Faculty Collaboration Database

14,15-EET analogs: characterization of structural requirements for agonist and antagonist activity in bovine coronary arteries. Pharmacol Res 2004 Jun;49(6):515-24

Date

03/18/2004

Pubmed ID

15026029

DOI

10.1016/j.phrs.2003.09.014

Scopus ID

2-s2.0-1542512379 (requires institutional sign-in at Scopus site)   55 Citations

Abstract

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.

Author List

Gauthier KM, Falck JR, Reddy LM, Campbell WB

Author

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

8,11,14-Eicosatrienoic Acid
Animals
Cattle
Coronary Vessels
Dose-Response Relationship, Drug
In Vitro Techniques
Muscle, Smooth, Vascular
Structure-Activity Relationship
Vasodilation