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Cytochrome P450 2C is an EDHF synthase in coronary arteries


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)1,2. Here we show that the induction of cytochrome P450 (CYP) 2C8/34 in native porcine coronary artery endothelial cells by β-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.

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Figure 1: Increased expression of CYP 2C enhances EDHF-mediated relaxation of PCA and generation of 11,12-EET.
Figure 2: Increased expression of CYP 2C enhances, and sulphaphenazole inhibits, the EDHF-mediated hyperpolarization of PCA.
Figure 3: CYP 2C8/34 antisense oligonucleotides attenuate the expression of CYP 2C protein and the EDHF-mediated relaxation of PCA.
Figure 4: CYP 2C antisense oligonucleotides abolish bradykinin-induced, EDHF-mediated hyperpolarization of PCA smooth muscle cells.

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We thank I. Winter, M. Stächele, N. Hinsch and S. Hauk for expert technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft and Institut de Recherches Internationales Servier.

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Correspondence to Ingrid Fleming.

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Fisslthaler, B., Popp, R., Kiss, L. et al. Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature 401, 493–497 (1999).

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