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Cardiovascular Research 2002 54(3):669-675; doi:10.1016/S0008-6363(02)00257-2
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Cytochrome P450 2C expression and EDHF-mediated relaxation in porcine coronary arteries is increased by cortisol

J. Bauersachsa,*, M. Christb, G. Ertla, U.R. Michaelisc, B. Fisslthalerc, R. Bussec and I. Flemingc

aMedizinische Klinik der Julius-Maximilians-Universität Würzburg, Joseph-Schneider-Str. 2, D-97080 Würzburg, Germany
bKlinik für Innere Medizin-Kardiologie, Philipps-Universität Marburg, Marburg, Germany
cInstitut für Kardiovaskuläre Physiologie, Klinikum der J. W. Goethe-Universität, Frankfurt/Main, Germany

* Corresponding author. Tel.: +49-931-201-59111; fax: +49-931-201-5302 j.bauersachs{at}medizin.uni-wuerzburg.de

Objectives/methods: In addition to nitric oxide (NO) and prostacyclin, endothelium-dependent dilation is mediated by the endothelium-derived hyperpolarizing factor (EDHF) which, in the coronary circulation, has been characterised as a metabolite of arachidonic acid synthesised by an cytochrome P450 (CYP) epoxygenase homologous to CYP 2C8/9. As the promotor regions of CYP 2C8 and 2C9 contain consensus sequences for glucocorticoid response elements, we determined the effect of cortisol on EDHF-mediated relaxations as well as on the expression of CYP 2C in isolated segments of porcine coronary artery. Results: Bradykinin-induced NO-mediated relaxation of KCl-constricted arterial rings was slightly attenuated following exposure to cortisol. However, EDHF-mediated relaxations of U46619 [GenBank] -constricted arterial rings assessed in the presence of the cyclo-oxygenase inhibitor diclofenac and the NO synthase inhibitor N{omega}nitro-L-arginine (0.3 mM), were significantly enhanced (maximum relaxation: 66±7%, P<0.05 vs. control rings: 36±8%). Cortisol treatment (0.1 µM, 24 h) did not affect the endothelium-independent relaxation elicited by sodium nitroprusside and acute incubation with cortisol (0.1 µM, 30 min) did not alter either NO- or EDHF-mediated responses. The expression of CYP 2C (quantified by RT-PCR, Western blot analysis and confocal microscopy) was enhanced in porcine coronary endothelial cells following incubation with cortisol for 18–24 h. Conclusions: These results demonstrate the concomitant upregulation of EDHF-mediated relaxations and CYP 2C expression by long-term treatment with cortisol. These observations support the concept that an epoxygenase homologous to CYP 2C8/9 plays a crucial role in the generation of EDHF-mediated responses in the coronary endothelium.

KEYWORDS Endothelial function; Endothelial factors; Coronary circulation; Vasoconstriction/dilation; Nitric oxide


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