Fig. 1.

Mechanisms of epoxyeicosatrienoic acid (EET) synthesis and transferable endothelium-derived hyperpolarizing factor (EDHF) action. Endothelial stimulus can result in arachidonic acid (AA) and other lipid substrate-mediated cytochrome P450 (CYP)-dependent synthesis and release of EETs, which are transferred across the internal elastic lamina (IEL) where they induce smooth muscle hyperpolarization directly and potentially via large conductance Ca²⁺-activated K⁺ channels (BK_Ca) and/or an EETs-receptor(R)-mediated mechanism. In specific vessels, EETs activate smooth muscle (SMC) vanilloid type 4 transient receptor potential channels (TRPV4) to induce Ca²⁺ influx that in turn activates sarcoplasmic reticulum (SR) ryanodine receptors (RyRs) to induce spatially localized Ca²⁺ sparks, thereby initiating hyperpolarizing BK_Ca activity, or, alternatively, via binding to the putative EET(R) which induces BK_Ca activity via a potential Gαs coupled mechanism. ER endoplasmic reticulum, IP₃ inositol 1,4,5-trisphosphate, PLA₂ phospholipase A₂, PLC phospholipase C