title: Cytochrome p-450 epoxygenase products contribute to attenuated vasoconstriction after chronic hypoxia.
abstract: The systemic vasculature exhibits attenuated vasoconstriction following chronic hypoxia (CH) that is associated with endothelium-dependent vascular smooth muscle (VSM) cell hyperpolarization. We hypothesized that increased production of arachidonic acid metabolites such as the cyclooxygenase product prostacyclin or cytochrome p-450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) contributes to VSM cell hyperpolarization following CH. VSM cell resting membrane potential (Em) was measured in superior mesenteric artery strips isolated from rats with control barometric pressure (Pb, congruent with 630 Torr) and CH (Pb, 380 Torr for 48 h). VSM cell Em was normalized between groups following administration of the CYP inhibitors 17-octadecynoic acid and SKF-525A. VSM cell hyperpolarization after CH was not altered by cyclooxygenase inhibition, whereas the selective CYP2C9 inhibitor sulfaphenazole normalized VSM cell Em between groups. Iberiotoxin also normalized VSM cell Em, which suggests that large-conductance, Ca2+-activated K+ (BKCa) channel activity is increased after CH. Sulfaphenazole administration restored phenylephrine-induced and myogenic vasoconstriction and Ca2+ responses of mesenteric resistance arteries isolated from CH rats to control levels. Western blot experiments demonstrated that CYP2C9 protein levels were greater in mesenteric arteries from CH rats. In addition, 11,12-EET levels were elevated in endothelial cells from CH rats compared with controls. We conclude that enhanced CYP2C9 expression and 11,12-EET production following CH contributes to BKCa channel-dependent VSM cell hyperpolarization and attenuated vasoreactivity.
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131-0001, USA. searley@salud.unm.edu
authors.forename: Scott
authors.initials: S
authors.lastname: Earley
authors.forename: Andrzej
authors.initials: A
authors.lastname: Pastuszyn
authors.forename: Benjimen R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008638:Mesenteric Arteries / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000378:metabolism; D011335:Proadifen / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D002121:Calcium Channel Blockers; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D024681:Potassium Channels, Calcium-Activated; C047008:17-octadecynoic acid; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D010105:Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000090762:Cytochrome P-450 CYP2J2; D011451:Prostaglandin-Endoperoxide Synthases; D015126:8,11,14-Eicosatrienoic Acid