(Hypertension. 2000;36:270.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Nifedipine Increases Cytochrome P4502C Expression and Endothelium-Derived Hyperpolarizing Factor–Mediated Responses in Coronary Arteries
From the Institut für Kardiovaskuläre Physiologie (B.F., N.H., T.C., R.P., R.B., I.F.), Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany; and Zentrum der Inneren Medizin (L.K.), Justus Liebig Universität Gießen, Gießen, Germany.
Correspondence to Dr Ingrid Fleming, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. E-mail Fleming{at}em.uni-frankfurt.de
Abstract—In addition to NO and prostacyclin, endothelial cells release a factor that elicits vasodilatation by hyperpolarizing the underlying vascular smooth muscle cells. In some vascular beds, this so-called endothelium-derived hyperpolarizing factor (EDHF) displays the characteristics of a cytochrome P450 (CYP)-derived arachidonic acid metabolite, such as an epoxyeicosatrienoic acid. Native porcine and cultured human coronary artery endothelial cells were screened for CYP epoxygenases, and CYP2B, CYP2C, and CYP2J were detected with reverse transcription–polymerase chain reaction. The CYP inducer ß-naphthoflavone and the Ca2+ antagonist nifedipine significantly increased CYP2C mRNA but did not change the expression of CYP2J or CYP2B. To determine the relationship between CYP2C expression and EDHF production in native endothelial cells, we incubated porcine coronary arteries with nifedipine. Nifedipine enhanced endothelial CYP2C protein expression, as well as the generation of 11,12-epoxyeicosatrienoic acid. In organ bath experiments, pretreatment with nifedipine enhanced bradykinin-induced, EDHF-mediated relaxations as well as the concomitant hyperpolarization of smooth muscle cells. The specific CYP2C9 inhibitor sulfaphenazole, on the other hand, significantly attenuated EDHF-mediated hyperpolarization and relaxation. These results demonstrate that in porcine coronary arteries, the elevated expression of a CYP epoxygenase, homologous to CYP2C8/9, is associated with enhanced EDHF-mediated hyperpolarization in response to bradykinin. Therefore, we propose that an isozyme of CYP2C is the most likely candidate for the CYP-dependent EDHF synthase in porcine coronary arteries.
Key Words: endothelium-derived hyperpolarizing factor • cytochrome P450 • nifedipine • arteries • potassium channels
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