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1 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
2 Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
3 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
4 Department of Entomology and Cancer Research Center, University of California Davis, Davis, California, USA
5 Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA
6 Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
7 Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Veterans Administration Medical Center, Milwaukee, Wisconsin, USA
* To whom correspondence should be addressed. E-mail: dgutt{at}mcw.edu.
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 (HCA). 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-) each induced a concentration-dependent dilation that was sensitive to blockade of large-conductance Ca2+-activated K+ (BKCa) 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 BKCa channels. Dilation was less with 8,9- and 14,15-DHET, but was similar with 11,12-DHET, compared to the corresponding EETs. Immunohistochemistry revealed prominent expression of cytochrome P450 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 to control, as measured by liquid chromatography electrospray-ionization mass spectrometry. In conclusion, EETs and DHETs dilate HCA by activating BKCa 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.
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