title: Aliskiren in combination with valsartan exerts synergistic protective effects against ventricular remodeling after myocardial infarction in mice.
abstract: The efficacy of aliskiren, a direct renin inhibitor, in ventricular remodeling after myocardial infarction (MI) compared with conventional renin-angiotensin system (RAS) inhibitors remains to be defined. This study was performed to examine the protective effects of aliskiren and its addition to valsartan, an angiotensin-II receptor blocker, against ventricular remodeling after MI. MI was induced in 8- to 12-week-old C57BL/6 mice by ligating the left anterior descending artery. At 3 days after MI, mice were divided into five groups and were treated with the following: (1) phosphate-buffered saline (PBS); (2) hydralazine (10 mg kg(-1) day(-1)); (3) valsartan (8 mg kg(-1) day(-1)); (4) aliskiren (25 mg kg(-1) day(-1)); and (5) combined aliskiren (25 mg kg(-1) day(-1)) and valsartan (8 mg kg(-1) day(-1)). With these doses of drugs, blood pressure-lowering effects compared with the PBS group were similar among the treated groups in sham-operated mice. At 28 days after MI, echocardiographic, hemodynamic and histological assessments demonstrated that monotherapy with valsartan or aliskiren alone significantly and similarly ameliorated ventricular remodeling after MI compared with the PBS and the hydralazine groups. Combination therapy of valsartan and aliskiren more greatly improved ventricular remodeling after MI with enhancement of angiogenesis and greater attenuation of tissue oxidative stress and inflammation. Our results indicate that aliskiren can be an alternative to conventional RAS inhibitors in the treatment of post-MI patients. Moreover, the dual therapy of valsartan and aliskiren may be more beneficial than either monotherapy. Further clinical trials will be warranted to sufficiently assess the safety and the efficacy of the use of aliskiren in post-MI patients.
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Higashikuni
authors.forename: Minoru
authors.initials: M
authors.lastname: Takaoka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwata
authors.forename: Kimie
authors.initials: K
authors.lastname: Tanaka
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
mesh_terms: D000577:Amides / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004357:Drug Synergism; D005650:Fumarates / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D005650:Fumarates; D013777:Tetrazoles; C446481:aliskiren; D000068756:Valsartan; D014633:Valine