14,15-Dihydroxyeicosatrienoic acid relaxes bovine coronary arteries by activation of K(Ca) channels.
Epoxyeicosatrienoic acids (EETs) cause vascular relaxation by activating smooth muscle large conductance Ca(2+)-activated K(+) (K(Ca)) 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 fivefold 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 K(Ca) channel activity in cell-attached patches and inside-out patches only when GTP was present. 14,15-[(14)C]EET methyl ester (Me) was converted to 14,15-[(14)C]DHET-Me, 14,15-[(14)C]DHET, and 14,15-[(14)C]EET by coronary arterial rings and endothelial cells but not by 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 K(Ca) channels. Endothelial cells, but not smooth muscle cells, convert EETs to DHETs, and this conversion results in a loss of vasodilator activity.
Campbell
William B
WB
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. wbcamp@mcw.edu
Deeter
Christine
C
Gauthier
Kathryn M
KM
Ingraham
Richard H
RH
Falck
J R
JR
Li
Pin-Lan
PL
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002417:Cattle; D018999:Charybdotoxin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology*; D004553:Electric Conductivity; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology
C107016:14,15-dihydroxyeicosatrienoic acid; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D010455:Peptides; D015221:Potassium Channels; D018999:Charybdotoxin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C064719:iberiotoxin; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D006160:Guanosine Triphosphate; D004851:Epoxide Hydrolases; D019204:GTP-Binding Proteins; D015126:8,11,14-Eicosatrienoic Acid; D000109:Acetylcholine; D002118:Calcium