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Cytochrome P-450 epoxygenase products contribute to attenuated vasoconstriction after chronic hypoxia

Vascular Physiology Group, Departments of ¹Cell Biology and Physiology and ²Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131

Submitted 6 December 2002 ; accepted in final form 27 February 2003

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 (E_m) was measured in superior mesenteric artery strips isolated from rats with control barometric pressure (PB, 630 Torr) and CH (PB, 380 Torr for 48 h). VSM cell E_m 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 E_m between groups. Iberiotoxin also normalized VSM cell E_m, which suggests that large-conductance, Ca²⁺-activated K⁺ (BK_Ca) 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 BK_Ca channel-dependent VSM cell hyperpolarization and attenuated vasoreactivity.

rat; epoxyeicosatrienoic acid; endothelial-derived hyperpolarizing factor; ratiometric calcium measurement; mesenteric circulation

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