Journal
CIRCULATION RESEARCH
Volume 108, Issue 5, Pages 566-U64Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.110.237636
Keywords
coronary arterioles; shear stress; reactive oxygen species
Funding
- NIH [R01 HL080704, R01 HL094971]
- Veterans Administration
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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 endothelium-denuded 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 Ca2+-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 iberiotoxin-or 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.)
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