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(Hypertension. 2007;49:590.)
© 2007 American Heart Association, Inc.

Norvartis Award

Arachidonic Acid Metabolites as Endothelium-Derived Hyperpolarizing Factors

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.

Correspondence to William B. Campbell, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail wbcamp{at}mcw.edu

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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