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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.


  1. Rubanyi,G. M. & Vanhoutte,P. M. Nature of endothelium-derived relaxing factor: are there two relaxing mediators? Circ. Res. 61, SII-61–SII-67 (1987).

    Google Scholar 

  2. Chen,G., Suzuki,H. & Weston,A. H. Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels. Br. J. Pharmacol. 95, 1165–1174 (1988).

    Article  CAS  Google Scholar 

  3. Quilley,J., Fulton,D. & McGiff,J. C. Hyperpolarizing factors. Biochem. Pharmacol. 54, 1059–1070 (1997).

    Article  CAS  Google Scholar 

  4. Miura,H. & Gutterman,D. D. Human coronary arteriolar dilation to arachidonic acid depends on cytochrome P-450 monoxygenase and Ca2+-activated K+ channels. Circ. Res. 83, 501–507 (1998).

    Article  CAS  Google Scholar 

  5. Hecker,M., Bara,A. T., Bauersachs,J. & Busse,R. Characterization of endothelium-derived hyperpolarizing factor as a cytochrome P450-derived arachidonic acid metabolite in mammals. J. Physiol. (Lond.) 481, 407–414 (1994).

    Article  CAS  Google Scholar 

  6. Popp,R. et al. A transferable, β-naphthoflavone-inducible, hyperpolarizing factor is synthesized by native and cultured porcine coronary endothelial cells. J. Physiol. (Lond.) 497, 699–709 (1996).

    Article  CAS  Google Scholar 

  7. Rosolowsky,M. & Campbell,W. B. Role of PGI2 and epoxyeicosatrienic acids in relaxation of bovine coronary arteries to arachidonic acid. Am. J. Physiol. 264, H327–H335 (1993).

    CAS  PubMed  Google Scholar 

  8. Pinto,A., Abraham,N. G. & Mullane,K. M. Arachidonic acid-induced endothelial-dependent relaxations of canine coronary arteries: contribution of a cytochrome P-450 dependent pathway. J. Pharmacol. Exp. Ther. 240, 856–882 (1987).

    CAS  PubMed  Google Scholar 

  9. Oltman,C. L., Weintraub,N. L., VanRollins,M. & Dellsperger,K. C. Epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids are potent vasodilators in the canine coronary microcirculation. Circ. Res. 83, 932–939 (1998).

    Article  CAS  Google Scholar 

  10. Fulton,D., Mahboubi,K., McGiff,J. C. & Quilley,J. Cytochrome P450-dependent effects of bradykinin in the rat heart. Br. J. Pharmacol. 114, 99–102 (1995).

    Article  CAS  Google Scholar 

  11. Bauersachs,J., Hecker,M. & Busse,R. Display of the characteristics of endothelium-derived hyperpolarizing factor by a cytochrome P450-derived arachidonic acid metabolite in the coronary microcirculation. Br. J. Pharmacol. 113, 1548–1553 (1994).

    Article  CAS  Google Scholar 

  12. Campbell,W. B., Gebremedhin,D., Pratt,P. F. & Harder,D. R. Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ. Res. 78, 415–423 (1996).

    Article  CAS  Google Scholar 

  13. Komori,K. & Vanhoutte,P. M. Endothelium-derived hyperpolarizing factor. Blood Vessels 27, 238–245 (1990).

    CAS  PubMed  Google Scholar 

  14. Alvarez,J., Montero,M. & García-Sancho,J. Cytochrome P450 may link intracellular Ca2+ stores with plasma membrane Ca2+ influx. Biochem. J. 274, 193–197 (1991).

    Article  CAS  Google Scholar 

  15. Alvarez,J., Montero,M. & García-Sancho,J. High affinity inhibition of Ca2+-dependent K+ channels by cytochrome P-450 inhibitors. J. Biol. Chem. 267, 11789–11793 (1992).

    CAS  PubMed  Google Scholar 

  16. Guengerich,F. P. Characterization of human cytochrome P450 enzymes. FASEB J. 6, 745–748 (1992).

    Article  CAS  Google Scholar 

  17. Mancy,A. et al. Interaction of sulfaphenazole derivatives with human liver cytochromes P450 2C: molecular origin of the specific inhibitory effects of sulfaphenazole on CYP 2C9 and consequences for the substrate binding site topology of CYP 2C9. Biochemistry 35, 16205–16212 (1996).

    Article  CAS  Google Scholar 

  18. Kiss,L. et al. Simultaneous analysis of 4- and 5-series lipoxygenase and cytochrome P450 products from different biological sources by reversed-phase high-performance liquid chromatographic technique. Anal. Biochem. 261, 16–28 (1998).

    Article  CAS  Google Scholar 

  19. Edwards,G. et al. K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396, 269–272 (1998).

    Article  ADS  CAS  Google Scholar 

  20. Pritchard, K. A. Jr, Wong,P. & Stemerman,M. B. Atherogenic concentrations of low density lipoprotein enhance endothelial cell generation of epoxyeicosatrienoic acid products. Am. J. Pathol. 136, 1381–1391 (1990).

    Google Scholar 

  21. Puntarulo,S. & Cederbaum,A. I. Production of reactive oxygen species by microsomes enriched in specific human cytochrome P450 enzymes. Free Radical Biol. Med. 24, 1324–1330 (1998).

    Article  CAS  Google Scholar 

  22. Bauersachs,J. et al. Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor. Circulation 94, 3341–3347 (1996).

    Article  CAS  Google Scholar 

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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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