J Physiol. 1997 Jun 1;501 ( Pt 2):331-41.  

Evidence against the involvement of cytochrome P450 metabolites in
endothelium-dependent hyperpolarization of the rat main mesenteric artery.

Vanheel B, Van de Voorde J.

Department of Physiology and Physiopathology, University of Gent, Belgium.
Bert.Vanheel@rug.ac.be

1. 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. 2. Application of acetylcholine (ACh; 1
microM) 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). 3. Proadifen (30 microM) completely and
reversibly inhibited the ACh-induced hyperpolarization. Conversely, the
imidazole antimycotics clotrimazole (30 microM) and miconazole (100 microM) had
less effect on the peak endothelium-dependent hyperpolarization. The suicide
substrate inhibitors 17-octadecynoic acid (17-ODYA; 5 microM) and
1-aminobenzotriazole (1-ABT; 2 mM) did not significantly influence
endothelium-dependent hyperpolarization. 4. The endothelium-independent
hyperpolarization (16 mV) evoked by leveromakalim (300 nM) was completely
inhibited by proadifen as well as by clotrimazole and miconazole but was not
affected by 17-ODYA or 1-ABT. 5. 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.

PMID: 9192305 [PubMed - indexed for MEDLINE]