Abstract 9323: Inhibitors of Soluble Epoxide Hydrolase Limit Niacin-induced Flushing
The use of niacin to treat dyslipidemias is limited by the frequent side effect of flushing, in part mediated by an increase in arachidonic acid (AA) metabolism and PGD2. However, interventions to block production of PGD2, or block its receptor, have limited efficacy. Since the enzyme soluble epoxide hydrolase (sEH) is involved in the cytochrome P450 pathway of AA, we hypothesized that inhibition of sEH would limit flushing. Using a murine model in which ear blood flow was measured using laser doppler, C57BL/6 mice were administered 30 mg/kg of niacin subcutaneously (n=5 in each group). Wild-type animals exhibited a 4.6 +/− 1.1 fold increase in ear blood flow after niacin, while sEH knockout mice had a markedly blunted response (1.8 +/− 0.3, P < 0.05). Animals pre-treated with the sEH inhibitor TPAU had a dose-dependent reduction in flushing (represented in the figure by tissue perfusion units [TPU]), with significant inhibition at 0.3 and 1 mg/kg (P < 0.05). Similar inhibition of flushing was also seen with two other sEH inhibitors, ADAU and sorafenib. Samples of plasma and ear tissue obtained at the time of maximal niacin vasodilation showed that niacin significantly increased PGD2, but decreased the P450 epoxyeicosatrienoic acids (EETs). While TPAU pre-treatment before niacin did not significantly affect PGD2, it restored EETs to baseline levels. In Conclusions, inhibition of sEH, either genetic or pharmacologic, limits vasodilation in a murine model of niacin-induced flushing. This effect is not due to any measured change in PGD2, suggesting other parallel mechanisms of flushing that can be viable pharmacologic targets.
- © 2010 by American Heart Association, Inc.