Journal
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS
Volume 16, Issue 1, Pages 87-95Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/1074248410381757
Keywords
Duchenne muscular dystrophy; dystrophin; mice; cardiomyopathy; angiotensin; echocardiography
Funding
- National Institute of Child Health and Human Development [K12HD001399-04]
- Department of Defense US Army Medical Research Acquisition Activity [W81XWH-05-1-0616]
- Foundation to Eradicate Duchenne Inc
- Muscular Dystrophy Association
- National Institute of Child Health and Human Development Wellstone Muscular Dystrophy Center [1U54HD053177-01A1]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01-AR050478]
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Recent studies showed that chronic administration of losartan, an angiotensin II type I receptor antagonist, improved skeletal muscle function in dystrophin-deficient mdx mice. In this study, C57BL/10ScSn-Dmd(mdx)/J female mice were either untreated or treated with losartan (n = 15) in the drinking water at a dose of 600 mg/L over a 6-month period. Cardiac function was assessed via in vivo high frequency echocardiography and skeletal muscle function was assessed using grip strength testing, Digiscan monitoring, Rotarod timing, and in vitro force testing. Fibrosis was assessed using picrosirius red staining and Image J analysis. Gene expression was evaluated using real-time polymerized chain reaction (RT-PCR). Percentage shortening fraction was significantly decreased in untreated (26.9% +/- 3.5%) mice compared to losartan-treated (32.2% +/- 4.2%; P < .01) mice. Systolic blood pressure was significantly reduced in losartan-treated mice (56 +/- 6 vs 69 +/- 7 mm Hg; P < .0005). Percentage cardiac fibrosis was significantly reduced in losartan-treated hearts (P < .05) along with diaphragm (P < .01), extensor digitorum longus (P < .05), and gastrocnemius (P < .05) muscles compared to untreated mdx mice. There were no significant differences in skeletal muscle function between treated and untreated groups. Chronic treatment with losartan decreases cardiac and skeletal muscle fibrosis and improves cardiac systolic function in dystrophin-deficient mdx mice.
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