Abstract 9659: Combination Therapy with Olmesartan and Azelnidipine Exerts Anti-Atherogenic Effects in Diabetic Apolipoprotein E-Deficient Mice

Abstract

Background: We have recently demonstrated that combination therapy with olmesartan (OLM), an angiotensin type 1 receptor blocker, and azelnidipine (AZL), an L-type Ca channel blocker, improves endothelial function more than each monotherapy in diabetic Apolipoprotein-deficient (ApoE -/- ) mice. In this study, we further examined whether this also is the case for atherosclrosis. Method and Results: We used male C57BL/6N (control) and streptozocin-induced diabetic ApoE -/- mice. The diabetic ApoE -/- mice were administered oral vehicle (untreated), OLM (30 mg/kg/day, PO), AZL (10 mg/kg/day, PO), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) for 5 weeks (n=8 each). Blood pressure was significantly elevated in the untreated group but was normalized by OLM+AZL or HYD. At 5 weeks, the extent of oil-red O staining in the aorta was markedly increased in the untreated group and was significantly ameliorated in the OLM+AZL group (P<0.05). In the HYD group, despite the normalization of blood pressure, the extent of atherosclrosis in the aorta was comparable with that in the untreated group. Similarly, both perivascular fibrosis and medial thickness of the epicardial coronary arteries were increased in the untreated group, both of which were ameliorated only in the OLM+AZL group (both P<0.05). In addition, cross-sectional area of cardiomyocyte was significantly increased in the untreated group and was significantly ameliorated only in the OLM+AZL group (P<0.05). To examine the mechanisms involved, dihydroethidium staining was performed, which showed that aortic ROS production was significantly increased in the untreated group and was significantly inhibited only in the OLM+AZL group (both P<0.05). Furthermore, both eNOS expression and activity (as examined by its phosphorylation at serine 1177) were increased only in the OLM+AZL group (P<0.05). The expression of RAGE (receptor for advanced glycation end-products) also tended to decrease in the AZL and OLM+AZL groups compared with the untreated group (both P=0.05). Conclusion: These results indicate that the combination therapy with OLM and AZL exerts anti-atherogenic effects more than each monotherapy in ApoE -/- mice in vivo, for which reduction of oxidative stress may be involved.