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as premature ventricular contractions (Wehling-Henricks et al.
2005
). Thus,
increased cardiomyocyte NO levels can improve prominent features of cardiac
dystrophic pathology in
mdx
mice.
Not only are increases in NO concentrations cardioprotective, but increases in
cGMP concentrations are also cardioprotective in
mdx
hearts (Khairallah et al.
2008
). Indeed, cardiomyocyte-specific expression of constitutively active NPR-A
(atrial natriuretic peptide receptor A guanylyl cyclase), a plasma membrane-associated
guanylyl cyclase, reduced cardiomyopathy in
mdx
hearts (Khairallah et al.
2008
).
The NPR-A transgene-mediated an increase in cGMP in dystrophin-deficient car-
diomyocytes improved cardiomyocyte viability, blunted the progressive increase in
LV end diastolic pressure (preload), and increased the cardiac power two-fold, but
did not protect
mdx
hearts against contraction-induced damage (Khairallah et al.
2008
). These data demonstrated that chronic increases in cardiomyocyte cGMP
levels could reduce cardiac dysfunction in
mdx
mice. In summary, as observed in
skeletal muscle, several different approaches indicate that enhanced NO-cGMP
signaling has potent antidystrophic effects in dystrophin-deficient hearts.
8 Use of PDE5A Inhibitors to Amplify cGMP Signaling
in
mdx
Mice
As described above, one of the consequences of NO signaling is an increase in sGC
activity, with a concomitant increase in cytosolic cGMP. While it is not possible to
selectively increase nNOS expression or activity using a pharmacological approach,
it is possible to enhance NO signal transduction by inhibiting the activity of cGMP-
hydrolyzing PDEs, such as PDE5A, thus raising cytosolic cGMP. Three studies of
the impact of PDE5A inhibition on the dystrophic pathology of cardiac and skeletal
muscle in the
mdx
mouse model of DMD have been reported and will now be
summarized.
In one published study of the cardiac effects of sildenafil-mediated inhibition of
PDE5A in
mdx
mice, Khairallah and coworkers reported that sildenafil adminis-
tered daily by intraperitoneal injection over 6 weeks (0.7 mg/kg/day) enabled
mdx
hearts to sustain a higher heart rate in response to increased workload (Khairallah
et al.
2008
). Sildenafil significantly reduced Evan's Blue dye uptake in
mdx
cardiomyocytes, indicative of reduced membrane permeability and suggestive of
decreased susceptibility to contraction-induced damage (Khairallah et al.
2008
).
Sildenafil also decreased
sgca1
(
a
1 subunit of sGC) and
Anf
(atrial natriuretic
factor) transcript expression, suggesting that inhibition of PDE5A improved
upstream cGMP signaling and decreased early pathological remodeling in
mdx
hearts, respectively. Cardioprotective effects were not due to utrophin upregulation.
In parallel independent studies, we have found that sildenafil confers significant
cardioprotection to old
mdx
hearts (Adamo et al.
2010
). Twelve-month-old
mdx
mice exhibit significant LV dysfunction, as indicated by a higher than normal MPI