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Articles in PresS, published online ahead of print January 17, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00597.2001
Submitted on July 20, 2001
Accepted on January 9, 2002
1 Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Beohringer Ingelheim Pharmaceutical, Ridgefield, CT, USA
3 Biochemistry, Univ Texas Southwestern Medical Center, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: wbcamp{at}mcw.edu.
Epoxyeicosatrienoic acids (EETs) cause vascular relaxation by activating smooth muscle large-conductance, calcium-activated potassium (KCa) channels. EETs are metabolized to dihydroxyeicosatrienoic acids (DHETs) by epoxide hydrolase. We examined the contribution of 14,15-DHET to 14,15-EET-induced relaxations and characterized its mechanism of action. 14,15-DHET relaxed U-46619-precontracted bovine coronary artery rings but was approximately 5-fold less potent than 14,15-EET. The relaxations were inhibited by charybdotoxin, iberiotoxin and increasing extracellular K to 20 mM. In isolated smooth muscle cells, 14,15-DHET increased an iberiotoxin-sensitive, outward K current and increased KCa channel activity in cell-attached patches and inside out patches only when GTP is present. 14C-14,15-EET-methyl ester (Me) was converted to 14C -14,15-DHET-Me, -14,15-DHET and -14,15-EET by coronary arterial rings and endothelial cells but not smooth muscle cells. The metabolism to 14,15-DHET was inhibited by the epoxide hydrolase inhibitors, 4-phenylchalcone oxide (4-PCO) and BIRD-0826. Neither inhibitor altered relaxations to acetylcholine, whereas relaxations to 14,15-EET-Me were increased slightly by BIRD-0826 but not by 4-PCO. 14,15-DHET relaxes coronary arteries through activation of KCa channels. Endothelial cells, but not smooth muscle cells convert EETs to DHETs, and this conversion results in a loss of vasodilator activity.
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