title: Endothelium-Derived Hyperpolarization and Coronary Vasodilation: Diverse and Integrated Roles of Epoxyeicosatrienoic Acids, Hydrogen Peroxide, and Gap Junctions.
abstract: Myocardial perfusion and coronary vascular resistance are regulated by signaling metabolites released from the local myocardium that act either directly on the VSMC or indirectly via stimulation of the endothelium. A prominent mechanism of vasodilation is EDH of the arteriolar smooth muscle, with EETs and H(2)O(2) playing important roles in EDH in the coronary microcirculation. In some cases, EETs and H(2)O(2) are released as transferable hyperpolarizing factors (EDHFs) that act directly on the VSMCs. By contrast, EETs and H(2)O(2) can also promote endothelial KCa activity secondary to the amplification of extracellular Ca(2+) influx and Ca(2+) mobilization from intracellular stores, respectively. The resulting endothelial hyperpolarization may subsequently conduct to the media via myoendothelial gap junctions or potentially lead to the release of a chemically distinct factor(s). Furthermore, in human isolated coronary arterioles dilator signaling involving EETs and H(2)O(2) may be integrated, being either complimentary or inhibitory depending on the stimulus. With an emphasis on the human coronary microcirculation, this review addresses the diverse and integrated mechanisms by which EETs and H(2)O(2) regulate vessel tone and also examines the hypothesis that myoendothelial microdomain signaling facilitates EDH activity in the human heart.
authors.affiliation: Bristol Heart Institute, University of Bristol, Bristol, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Ellinsworth
authors.affiliation: Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Maroochydore, Queensland, Australia.
authors.forename: Shaun L
authors.initials: SL
authors.lastname: Sandow
authors.affiliation: Bristol Heart Institute, University of Bristol, Bristol, UK.
authors.forename: Nilima
authors.initials: N
authors.lastname: Shukla
authors.affiliation: Division of Research Infrastructure, National Center for Research Resources, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Bristol Heart Institute, University of Bristol, Bristol, UK.
authors.forename: Jamie Y
authors.initials: JY
authors.lastname: Jeremy
authors.affiliation: Division of Cardiovascular Medicine, Departments of Medicine, Physiology and Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D003331:Coronary Vessels / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D017629:Gap Junctions / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology*
chemical_list: D015777:Eicosanoids; D006861:Hydrogen Peroxide
keywords: Ca2+-activated K+ channels; NADPH oxidase; connexins; coronary artery disease; coronary blood flow; cytochrome P450 epoxygenases; endothelium-derived hyperpolarization; endothelium-derived hyperpolarizing factor; epoxyeicosatrienoic acids; gap junctions; human coronary microcirculation; hydrogen peroxide; mitochondrial electron transport chain; myoendothelial signaling microdomains; nitric oxide; transient receptor potential channels