Fisslthaler B, Popp R, Kiss L, Potente M, Harder D R, Fleming I, Busse R
Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany.
Nature. 1999 Sep 30;401(6752):493-7. doi: 10.1038/46816.
In most arterial beds a significant endothelium-dependent dilation to various stimuli persists even after inhibition of nitric oxide synthase and cyclo-oxygenase. This dilator response is preceded by an endothelium-dependent hyperpolarization of vascular smooth muscle cells, which is sensitive to a combination of the calcium-dependent potassium-channel inhibitors charybdotoxin and apamin, and is assumed to be mediated by an unidentified endothelium-derived hyperpolarizing factor (EDHF). Here we show that the induction of cytochrome P450 (CYP) 2C8/34 in native porcine coronary artery endothelial cells by beta-naphthoflavone enhances the formation of 11,12-epoxyeicosatrienoic acid, as well as EDHF-mediated hyperpolarization and relaxation. Transfection of coronary arteries with CYP 2C8/34 antisense oligonucleotides results in decreased levels of CYP 2C and attenuates EDHF-mediated vascular responses. Thus, a CYP-epoxygenase product is an essential component of EDHF-mediated relaxation in the porcine coronary artery, and CYP 2C8/34 fulfils the criteria for the coronary EDHF synthase.
在大多数动脉床中，即使在一氧化氮合酶和环氧化酶受到抑制后，对各种刺激的显著内皮依赖性舒张作用仍然存在。这种舒张反应之前会出现血管平滑肌细胞的内皮依赖性超极化，该超极化对钙依赖性钾通道抑制剂蝎毒素和蜂毒明肽的组合敏感，并被认为是由一种未确定的内皮源性超极化因子（EDHF）介导的。在这里，我们表明，β-萘黄酮诱导天然猪冠状动脉内皮细胞中的细胞色素P450（CYP）2C8/34可增强11,12-环氧二十碳三烯酸的形成，以及EDHF介导的超极化和舒张。用CYP 2C8/34反义寡核苷酸转染冠状动脉会导致CYP 2C水平降低，并减弱EDHF介导的血管反应。因此，一种CYP-环氧加氧酶产物是猪冠状动脉中EDHF介导的舒张的重要组成部分，并且CYP 2C8/34符合冠状动脉EDHF合酶的标准。
