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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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          Abstract

          Background Duchenne muscular dystrophy (DMD) is the most common inherited form of muscular dystrophy, which results in skeletal muscle weakness by age 6. In its later stages DMD leads to dilated cardiomyopathy and heart failure with high level of mortality. At present there are no effective treatments for most of the cardiac pathology in DMD patients. Results Recently we showed that sildenafil could reverse much of the cardiac dysfunction in the mdx mouse model of DMD. Treatments with sildenafil (in the drinking water) resulted in significant improvements in cardiac function, analyzed by the myocardial performance index (MPI) and Ea/Aa ratios [1]. Similar improvements in cardiac functions were also observed when sildenafil was administered daily for one week by oral gavage (60 mg/kg). However, daily administration of tadalafil by oral gavage (4 and 20 mg/kg) did not produce any improvement in the myocardial performance index. In order to provide a reliable indicator for efficacy of dosing of different PDE5 inhibitors we examined the levels of PDE5 phosphorylation in tissues known to express PDE5, e.g. lung and blood vessels, as a biological indicator of cGMP induced PKG activation in vivo. We found that both tadalafil and sildenafil caused time-dependent equivalent phosphorylation of PDE5 in these tissues. Similar PDE5 phosphorylation patterns were observed in cardiac tissue extracts. Since no PDE5 expression has been detected in adult mouse cardiac myocytes, we consider phospho-PDE5 in the cardiac samples to be from cardiac blood vessels, myofibroblasts and even platelets from residual blood. Differential effects of PDE5 inhibitors on cardiac dysfunctions in MDX mice could point to PDE1C, which can be partially inhibited by sildenafil, but not by tadalafil. PDE1C is the calcium/calmodulin cGMP/cAMP PDE, most highly expressed in mouse cardiac myocytes. However, the functions of PDE1C in myocytes have not been determined. We used specific PDE1 inhibitors (Intra-Cellular Therapies, NY) and found that these inhibitors could substantially stimulate cGMP-induced phosphorylation of phospholamban by C-type natriuretic peptide (CNP). Moreover, in cardiac myocytes, isolated from PDE1C KO mice, CNP-induced phosphorylation of phospholamban was substantially higher, and no additional increase of its phosphorylation was detected with PDE1 specific inhibitors. However, we did not detect any induction of phosholamban phosphorylation when sildenafil was applied to mouse cardiac myocytes even at high concentrations; and tadalafil did not have any effects as well. Although the pattern of PDE5 phosphorylation after sildenafil and tadalafil application by oral gavage corresponded to the differences in the pharmacokinetics of these drugs, they produced differential changes in ERK, VASP and GSKb phosphorylation in lung and heart, often in different directions. Conclusion These data suggest that the sildenafil and tadalafil differential effects could be the result of indirect effects of these drugs on other cell types, subsequently affecting cardiac functions. However, PDE1 specific inhibitors appear to be new potential agents for direct regulation of phospholamban phosphorylation and calcium homeostasis in the heart.

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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

            Conference
            BMC Pharmacol Toxicol
            BMC Pharmacol Toxicol
            BMC Pharmacology & Toxicology
            BioMed Central
            2050-6511
            2013
            29 August 2013
            : 14
            : Suppl 1
            : O38
            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
            Article
            2050-6511-14-S1-O38
            10.1186/2050-6511-14-S1-O38
            3765472
            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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