Evaluation of the Therapeutic Utility of Phosphodiesterase 5A Inhibition in the mdx Mouse Model of Duchenne Muscular Dystrophy - Phosphodiesterases as Drug Targets - page 337

1.0

0.9

0.8

0.7

*

0.6

0.5

0.4

0.3

mdx

0.2 wild type

mdx 0.1

+ sildenafil

0.0

12 months 15 months

Fig. 2 Sildenafil treatment reverses cardiomyopathy in old mdx mice. Twelve-month-old mdx
mice exhibit significant left ventricle dysfunction as indicated by a high myocardial performance
index compared with wild-type mice ( # p < 0.05). Twelve-month-old mdx mice treated for
3 months with the PDE5 inhibitor sildenafil ad libitum exhibited a significantly reduced
( p < 0.05) myocardial performance index comparable to wild-type controls. Sildenafil treatment
can reverse established global left ventricle dysfunction in old mdx mice (Adamo et al. 2010 )

measured by echocardiography (Spurney et al. 2008 ; Adamo et al. 2010 , Fig. 2 ).
Treatment of 12-month-old mdx mice for 3 months with sildenafil in their drinking
water significantly reduces MPI to wild-type levels (Adamo et al. 2010 , Fig. 2 ).
Thus, sildenafil can reverse established left ventricle dysfunction, even in aged mdx
mice. These data suggest that older DMD patients with established cardiomyopathy
may benefit from PDE5A inhibition.
Since cardiomyocytes express very little or no PDE5A, the question remains as
to how PDE5A inhibition reduces cardiac pathology and dysfunction in the mdx
heart (Takimoto et al. 2005 ; Lukowski et al. 2010 ). PDE5A protein expression may
be higher in mdx cardiomyocytes, but at present it is unknown whether PDE5A
levels or action are affected by the loss of dystrophin. Sildenafil may exert some of
its cardioprotective effects by inhibiting PDE5A activity in VSMC of the systemic
or cardiac vasculature. In addition, off-target effects of sildenafil on PDE1C could
contribute to cardiomyocyte-specific effects of sildenafil. Like PDE5A, PDE1C can
hydrolyze cGMP. But unlike PDE5A, PDE1C is found in abundance in cardiomyo-
cytes (Bender and Beavo 2006 ). High nanomolar concentrations of sildenafil can
inhibit PDE1C activity; therefore, inhibition of PDE1C could also account for some
of the cardioprotective effects of sildenafil (Lukowski et al. 2010 ; Vandeput et al.
2009 ). Nonetheless, it is clear that increasing cGMP levels sildenafil treatment
reduces cardiac pathology and dysfunction in mdx hearts (Khairallah et al. 2008 ).
On the basis of these findings, Khairallah and coworkers proposed that upregulation
of cGMP by PDE5 inhibition should be explored as a new therapeutic approach to
treating DMD.
The impact of PDE5 inhibition on contraction-induced muscle damage during
ischemic exercise has also been investigated in mdx mice (Asai et al. 2007 ).
Restoration of postcontraction blood flow to the sternomastoid muscle in situ was