TY - JOUR
T1 - Combination therapy with olmesartan and azelnidipine improves EDHF-mediated responses in diabetic apolipoprotein E-deficient mice
AU - Hosoya, Maki
AU - Ohashi, Junko
AU - Sawada, Ayuko
AU - Takaki, Aya
AU - Shimokawa, Hiroaki
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Angiotensin-receptor blocker
KW - Calcium-channel blocker
KW - Endothelium-dependent relaxation
KW - Endothelium-derived hyperpolarizing factor
KW - Microcirculation
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U2 - 10.1253/circj.CJ-09-0862
DO - 10.1253/circj.CJ-09-0862
M3 - Article
C2 - 20154404
AN - SCOPUS:77950648451
VL - 74
SP - 798
EP - 806
JO - Circulation Journal
JF - Circulation Journal
SN - 1346-9843
IS - 4
ER -