title: Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BK(Ca) channels: implications for soluble epoxide hydrolase inhibition.
abstract: Epoxyeicosatrienoic acids (EETs) are metabolized by soluble epoxide hydrolase (sEH) to form dihydroxyeicosatrienoic acids (DHETs) and are putative endothelium-derived hyperpolarizing factors (EDHFs). EDHFs modulate microvascular tone; however, the chemical identity of EDHF in the human coronary microcirculation is not known. We examined the capacity of EETs, DHETs, and sEH inhibition to affect vasomotor tone in isolated human coronary arterioles (HCAs). HCAs from right atrial appendages were prepared for videomicroscopy and immunohistochemistry. In vessels preconstricted with endothelin-1, three EET regioisomers (8,9-, 11,12-, and 14,15-EET) each induced a concentration-dependent dilation that was sensitive to blockade of large-conductance Ca2+-activated K+ (BK(Ca)) channels by iberiotoxin. EET-induced dilation was not altered by endothelial denudation. 8,9-, 11,12-, and 14,15-DHET also dilated HCA via activation of BK(Ca) channels. Dilation was less with 8,9- and 14,15-DHET but was similar with 11,12-DHET, compared with the corresponding EETs. Immunohistochemistry revealed prominent expression of cytochrome P-450 (CYP450) 2C8, 2C9, and 2J2, enzymes that may produce EETs, as well as sEH, in HCA. Inhibition of sEH by 1-cyclohexyl-3-dodecylurea (CDU) enhanced dilation caused by 14,15-EET but reduced dilation observed with 11,12-EET. DHET production from exogenous EETs was reduced in vessels pretreated with CDU compared with control, as measured by liquid chromatography electrospray-ionization mass spectrometry. In conclusion, EETs and DHETs dilate HCA by activating BK(Ca) channels, supporting a role for EETs/DHETs as EDHFs in the human heart. CYP450s and sEH may be endogenous sources of these compounds, and sEH inhibition has the potential to alter myocardial perfusion, depending on which EETs are produced endogenously.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Larsen
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miura
authors.forename: Ossama A
authors.initials: OA
authors.lastname: Hatoum
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
mesh_terms: D000368:Aged; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D015777:Eicosanoids / Q000378:metabolism / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D012995:Solubility; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015777:Eicosanoids; D051036:Large-Conductance Calcium-Activated Potassium Channels; D014665:Vasodilator Agents; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D004851:Epoxide Hydrolases