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in normal and dystrophin-deficient muscles and the potential of PDE5A inhibition
as a therapeutic approach for the treatment of cardiovascular deficits in DMD.
Keywords Cardiac muscle
Cardiomyopathy
cGMP
Duchenne Muscular Dys-
trophy
Dystrophin
Mdx
Nitric oxide
nNOS
Neuronal nitric oxide synthase
PDE5
PDE5 inhibitors
Sildenafil
Skeletal muscle
1
Introduction
The absence of normal neuronal nitric oxide (NO) synthase mu (nNOS m ) signaling
in the muscles of humans and mice is a well-described consequence of the loss of
dystrophin, the primary cause of Duchenne Muscular Dystrophy (DMD). The
absence of nNOS m signaling impairs blood supply to contracting skeletal muscles,
exposing working muscles to continuous damaging ischemic insult (Thomas et al.
1998 ; Asai et al. 2007 ). At present, it is not possible to selectively increase nNOS
expression or activity using a pharmacological approach, but it is possible to mimic
some of the effects of increased nNOS activity, which increases synthesis of cGMP
and cGMP signaling (or circumvent aberrant upstream nNOS signaling) by inhibit-
ing the activity of downstream cGMP-hydrolyzing phosphodiesterases (PDEs).
Recent efforts to pharmacologically enhance nNOS-cGMP signaling in dystro-
phic muscles have involved the targeted inhibition of PDE5A with sildenafil
(Viagra ® , Revatio ® ) or tadalafil (Cialis ® ), commonly used to treat erectile dysfunc-
tion and pulmonary hypertension. In the presence of a stimulus of cGMP synthesis
such as NO, PDE5A inhibitors block cGMP breakdown, thereby raising cellular
cGMP concentrations in many tissues such as smooth muscle. Inhibition of PDE5A
is a highly attractive therapeutic approach for treating DMD for at least five reasons.
First, there is strong evidence for pronounced vascular dysfunction in DMD, partic-
ularly reduced blood delivery to active muscle (Mendell et al. 1971 ; Thomas et al.
1998 ; Sander et al. 2000 ). Second, in several animal models, PDE5A inhibition has
been shown to provide beneficial effects on skeletal, smooth, and cardiac muscle
tissues (Asai et al. 2007 ; Khairallah et al. 2008 ; Reffelmann and Kloner 2009 ).
Third, the ability to treat all muscle tissues is very important since therapeutic
approaches that correct only skeletal muscle dysfunction increase cardiac workload,
which is damaging to the weakened dystrophic heart (Townsend et al. 2008 ). Those
approaches that fail to address vascular dysfunction resulting from impaired nNOS
signaling in smooth muscle result in significant unopposed sympathetic vasocon-
striction known to exacerbate skeletal muscle damage (Ito et al. 2006 ). Fourth,
increases in cGMP levels or PDE5A inhibition confer substantial cardioprotective
effects in several animal models including improved diastolic dysfunction (Takimoto
et al. 2005 ; Das et al. 2008 ; Reffelmann and Kloner 2009 ). This is an important
consideration since existing treatments for DMD-associated cardiomyopathy, includ-
ing angiotensin-converting enzyme (ACE) inhibitors and b -adrenergic blockade,
predominantly address systolic, but not the diastolic dysfunction in DMD patients
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