Published Online
on January 2, 2007

A more recent version of this article appeared on March 1, 2007

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Submitted on November 1, 2006
Revised on November 21, 2006

Arachidonic Acid Metabolites as Endothelium-Derived Hyperpolarizing Factors

William B. Campbell^* and John R. Falck

From the Department of Pharmacology and Toxicology (W.B.C.), Medical College of Wisconsin, Milwaukee; and the Department of Biochemistry (J.R.F.), University of Texas Southwestern Medical Center, Dallas.

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

Abstract--The endothelium regulates vascular tone through the release of a number of soluble mediators, including NO, prostaglandin I₂, and endothelium-derived hyperpolarizing factor. Epoxyeicosatrienoic acids are cytochrome P450 epoxygenase metabolites of arachidonic acid. They are synthesized by the vascular endothelium and open calcium-activated potassium channels, hyperpolarize the membrane, and relax vascular smooth muscle. Endothelium-dependent relaxations to acetylcholine, bradykinin, and shear stress that are not inhibited by cyclooxygenase and NO synthase inhibitors are mediated by the endothelium-derived hyperpolarizing factor. In arteries from experimental animals and humans, the non-NO, non-prostaglandin-mediated relaxations and endothelium-dependent hyperpolarizations are blocked by cytochrome P450 inhibitors, calcium-activated potassium channel blockers, and epoxyeicosatrienoic acid antagonists. Acetylcholine and bradykinin stimulate epoxyeicosatrienoic acid release from endothelial cells and arteries. These findings indicate that epoxyeicosatrienoic acids act as endothelium-derived hyperpolarizing factors and regulate arterial tone.

Key words: Cytochrome P450 system • endothelium • arachidonic acid • vascular relaxation • endothelium-derived hyperpolarizing factor

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