title: Anti-atherogenic effects of the combination therapy with olmesartan and azelnidipine in diabetic apolipoprotein E-deficient mice.
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.
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Noda
authors.forename: Maki
authors.initials: M
authors.lastname: Hosoya
authors.forename: Sota
authors.initials: S
authors.lastname: Nakajima
authors.forename: Junko
authors.initials: J
authors.lastname: Ohashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D050197:Atherosclerosis / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001391:Azo Compounds / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D013599:Systole / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D001391:Azo Compounds; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007093:Imidazoles; D013777:Tetrazoles; D001383:Azetidinecarboxylic Acid; C437965:olmesartan; D052250:Nitric Oxide Synthase Type III; C011049:oil red O; C061679:azelnidipine