title: Activation of vascular BK channels by docosahexaenoic acid is dependent on cytochrome P450 epoxygenase activity.
abstract: OBJECTIVE
  n-3 Polyunsaturated fatty acids (PUFAs) are known to protect the cardiovascular system and improve blood pressure control. These important dietary constituents are converted into bioactive metabolites, but their role in regulation of the cardiovascular system is unclear. In particular, the functions of the cytochrome P450 (CYP) metabolites of n-3 PUFAs remain virtually unexplored. In this study, we examined the effects of docosahexaenoic acid (DHA) on the regulation of large-conductance calcium-activated potassium (BK) channel activities in coronary arterial smooth muscle cells.
  
  
  RESULTS
  Using whole-cell patch-clamp techniques, we found that DHA is a potent activator of BK currents in rat coronary arterial smooth muscle cells with an EC(50) of 0.23 ± 0.03 µM. This effect was abolished by pre-incubation with the CYP epoxygenase inhibitor, SKF525A (10 µM). The effects of DHA on the BK channels were reproduced by 16,17-epoxydocosapentaenoic acid (16,17-EpDPE) with an EC(50) of 19.7 ± 2.8 nM. The physiological role of the CYP metabolites of DHA was confirmed by measuring DHA-mediated vasodilatation in isolated rat coronary arteries. DHA dilated pressurized isolated coronary arteries in a dose-dependent manner, and the DHA effects were abolished after pre-treatment with SKF525A (10 µM) or with iberiotoxin (100 nM). In addition, 16,17-EpDPE directly produced coronary vasodilatation that was iberiotoxin sensitive.
  
  
  CONCLUSIONS
  These results suggest that DHA-mediated vasodilatation is mediated through CYP epoxygenase metabolites by activation of vascular BK channels.
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Ru-xing
authors.initials: RX
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chai
authors.forename: Tong
authors.initials: T
authors.lastname: Lu
authors.forename: Hon-Chi
authors.initials: HC
authors.lastname: Lee
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D004281:Docosahexaenoic Acids; C064719:iberiotoxin; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D000090762:Cytochrome P-450 CYP2J2; D011188:Potassium