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Differential effects of PDE5 inhibitors on cardiac dysfunction in the MDX ouse model of Duchenne muscular dystrophy

, 1 , 1 , 1 , 2 , 3 , 4 , 5 , 5 , 2 , 1 , 1

BMC Pharmacology & Toxicology

BioMed Central

6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

28-30 June 2013

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      Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy.

      Duchenne muscular dystrophy (DMD) is a progressive and fatal genetic disorder of muscle degeneration. Patients with DMD lack expression of the protein dystrophin as a result of mutations in the X-linked dystrophin gene. The loss of dystrophin leads to severe skeletal muscle pathologies as well as cardiomyopathy, which manifests as congestive heart failure and arrhythmias. Like humans, dystrophin-deficient mice (mdx mice) show cardiac dysfunction as evidenced by a decrease in diastolic function followed by systolic dysfunction later in life. We have investigated whether sildenafil citrate (Viagra), a phosphodiesterase 5 (PDE5) inhibitor, can be used to ameliorate the age-related cardiac dysfunction present in the mdx mice. By using echocardiography, we show that chronic sildenafil treatment reduces functional deficits in the cardiac performance of aged mdx mice, with no effect on normal cardiac function in WT controls. More importantly, when sildenafil treatment was started after cardiomyopathy had developed, the established symptoms were rapidly reversed within a few days. It is recognized that PDE5 inhibitors can have cardioprotective effects in other models of cardiac damage, but the present study reports a prevention and reversal of pathological cardiac dysfunction as measured by functional analysis in a mouse model of DMD. Overall, the data suggest that PDE5 inhibitors may be a useful treatment for the cardiomyopathy affecting patients with DMD at early and late stages of the disease.
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        Author and article information

        Affiliations
        [1 ]Departments of Pharmacology, University of Washington, Seattle, WA 98195, USA
        [2 ]Institut für Pharmakologie und Toxikologie, TU, München, Germany
        [3 ]Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA
        [4 ]Departments of Cardiology, University of Washington, Seattle, WA 98195, USA
        [5 ]Intra-Cellular Therapies, Inc, New York , NY 10032, USA
        Contributors
        Conference
        BMC Pharmacol Toxicol
        BMC Pharmacol Toxicol
        BMC Pharmacology & Toxicology
        BioMed Central
        2050-6511
        2013
        29 August 2013
        : 14
        : Suppl 1
        : O38
        3765472
        2050-6511-14-S1-O38
        10.1186/2050-6511-14-S1-O38
        Copyright ©2013 Rybalkin et al; licensee BioMed Central Ltd.

        This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

        6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications
        Erfurt, Germany
        28-30 June 2013
        Categories
        Oral Presentation

        Toxicology

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