17R(18S)-EpETE is an oxylipin and a cytochrome P450 metabolite of eicosapentaenoic acid .1,217R(18S)-EpETE is an activator of large-conductance calcium-activated potassium (BKCa) channels, increasing the potassium current amplitude by 15-fold in isolated rat cerebral artery vascular smooth muscle cells (VSMCs) at +60 mV when used at a concentration of 50 nM.2It has negative chronotropic effects in isolated neonatal rat cardiomyocytes (NRCMs; EC50= ~1-2 nM) and prevents calcium-induced increases in the spontaneous beating of NRCMs.3,4 1.Schwarz, D., Kisselev, P., Ericksen, S.S., et al.Arachidonic and eicosapentaenoic acid metabolism by human CYP1A1: Highly steroselective formation of 17(R), 18(S)-epoxyeicosatetraenoic acidBiochem. Pharmacol.67(8)1445-1457(2004) 2.Lauterbach, B., Barbosa-Sicard, E., Wang, M.H., et al.Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activatorsHypertension39(2 Pt. 2)609-613(2002) 3.Falck, J.R., Wallukat, G., Puli, N., et al.17(R),18(S)-Epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: Structure-activity relationships and stable analoguesJ. Med. Chem.54(12)4109-4118(2011) 4.Arnold, C., Markovic, M., Blossey, K., et al.Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of omega-3 fatty acidsJ. Biol. Chem.285(43)32720-32733(2010)

Eicosapentaenoic acid is converted to epoxyeicosatetraenoic acids (EpETEs) by several cytochrome P450 isoforms. The major product of this epoxygenase pathway, (±)17(18)-EpETE , relaxes vascular and airway smooth muscle by activating large conductance Ca2+-activated K+ (BKCa) channels by directly interacting with BKα channel subunits. (±)8(9)-EpETE is an epoxygenase pathway product produced from EPA by CYP450 both in vitro and in vivo. The biological actions and physiological effects of this epoxide remain to be determined.

EDHF (endothelium-derived hyperpolarizing factor) is an unidentified mediator released from vascular endothelial cells in response to acetylcholine and bradykinin which is distinct from the NOS- (nitric oxide) and COX-derived (prostacyclin) vasodilators. Cytochrome P450 (CYP450) metabolism of polyunsaturated fatty acids, produces epoxides such as (±)14(15)-EpETrE which are prime candidates for the actual active mediator. However, the CYP450 metabolites of eicosapentaenoic acid and docosahexaenoic acid have been little studied relative to arachidonate epoxygenase metabolites. (±)14(15)-EpETE is the ω-3 homolog of 14(15)-EpETrE, derived via epoxidation of the 14,15-double bond of EPA. The EDHF activity of (±)14(15)-EpETE has not yet been determined.