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Am J Physiol Heart Circ Physiol (September 19, 2002). doi:10.1152/ajpheart.00831.2001
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Articles in PresS, published online ahead of print September 19, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00831.2001
Submitted on September 21, 2001
Accepted on September 3, 2002

Comparison of the Vasodilatory Properties of 14,15-EET Analogs: Structural Requirements for Dilation

John 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*

1 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA
2 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA

* To whom correspondence should be addressed. E-mail: wbcamp{at}mcw.edu.

Epoxyeicosatrienoic acids (EETs) are endothelial-derived vasodilators. In vascular smooth muscle cells, the EETs activate large-conductance, calcium-activated potassium (KCa ) channels, hyperpolarize the membrane and cause relaxation. Since 14,15-, 11,12-, 8,9- and 5,6-EET are equipotent in relaxing the coronary artery, we wondered what are the structural requirements for biological activity. We tested the effect of a series of 19 analogs of 14,15-EET on vascular tone to determine the portions of the 14,15-EET molecule required for activity. 14,15-EET relaxed the U46619-precontracted bovine coronary arterial rings in a concentration-related manner with an ED50 of approximately 10 -6M. Changing the carbon-1 carboxyl group to an alcohol resulted in loss of activity while 14,15-EET-methyl ester and 14,15-EET-methylsulfonimide retained full activity. Shortening the distance between 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 the {Delta}8 double bonds had full activity and potency. However, the analogs with only a {Delta}5 or {Delta}11 double bond had reduced potency. Conversion of the 14,15-epoxy group to a sulfur (14,15-thiirane) or nitrogen (14,15-aziridine) resulted in a 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. 14,15-DHET, the hydrolysis product of 14,15-EET, relaxed the coronary artery but was approximately 5-fold less potent than 14,15-EET. These studies indicate that specific structural features of the 14,15-EET molecule are required for relaxation of the bovine coronary artery. These features include an acidic group at carbon-1, a {Delta}8 double bond and a 14(S),15(R)-(cis)-epoxy group.




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