Combination therapy with olmesartan and azelnidipine improves EDHF-mediated responses in diabetic apolipoprotein E-deficient mice

Background: The endothelium modulates vascular tone by synthesizing and releasing several vasodilating factors, including vasodilator prostaglandins, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). In the present study, we examined whether an angiotensin-receptor blocker, a calcium-channel blocker or their combination improved EDHF-mediated responses in diabetic apolipoprotein E-deficient (ApoE-/-) mice. Methods and Results: We used male C57BL/6N (control) and streptozocin-induced diabetic ApoE-/- mice. The diabetic ApoE-/- mice were administered oral vehicle (untreated), olmesartan (OLM, 30 mg·kg^-1·day^-1), azelnidipine (AZL, 10 mg·kg^-1·day^-1), their combination (OLM + AZL), or hydralazine (HYD 5 mg·kg^-1·day^-1) for 5 weeks. In the untreated group, systolic blood pressure was significantly higher and both EDHF-mediated relaxation and endothelium-dependent hyperpolarization were markedly reduced as compared with the control group. Although EDHF-mediated relaxation was not significantly improved in the HYD, OLM and AZL groups, it was significantly improved in the OLM + AZL group, as was also the case with phosphorylation of Akt and endothelial NO synthase (eNOS). In contrast, the endothelium-independent relaxation response to sodium nitroprusside or NS-1619 (a direct opener of KCa channels) was unaltered in any group. Conclusions: OLM + AZL may improve the severely impaired EDHF-mediated responses in diabetic ApoE-/- mice, in which activation of the endothelial Akt-eNOS pathway may be involved.