Cytochrome P4502C expression and EDHF-mediated relaxation in porcine coronary arteries is increased by cortisol

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 X 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-constricted arterial rings assessed in the presence of the cyclo-oxygenase inhibitor diclofenac and the NO synthase inhibitor N(60)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 muM, 24 h) did not affect the endothelium-independent relaxation elicited by sodium nitroprusside and acute incubation with cortisol (0.1 muM, 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. (C) 2002 Elsevier Science B.V. All rights reserved.