| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Milwaukee, Wisconsin, United States; Chemical Preparations Research, Alcon Research, Ltd., Fort Worth, Texas, United States
3 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States; Milwaukee, Wisconsin, United States
4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States
5 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee,, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: kgauth{at}mcw.edu.
Previous studies indicate that 11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA) is an endothelium-derived hyperpolarizing factor in the rabbit aorta and mediates a portion of the relaxation response to acetylcholine. It is formed 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 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 phase-HPLC, 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, calcium-activated potassium channels. In comparison, 11(S),12(R),15(S),5(Z),8(Z),13(E)-THETA relaxed the aorta by 22% at 10-4 M. The other six stereoisomers were inactive in this assay. Using whole cell patch clamp, 11(R),12(S),15(S),5(Z),8(Z),13(E)-THETA (10-4 M) increased outward potassium current in isolated aortic smooth muscle cells by 119 ± 36% at +60 mV while 11(R),12(R),15(S),5(Z),8(Z),13(E)-THETA (10-4 M) increased current by only 20 ± 2%. The 11(R),12(S),15(S),5(Z),8(Z),13(E)-THETA-stimulated increase in potassium 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 potassium channels. The specific structural and stereochemical requirements for potassium channel activation suggest that 11,12,15-THETA has a specific binding site or receptor involved in these actions.
This article has been cited by other articles:
|
|
 |
|
  Y. Chawengsub, K. M. Gauthier, K. Nithipatikom, B. D. Hammock, J. R. Falck, D. Narsimhaswamy, and W. B. Campbell Identification of 13-Hydroxy-14,15-epoxyeicosatrienoic Acid as an Acid-stable Endothelium-derived Hyperpolarizing Factor in Rabbit Arteries J. Biol. Chem., November 6, 2009; 284(45): 31280 - 31290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chawengsub, K. M. Gauthier, and W. B. Campbell Role of arachidonic acid lipoxygenase metabolites in the regulation of vascular tone Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H495 - H507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
