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Am J Physiol Heart Circ Physiol 284: H337-H349, 2003. First published September 19, 2002; doi:10.1152/ajpheart.00831.2001
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Vol. 284, Issue 1, H337-H349, January 2003

Comparison of vasodilatory properties of 14,15-EET analogs: structural requirements for dilation

J. R. Falck1, U. Murali Krishna1, Y. Krishna Reddy1, P. Srinagesh Kumar1, K. Malla Reddy1, Sarah B. Hittner2, Christine Deeter2, Kamalesh K. Sharma1, Kathryn M. Gauthier2, and William B. Campbell2

2 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and 1 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Epoxyeicosatrienoic acids (EETs) are endothelium-derived eicosanoids that activate potassium channels, hyperpolarize the membrane, and cause relaxation. We tested 19 analogs of 14,15-EET on vascular tone to determine the structural features required for activity. 14,15-EET relaxed bovine coronary arterial rings in a concentration-related manner (ED50 = 10-6 M). Changing the carboxyl to an alcohol eliminated dilator activity, whereas 14,15-EET-methyl ester and 14,15-EET-methylsulfonimide retained full activity. Shortening the distance between the carboxyl and epoxy groups reduced the agonist potency and activity. Removal of all three double bonds decreased potency. An analog with a Delta 8 double bond had full activity and potency. However, the analogs with only a Delta 5 or Delta 11 double bond had reduced potency. Conversion of the epoxy oxygen to a sulfur or nitrogen resulted in loss of activity. 14(S),15(R)-EET was more potent than 14(R),15(S)-EET, and 14,15-(cis)-EET was more potent than 14,15-(trans)-EET. These studies indicate that the structural features of 14,15-EET required for relaxation of the bovine coronary artery include a carbon-1 acidic group, a Delta 8 double bond, and a 14(S),15(R)-(cis)-epoxy group.

endothelium-derived hyperpolarizing factor; cytochrome P-450; arachidonic acid; epoxyeicosatrienoic acid


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