Integrative Physiology H2O2 Is the Transferrable Factor Mediating Flow-Induced Dilation in Human Coronary Arterioles

Rationale: Endothelial derived hydrogen peroxide (H2O2) is a necessary component of the pathway regulating flow-mediated dilation (FMD) in human coronary arterioles (HCAs). However, H2O2 has never been shown to be the endothelium-dependent transferrable hyperpolarization factor (EDHF) in response to shear stress. Objective: We examined the hypothesis that H2O2 serves as the EDHF in HCAs to shear stress. Methods and Results: Two HCAs were cannulated in series (a donor intact vessel upstream and endotheliumdenuded detector vessel downstream). Diameter changes to flow were examined in the absence and presence of polyethylene glycol catalase (PEG-CAT). The open state probability of large conductance Ca -activated K (BKCa) channels in smooth muscle cells downstream from the perfusate from an endothelium-intact arteriole was examined by patch clamping. In some experiments, a cyanogen bromide–activated resin column bound with CAT was used to remove H2O2 from the donor vessel. When flow proceeds from donor to detector, both vessels dilate (donor: 68 7%; detector: 45 11%). With flow in the opposite direction, only the donor vessel dilates. PEG-CAT contacting only the detector vessel blocked FMD in that vessel (6 4%) but not in donor vessel (61 13%). Paxilline inhibited dilation of endothelium-denuded HCAs to H2O2. Effluent from donor vessels elicited K channel opening in an iberiotoxinor PEG-CAT–sensitive fashion in cell-attached patches but had little effect on channel opening on inside-out patches. Vasodilation of detector vessels was diminished when exposed to effluent from CAT-column. Conclusions: Flow induced endothelial production of H2O2, which acts as the transferrable EDHF activating BKCa channels on the smooth muscle cells. (Circ Res. 2011;108:566-573.)