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

J R Falck, U. Murali Krishna, Y. Krishna Reddy, P. Srinagesh Kumar, K. Malla Reddy, Sarah B. Hittner, Christine Deeter, Kamalesh K. Sharma, Kathryn M. Gauthier, William B. Campbell

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66 Scopus citations

Abstract

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 Δ8 double bond had full activity and potency. However, the analogs with only a Δ5 or Α11 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 Δ8 double bond, and a 14(S),15(R)-(cis)-epoxy group.

Original languageEnglish (US)
Pages (from-to)H337-H349
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume284
Issue number1 53-1
StatePublished - Jan 1 2003

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Keywords

  • Arachidonic acid
  • Cytochrome P-450
  • Endothelium-derived hyperpolarizing factor
  • Epoxyeicosatrienoic acid

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Falck, J. R., Krishna, U. M., Reddy, Y. K., Kumar, P. S., Reddy, K. M., Hittner, S. B., Deeter, C., Sharma, K. K., Gauthier, K. M., & Campbell, W. B. (2003). Comparison of vasodilatory properties of 14,15-EET analogs: Structural requirements for dilation. American Journal of Physiology - Heart and Circulatory Physiology, 284(1 53-1), H337-H349.