which H2O2 elicits smooth muscle hyperpolarization are not well understood. An important mode of action of H2O2 involves the oxidation of cysteine residues in its target proteins, including protein kinase G (PKG)-I , thereby modulating their activities. Objective: Here we hypothesize that H2O2 dilates HCAs through direct oxidation and activation of PKG-I leading to the opening of the large-conductance Ca -activated K (BKCa) channel and subsequent smooth muscle hyperpolarization. Methods and Results: Flow and H2O2 induced pressure gradient/concentration-dependent vasodilation in isolated endothelium-intact and -denuded HCAs, respectively. The dilation was largely abolished by iberiotoxin,