Nifedipine increases cytochrome P4502C expression and endothelium-derived hyperpolarizing factor-mediated responses in coronary arteries

In addition to NO and prostacyclin, endothelial cells release a factor that elicits vasodilatation by hyperpolarizing the underlying vascular smooth m uscle cells. In some vascular beds, this so-called endothelium-derived hype rpolarizing 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 w ere screened for CYP epoxygenases, and CYP2B, CYP2C, and CYP2J were detecte d with reverse transcription-polymerase chain reaction. The CYP inducer bet a-naphthoflavone and the Ca2+ antagonist nifedipine significantly increased CYP2C mRNA but did not change the expression of CYP2J or CYP2B. To determi ne 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 ge neration of 11,12-epoxyeicosatrienoic acid. In organ bath experiments, pret reatment with nifedipine enhanced bradykinin-induced, EDHF-mediated relaxat ions as well as the concomitant hyperpolarization of smooth muscle cells. T he specific CYP2C9 inhibitor sulfaphenazole, on the other hand, significant ly 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 propos e that an isozyme of CYP2C is the most likely candidate for the CYP-depende nt EDHF synthase in porcine coronary arteries.