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This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/H1281    most recent 00792.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Lee, T.-M. Articles by Chang, N.-C. Search for Related Content PubMed PubMed Citation Articles by Lee, T.-M. Articles by Chang, N.-C.

Additive effects of combined blockade of AT₁ receptor and HMG-CoA reductase on left ventricular remodeling in infarcted rats

¹Cardiology Section, Department of Medicine, Taipei Medical University and Chi-Mei Medical Center, Tainan; ²National Taiwan University and Department of Pharmacy, National Taiwan University Hospital, Taipei; ³Department of Surgery, Municipal Jen-Ai Hospital, Taipei; and ⁴Cardiology Section, Department of Medicine, Taipei Medical University and Hospital, Taipei, Taiwan

Submitted 25 July 2005 ; accepted in final form 20 March 2006

Both angiotensin receptor antagonists and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to attenuate cardiomyocyte hypertrophy after myocardial infarction. Whether combination treatment may be superior to either drug alone on cardiomyocyte hypertrophy remains unclear. After ligation of the left anterior descending artery, rats were randomized to both, one, or neither of the angiotensin receptor antagonists olmesartan (0.01, 0.1, 1, and 2 mg·kg^–1·day^–1) and HMG-CoA reductase inhibitor pravastatin (5 mg·kg^–1·day^–1) for 4 wk. Each drug, when given alone, decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone when compared with vehicles. However, compared with either drug alone, combined olmesartan and pravastatin prevent cardiomyocyte hypertrophy to a larger extent, which was further confirmed by downregulation of the left ventricular atrial natriuretic peptide mRNA. The myocardial endothelin-1 levels at the border zone were 6.5-fold higher (P <0.0001) in the vehicle group compared with the sham group, which can be inhibited after pravastatin administration. Combination treatment significantly attenuated cardiomyocyte hypertrophy in a dose-dependent manner, although tissue endothelin-1 levels remained stable in combination groups of different olmesartan doses. Measurements of the arrhythmic score mirrored those of cardiomyocyte hypertrophy. Dual therapy with pravastatin and olmesartan, which produced an additive reduction in cardiomyocyte hypertrophy and cardiac fibrosis after myocardial infarction through different mechanisms, decreases the propensity of the heart to arrhythmogenesis. Pravastatin administration provided favorable ventricular remodeling, probably through decreased tissue endothelin-1 level. In contrast, olmesartan-related attenuated cardiomyocyte hypertrophy is independent of endothelin-1 pathway.

arrhythmias; hypertrophy; myocardial infarction; myocytes; 3-hydroxy-3-methylgultaryl coenzyme A

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