Combination Therapy With Olmesartan and Azelnidipine Improves EDHF-Mediated Responses in Diabetic Apolipoprotein E-Deficient Mice

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Author(s)

    • HOSOYA Maki
    • Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
    • OHASHI Junko
    • Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
    • SAWADA Ayuko
    • Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
    • TAKAKI Aya
    • Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
    • SHIMOKAWA Hiroaki
    • Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine

Abstract

<b><i>Background:</i></b> 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<sup>-/-</sup>) mice. <b><i>Methods and Results:</i></b> We used male C57BL/6N (control) and streptozocin-induced diabetic ApoE<sup>-/-</sup> mice. The diabetic ApoE<sup>-/-</sup> mice were administered oral vehicle (untreated), olmesartan (OLM, 30 mg·kg<sup>-1</sup>·day<sup>-1</sup>), azelnidipine (AZL, 10 mg·kg<sup>-1</sup>·day<sup>-1</sup>), their combination (OLM + AZL), or hydralazine (HYD 5 mg·kg<sup>-1</sup>·day<sup>-1</sup>) 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 K<sub>Ca</sub> channels) was unaltered in any group. <b><i>Conclusions:</i></b> OLM + AZL may improve the severely impaired EDHF-mediated responses in diabetic ApoE<sup>-/-</sup> mice, in which activation of the endothelial Akt - eNOS pathway may be involved. (<i>Circ J</i> 2010; <b>74:</b> 798-806)<br>

Journal

  • Circulation Journal

    Circulation Journal 74(4), 798-806, 2010-03-25

    The Japanese Circulation Society

References:  55

Cited by:  6

Codes

  • NII Article ID (NAID)
    10026472808
  • NII NACSIS-CAT ID (NCID)
    AA11591968
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    13469843
  • Data Source
    CJP  CJPref  J-STAGE 
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