Dissertation/Thesis Abstract

The Effect of Phosphodiesterase 5A Inhibitors on Skeletal and Cardiac Muscle Function in Dystrophin-Deficient (mdx) Mice
by Adamo, Candace Marie, Ph.D., University of Washington, 2011, 87; 3472334
Abstract (Summary)

Duchenne muscular dystrophy (DMD) is a severe and ultimately fatal disease characterized by progressive muscle wasting and weakness. DMD is caused by the absence of a functional dystrophin protein, which leads to severe skeletal muscle pathologies as well as cardiomyopathy. The loss of dystrophin leads to reduced expression and mislocalization of dystrophin-associated proteins including neuronal nitric oxide synthase mu (nNOSμ). nNOSμ plays a key role in nitric oxide (NO) production and subsequent downstream signaling via the second messenger, cGMP. Disrupted NO-cGMP signaling to the vasculature results in muscle fatigue and unopposed sympathetic vasoconstriction during exercise, thereby increasing contraction-induced damage in dystrophin-deficient muscles. We have investigated whether blockade of cGMP hydrolysis by the FDA-approved phosphodiesterase 5A (PDESA) inhibitors, sildenafil citrate (Viagra®) and tadalafil (Cialis®), can be used to ameliorate the progressive skeletal and cardiac dysfunction present in dystrophin-deficient (mdx) mice. Based on the findings listed in this dissertation, we conclude that chronic sildenafil treatment has no effect on dystrophic skeletal muscle damage or function, but drastically improves diastolic dyfunction in old mdx mice. Currently, there are no validated therapeutic approaches that effectively target diastolic dysfunction. Thus, cGMP enhancement by sildenafil may be an effective treatment of other forms of diastolic dysfunction. More importantly, when sildenafil treatment was started after cardiomyopathy had developed, the established symptoms were rapidly reversed within a few days. Surprisingly, there was no effect seen after tadalafil treatment. The difference between sildenafil and tadalafil may be due to partial inhibition of PDE1C in cardiomyocytes, identifying a previously underestimated role for PDE1C inhibition in the cardioprotective mechanism of sildenafil. Hemodynamic analysis also provided new evidence that long-term sildenafil treatment can reduce the heightened sympathetic activity in mdx4cv mice, thus preventing increased cardiac workload and eventual dysfunction. Using these findings, we suggest alternative mechanisms by which sildenafil improves mdx4cv cardiac performance. One possible mechanism would be that short-term treatment of sildenafil, and not tadalafil, improves mdx4cv cardiac performance, and is possibly mediated by PDE1C inhibition in cardiomyocytes. We propose a second potential mechanism where long-term sildenafil treatment may improve cardiac performance by suppressing heightened sympathetic activity, rather than reducing systemic blood pressure or cardiac remodeling. In this dissertation, I will address NO-cGMP signaling in normal and dystrophin-deficient muscles and the potential of PDE5A/1C inhibition as a therapeutic approach for the treatment of cardiac dysfunction in DMD.

Indexing (document details)
Advisor: Beavo, Joseph A.
Commitee:
School: University of Washington
School Location: United States -- Washington
Source: DAI-B 72/11, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Pharmacology, Medical imaging, Physiology
Keywords: Cardiac muscle, Duchenne muscular dystrophy, Dystrophin, Phosphodiesterase, Skeletal muscle
Publication Number: 3472334
ISBN: 978-1-124-86156-2
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