Cytochrome P450 activity and endothelial dysfunction in insulin resistance

Impaired endothelium-dependent relaxation attributable to nitric oxide/pros tacyclin-independent factor (endothelium-dependent hyperpolarizing factor; EDHF) has been demonstrated in the small mesenteric arteries of insulin-res istant rats. The purpose of this study was to determine if modulation of th e cytochrome P450 enzyme system would restore EDHF-mediated relaxation in i nsulin-resistant rats. Sprague-Dawley rats were randomized to control (n = 32) or insulin-resistant (n = 32) groups. Each group was further randomized to treatment (n = 48) or placebo (n = 16). Miconazole (3 days) and phenoba rbital (3 and 14 days) achieved cytochrome P450 inhibition and induction, r espectively. Following drug treatment, mean arterial pressure was measured and vascular function was assessed in small mesenteric arteries in vitro. S pecifically, acetylcholine-induced relaxation alone and in the presence of indomethacin plus N-nitro-L-arginine (LNNA) or KCl was determined. Miconazo le reduced the maximal relaxation in response to acetylcholine in control r ats. Similarly, in the presence of LNNA plus indomethacin, acetylcholine-in duced relaxation was impaired in the miconazole-treated control group versu s the placebo group, whereas relaxation in the presence of KCI was unchange d. Miconazole did not affect relaxation in insulin-resistant arteries. In c ontrast, 3- and 14-day treatment with phenobarbital significantly improved acetylcholine-induced relaxation in insulin-resistant arteries. Likewise, a cetylcholine-mediated relaxation in the presence of LNNA plus indomethacin was also improved after phenobarbital treatment, while relaxation in the pr esence of KCl was unchanged. Phenobarbital treat ment did not affect the co ntrol group. Miconazole treatment increased the mean arterial pressure in c ontrol rats, while 14-day phenobarbital treatment normalized the mean arter ial pressure in insulin-resistant rats. Cytochrome P450 induction results i n the restoration of EDHF-mediated relaxation in small mesenteric arteries and the normalization of mean arterial pressure in insulin-resistant rats. Thus, endothelial dysfunction secondary to insulin resistance can be revers ed by the induction of cytochrome P450. Copyright (C) 2000 S. Karger AG, Ba sel.