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(Hypertension. 2005;45:681.)
© 2005 American Heart Association, Inc.

Original Articles

Stable 5,6-Epoxyeicosatrienoic Acid Analog Relaxes Coronary Arteries Through Potassium Channel Activation

Wenqi Yang; Kathryn M. Gauthier; L. Manmohan Reddy; Bhavani Sangras; Kamalesh K. Sharma; Kasem Nithipatikom; John R. Falck; William B. Campbell

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

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

5,6-Epoxyeicosatrienoic acid (5,6-EET) is a cytochrome P450 epoxygenase metabolite of arachidonic acid that causes vasorelaxation. However, investigations of its role in biological systems have been limited by its chemical instability. We developed a stable agonist of 5,6-EET, 5-(pentadeca-3(Z),6(Z),9(Z)-trienyloxy)pentanoic acid (PTPA), in which the 5,6-epoxide was replaced with a 5-ether. PTPA obviates chemical and enzymatic hydrolysis. In bovine coronary artery rings precontracted with U46619, PTPA (1 nmol/L to 10 µmol/L) induced concentration-dependent relaxations, with maximal relaxation of 86±5% and EC₅₀ of 1 µmol/L. The relaxations were inhibited by the cyclooxygenase inhibitor indomethacin (10 µmol/L; max relaxation 43±9%); the ATP-sensitive K⁺ channel inhibitor glybenclamide (10 µmol/L; max relaxation 49±6%); and the large conductance calcium-activated K⁺ channel inhibitor iberiotoxin (100 nmol/L; max relaxation 38±6%) and abolished by the combination of iberiotoxin with indomethacin or glybenclamide or increasing extracellular K⁺ to 20 mmol/L. Whole-cell outward K⁺ current was increased nearly 6-fold by PTPA (10 µmol/L), which was also blocked by iberiotoxin. Additionally, we synthesized 5-(pentadeca-6(Z),9(Z)-dienyloxy)pentanoic acid and 5-(pentadeca-3(Z),9(Z)-dienyloxy)pentanoic acid (PDPA), PTPA analogs that lack the 8,9 or 11,12 double bonds of arachidonic acid and therefore are not substrates for cyclooxygenase. The PDPAs caused concentration-dependent relaxations (max relaxations 46±13% and 52±7%, respectively; EC₅₀ 1µmol/L), which were not altered by glybenclamide but blocked by iberiotoxin. These studies suggested that PTPA induces relaxation through 2 mechanisms: (1) cyclooxygenase-dependent metabolism to 5-ether–containing prostaglandins that activate ATP-sensitive K⁺ channels and (2) activation of smooth muscle large conductance calcium-activated K⁺ channels. PDPAs only activate large conductance calcium-activated K⁺ channels.

Key Words: arachidonic acids • cyclooxygenase • endothelium-derived factors

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