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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/H1467    most recent 01052.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Gauthier, K. M. Articles by Campbell, W. B. PubMed PubMed Citation Articles by Gauthier, K. M. Articles by Campbell, W. B.

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

¹Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; ²Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, and ³Chemical Preparations Research, Alcon Research, Ltd., Fort Worth, Texas

Submitted 11 September 2007 ; accepted in final form 16 January 2008

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.

endothelium-derived hyperpolarizing factor; smooth muscle cells; potassium channels; arachidonic acid

This article has been cited by other articles:

				Y. Chawengsub, N. T. Aggarwal, K. Nithipatikom, K. M. Gauthier, S. Anjaiah, B. D. Hammock, J. R. Falck, and W. B. Campbell Identification of 15-hydroxy-11,12-epoxyeicosatrienoic acid as a vasoactive 15-lipoxygenase metabolite in rabbit aorta Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1348 - H1356. [Abstract] [Full Text] [PDF]