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Wharton et al. 2005 ). The level of expression of PDE5 is much higher in the
pulmonary circulation than the systemic circulation, suggesting that pulmonary
specificity is possible by targeting PDE5 (Corbin et al. 2005 ). With respect to PAH,
increased expression, both at the level of mRNA and protein, increased phosphory-
lation and activity of PDE5 have been reported in a number of animal models of
PAH, and importantly, also in patients with PAH, which would, at least in part,
explain the disease-related decrease in cGMP levels and impaired endothelium-
dependent pulmonary vasodilation (Black et al. 2001 ; Cohen et al. 1996 ; Hanson
et al. 1998 ; Maclean et al. 1997 ; Murray et al. 2007 ; Wharton et al. 2005 ). In animal
models of PAH, the PDE5 inhibitors zaprinast, E4021, and E4010, via increasing
[cGMP] I , vasodilate the pulmonary circulation; importantly, this vasodilation
occurs without systemic effects (Cohen et al. 1996 ; Eddahibi et al. 1998 ; Hanasato
et al. 1999 ; Ichinose et al. 1998 ; Jeffery and Wanstall 1998 ). E4010 was shown
to improve mortality in monocrotaline-treated rats by 84% and in parallel to
attenuate the development of hypoxia-induced PAH by reducing the increase in
mPAP and the characteristic increase in medial wall thickness (Hanasato et al.
1999 ; Kodama and Adachi 1999 ). These data, together with those in Fig. 2a ,
which show that zaprinast significantly decreases serum-induced proliferation of
PAH-PASMCs, suggest that in addition to being potent vasodilators PDE5 inhibi-
tors are also antiproliferative and proapoptotic. However, since 10 m M zaprinast
can also block PDE1 activity, its effects could also be attributed to inhibition of
this isoform.
The approval by the FDA of three oral PDE5 inhibitors for the treatment of
erectile dysfunction, namely sildenafil (Viagra
), tadalafil (Cialis
), and varde-
nafil (Levitra
) opened up the possibility that PDE5 inhibitors could be used
clinically to treat PAH. Evidence supports both the acute and the long-term use
of these PDE5 inhibitors in a number of forms of experimental and clinical PAH.
In 2007, the same formulation of sildenafil (marketed as Revatio) was approved for
treatment of PAH, and the two other PDE5 inhibitors, tadalafil (marketed as
Adcirca) and vardenafil (marketed as Levitra, used off-label), have more recently
been tested in patients with PAH. Zhao et al. ( 2001 ) examined the effect of
sildenafil on hypoxia-induced mice and healthy human volunteers in whom PAH
was induced by inhaling a low oxygen concentration, which produced a 56%
increase in mPAP (Zhao et al. 2001 ). A single dose of sildenafil (100 mg) inhibited
the hypoxic rise in mPAP without systemic vasodilation and attenuated the increase
in mPAP, RV hypertrophy, and remodeling in mice chronically exposed to hypoxia.
Figure 2c, d show that sildenafil relaxes both the main and the first branch PA from
the chronic-hypoxic rat, a response that is comparable to that in control-PA. It is
important to highlight, which will be discussed below in further detail, that some of
the effects of sildenafil may be due to partial blockade of PDE1 activity [since the
IC 50 of sildenafil for PDE1 is achievable both in vivo and in vitro, (Paul et al.
2005 )].
Clinically, sildenafil has been shown to be therapeutically useful in 80-90%
of IPAH, and PAH secondary to HIV, thromboembolic pulmonary hypertension
or portopulmonary hypertension: however, a lack of evidence has as-yet been
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