Cytochrome P-450 epoxygenase products contribute to attenuated vasoconstriction after chronic hypoxia
Cytochrome P-450 epoxygenase products contribute to attenuated vasoconstriction after chronic hypoxia
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DOI：
10.1152/ajpheart.01052.2002
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发表时间：
2003-07-01
影响因子：
4.8
通讯作者：
Walker, BR
中科院分区：
文献类型：
--
作者：
Earley, S;Pastuszyn, A;Walker, BR
慢性缺氧（CH）后，全身血管系统表现出减弱的血管收缩，这与内皮依赖性血管平滑肌（VSM）细胞超极化有关。我们假设花生四烯酸代谢产物（例如环氧合酶产物前列环素或细胞色素P-450（CYP）环氧合酶衍生的环氧二十碳三烯酸（EET））的产生增加有助于CH后的VSM细胞超极化。在控制气压下测量了从大鼠分离的上级肠系膜动脉条中的VSM细胞静息膜电位（E-m）（PB，与630托一致）和CH（PB，380托，48小时）。在给予β抑制剂17-十八炔酸和SKF-525 A后，各组间的VSM细胞E-m标准化。CH后VSM细胞超极化未被环氧合酶抑制剂改变，而选择性CYP2C9抑制剂磺胺苯吡唑使两组间VSM细胞E-m正常化。伊比利亚毒素也正常VSM细胞E-m，这表明，大电导，钙激活的K+（BKCa）通道活性增加后CH。磺胺苯吡唑管理恢复苯肾上腺素诱导的和肌源性血管收缩和Ca 2+反应的肠系膜阻力动脉CH大鼠分离到对照水平。Western blot实验表明，CYP2C9蛋白水平更高的肠系膜动脉从CH大鼠。此外，与对照组相比，CH大鼠内皮细胞中的11，12-EET水平升高。我们的结论是，增强CYP2C9的表达和11，12-EET生产后CH BKCa通道依赖性VSM细胞超极化和衰减的血管反应性。
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) epoxy-genase-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, congruent to630 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+ (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.