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1 Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
2 Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
* To whom correspondence should be addressed. E-mail: searley{at}salud.unm.edu.
The systemic vasculature exhibits attenuated vasoconstrictor responsiveness following chronic hypoxic (CH) exposure 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 P450 (CYP) epoxigenase-derived epoxyecicosatrienoic acids (EETs) contributes to VSM cell hyperpolarization following CH. VSM cell resting membrane potential (Em) was measured via intracellular microelectrode in superior mesenteric artery (SMA) strips isolated from control (PB 
630 torr) and CH (PB = 380 torr; 48 hours) rats. We found that VSM cell Em was normalized between groups following administration of the cytochrome P450 (CYP) inhibitors 17-ODYA and SKF-525A. In addition, VSM cell hyperpolarization following CH was not altered by cyclooxygenase inhibition, whereas the selective CYP2C9 inhibitor sulfaphenazole normalized VSM cell Em between control and CH rats. Furthermore, the large conductance Ca2+-activated K+ (BKCa) channel antagonist iberiotoxin also normalized VSM cell Em between the groups, suggesting that the activity of this channel is increased following prolonged hypoxic exposure. Sulfaphenazole administration also restored both phenylephrine-induced and myogenic vasoconstrictor and Ca2+ responses of fura-loaded 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 compared to controls. In addition, 11,12 EET levels were elevated in endothelial cells harvested from CH rats compared to controls, whereas levels of 11,12 EET in vessels from CH rats that were treated with sulfaphenazole were not different from those of control rats. We conclude that enhanced CYP2C9 expression and 11,12 EET production following CH contributes to BKCa channel-dependent VSM cell hyperpolarization and attenuated vasoreactivity.
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