Arachidonic acid metabolites contribute to the regulation of vascular tone and 
therefore tissue blood flow. The vascular endothelium metabolizes arachidonic 
acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs. The 
placement of the epoxide group can occur on any of the double bonds of 
arachidonic acid resulting in four EET regioisomers; 5,6-, 8,9-, 11,12- and 
14,15-EET. In the vasculature, EETs are key components of cellular signaling 
cascades that culminate in the activation of smooth muscle potassium channels to 
induce membrane hyperpolarization and vascular relaxation. In some vasculatures 
such as bovine coronary arteries, EET regioisomers are equipotent in inducing 
relaxations, while in other arteries, a specific EET regioisomer induces 
relaxation while others do not. Therefore, the position of the double bonds 
and/or the epoxide group may alter vascular agonist activity. This observation 
suggests that small alterations in the chemical structure of EETs can 
significantly impact vascular activity. To explore this hypothesis, we 
synthesized a series of EET analogs and characterized their vasodilator agonist 
and antagonist activity in bovine coronary arteries. In this chapter, we first 
review the mechanisms of EET-dependent relaxations in bovine coronary arteries 
to familiarize the reader with the role of EETs in these arteries. The second 
component is a synopsis of the functional characterization of the 14,15-EET 
analogs and the resulting description of structural components required for 
vascular dilator activity. Lastly, we discussed the characterization of three 
14,15-EET analogs with specific EET-antagonist activity and compared this to the 
activity of similar 11,12-EET analogs. These studies have revealed that specific 
structural components of the 14,15-EET molecule are critical for dilator 
activity and that alteration of these components influences agonist activity and 
may confer antagonist properties.