Anti-atherogenic effects of the combination therapy with olmesartan and azelnidipine in diabetic apolipoprotein E-deficient mice

Kazuki Noda, Maki Hosoya, Sota Nakajima, Junko Ohashi, Yoshihiro Fukumoto, Hiroaki Shimokawa

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Many studies have aimed to identify anti-atherogenic agents in cardiovascular medicine. We have recently demonstrated that the combination therapy with olmesartan (OLM), an angiotensin II receptor blocker, and azelnidipine (AZL), a dihydroprydine calcium-channel blocker, improves endothelial function in diabetic Apolipoprotein-deficient (ApoE-/-) mice. In the present study, we examined whether this combination therapy also inhibits atherosclerosis in mice. We used male control and streptozocin-induced diabetic ApoE-/- mice. Diabetic ApoE-/- mice were orally treated for 5 weeks with vehicle (Untreated), OLM (30 mg/ kg/day), AZL (10 mg/kg/day), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) as an antihypertensive control. At 5 weeks, systolic blood pressure was significantly elevated in Untreated but was normalized in OLM+AZL and HYD. The atherosclerosis area in the thoracic aorta, perivascular fibrosis and medial thickness of the coronary arteries were increased in Untreated and were ameliorated in OLM+AZL but not in HYD. Staining with a fluorescent probe dihydroethidium showed that production of reactive oxygen species was increased in Untreated, and ameliorated in OLM+AZL. Consistent with these findings, macrophage infiltration in the kidney and the expression of receptor for advanced glycation end-products in the heart, kidney and liver were increased in Untreated and were all ameliorated in OLM+AZL, associated with up-regulation of endothelial NO syntheses (eNOS). In conclusion, the combination therapy with OLM and AZL exerts anti-atherogenic effect in diabetic ApoE-/- mice through suppression of oxidative stress and activation of eNOS, independent of its blood pressure-lowering effects. Clinically, this combination therapy may be useful for patients with hypertension, hyperlipidemia and diabetes.

Original languageEnglish
Pages (from-to)305-315
Number of pages11
JournalTohoku Journal of Experimental Medicine
Volume228
Issue number4
DOIs
Publication statusPublished - 2012

Keywords

  • Angiotensin II receptor blocker
  • Atherosclerosis
  • Calcium channel blocker
  • Combination therapy
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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