Cytochrome P450 Activity and Endothelial Dysfunction in Insulin Resistance

Abstract

Impaired endothelium-dependent relaxation attributable to nitric oxide/prostacyclin-independent factor (endothelium-dependent hyperpolarizing factor; EDHF) has been demonstrated in the small mesenteric arteries of insulin-resistant rats. The purpose of this study was to determine if modulation of the cytochrome P450 enzyme system would restore EDHF-mediated relaxation in insulin-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 phenobarbital (3 and 14 days) achieved cytochrome P450 inhibition and induction, respectively. Following drug treatment, mean arterial pressure was measured and vascular function was assessed in small mesenteric arteries in vitro. Specifically, acetylcholine-induced relaxation alone and in the presence of indomethacin plus N-nitro-L-arginine (LNNA) or KCl was determined. Miconazole reduced the maximal relaxation in response to acetylcholine in control rats. Similarly, in the presence of LNNA plus indomethacin, acetylcholine-induced relaxation was impaired in the miconazole-treated control group versus the placebo group, whereas relaxation in the presence of KCl was unchanged. Miconazole did not affect relaxation in insulin-resistant arteries. In contrast, 3- and 14-day treatment with phenobarbital significantly improved acetylcholine-induced relaxation in insulin-resistant arteries. Likewise, acetylcholine-mediated relaxation in the presence of LNNA plus indomethacin was also improved after phenobarbital treatment, while relaxation in the presence of KCl was unchanged. Phenobarbital treatment did not affect the control group. Miconazole treatment increased the mean arterial pressure in control rats, while 14-day phenobarbital treatment normalized the mean arterial pressure in insulin-resistant rats. Cytochrome P450 induction results in 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 reversed by the induction of cytochrome P450.