11(R),12(S),15(S)-trihydroxyeicosa-5(Z),8(Z),13(E)-trienoic acid: An endothelium-derived 15-lipoxygenase metabolite that relaxes rabbit aorta

Kathryn M. Gauthier, Yuttana Chawengsub, Daniel H. Goldman, Raymond E. Conrow, Siddam Anjaiah, J. R. Falck, William B. Campbell

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18 Scopus citations


Previous studies indicate that 11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA), an endothelium-derived hyperpolarizing factor in the rabbit aorta, mediates a portion of the relaxation response to acetylcholine by sequential metabolism of arachidonic acid by 15-lipoxygenase, hydroperoxide isomerase, and epoxide hydrolase. To determine the stereochemical configuration of the endothelial 11,12,15-THETA, its activity and chromatographic migration were compared with activity and migration of eight chemically synthesized stereoisomers of 11,12,15(S)-THETA. Of the eight isomers, only 11(R),12(S),15(S)-trihydroxyeicosa-5(Z),8(Z),13(E)-trienoic acid comigrated with the biological 11,12,15-THETA on reverse- and normal-phase HPLC and gas chromatography. The same THETA isomer (10-7-10-4 M) relaxed the rabbit aorta in a concentration-related manner (maximum relaxation = 69 ± 5%). These relaxations were blocked by apamin (10-7 M), an inhibitor of small-conductance Ca2+-activated K+ channels. In comparison, 11(S),12(R),15(S),5(Z),8(Z),13(E)-THETA (10-4 M) relaxed the aorta by 22%. The other six stereoisomers were inactive in this assay. With use of the whole cell patch-clamp technique, it was shown that 10-4 M 11(R),12(S),15(S),5(Z), 8(Z),13(E)-THETA increased outward K+ current in isolated aortic smooth muscle cells by 119 ± 36% at +60 mV, whereas 10-4 M 11(R),12(R),15(S),5(Z),8(Z),13(E)-THETA increased outward K+ current by only 20 ± 2%. The 11(R),12(S),15(S),5(Z) ,8(Z),13(E)-THETA-stimulated increase in K+ current was blocked by pretreatment with apamin. These studies suggest that 11(R),12(S),15(S)- trihydroxyeicosa-5(Z),8(Z),13(E)-trienoic acid is the active stereoisomer produced by the rabbit aorta. It relaxes smooth muscle by activating K + channels. The specific structural and stereochemical requirements for K+ channel activation suggest that a specific binding site or receptor of 11,12,15-THETA is involved in these actions.

Original languageEnglish (US)
Pages (from-to)H1467-14H72
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number3
StatePublished - Mar 2008


  • Arachidonic acid
  • Endothelium-derived hyperpolarizing factor
  • Potassium channels
  • Smooth muscle cells

ASJC Scopus subject areas

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


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