Evidence Against the Involvement of Cytochrome P450 Metabolites in Endothelium‐Dependent Hyperpolarization of the Rat Main Mesenteric Artery

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Abstract
The influence of different inhibitors of cytochrome P450 mono‐oxygenase on the endothelium‐dependent and ‐independent hyperpolarization in the isolated rat main mesenteric artery was investigated. Application of acetylcholine (ACh; 1 μm) for 10 min evoked an endothelium‐dependent peak hyperpolarization of about 18 mV followed by a partial recovery to a level 7 mV more negative than the resting value (‐50.2 ± 0.5 mV). Proadifen (30 μm) completely and reversibly inhibited the ACh‐induced hyperpolarization. Conversely, the imidazole antimycotics clotrimazole (30 μm) and miconazole (100 μm) had less effect on the peak endothelium‐dependent hyperpolarization. The suicide substrate inhibitors 17‐octadecynoic acid (17‐ODYA; 5 μm) and 1‐aminobenzotriazole (1‐ABT; 2 mm) did not significantly influence endothelium‐dependent hyperpolarization. The endothelium‐independent hyperpolarization (16 mV) evoked by levcromakalim (300 nm) was completely inhibited by proadifen as well as by clotrimazole and miconazole but was not affected by 17‐ODYA or 1‐ABT. These results do not support the view that the ACh‐induced endothelium‐dependent hyperpolarization in the rat mesenteric artery is mediated by cytochrome P450 mono‐oxygenase metabolites. Proadifen and imidazole antimycotics impair the activation of ATP‐regulated K+ channels in mesenteric artery cells, rendering non‐specific inhibition of smooth muscle K+ channel activation an alternative explanation for the inhibitory influence of some (but not all) P450 inhibitors on endothelium‐dependent hyperpolarization in this preparation.