Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BK_Cachannels: 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.

Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function

“…19 The recent development of sEH inhibitors has helped to determine the physiological consequences of enhanced CYP activity and EET formation. Inhibitors of this enzyme enhance iberiotoxin-sensitive, EETinduced vasodilator responses in isolated human coronary arterioles, 20 highlighting the potential relevance of this pathway in humans. The latter observation is, however, controversial, and the bradykinin-induced relaxation of human small coronary arteries (diameter Ϸ300 m) has also been recently described as depending on the activation of guanylyl cyclase, inwardly rectifying K ϩ channels, and the Na…”

11,12-Epoxyeicosatrienoic acid induces vasodilator response in the rat perfused mesenteric vasculature

“…Activation of large‐conductance calcium‐activated K + channels (BK ca ) has been suggested to play a role in vasodilation induced by EETs 31, 32. Iberiotoxin, a selective and reversible inhibitor of high‐conductance calcium‐activated potassium channel (BK ca inhibitor), could not block the vasodilator effect produced by 11, 12‐EET in the mesenteric vasculature.…”

“…Campbell et al 35. and Larsen et al 31. demonstrated that 20%‐30% of the 14, 15‐EET‐induced relaxation of coronary artery is resistant to the specific BK ca channel blocker iberiotoxin.…”

Potentiation of EDHF-mediated relaxation by chloride channel blockers

“…In addition, EETs may also stimulate vanilloid transient receptor potential channels 4 [44] , which increase Ca 2+ influx, and subsequently activate BK Ca channels in vascular smooth muscle cells. However, it has been demonstrated that around onethird of the 14,15-EET-induced relaxation of coronary artery is resistant to BK Ca channel blocker [45,46] . It clearly indicates that other ion channels may be involved in EETs-induced relaxation.…”