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of sildenafil on pulmonary hemodynamics is dependent, in part, on the bioactivity
of natriuretic peptides, the latter of which may be possible new therapeutic app-
roaches (Baliga et al. 2008 ; Klinger et al. 2006 ). Thus, although long-term studies are
required, therapy with PDE5 inhibitors appears safe and shows clinical benefit.
PDE5 inhibitors are known to enhance cGMP/PKG signaling but the mechanisms
and downstream mediators for their antiproliferative and vasodilatory actions have
not been fully elucidated; inhibition of PKG reverses many of the effects of sildenafil
(Li et al. 2009 ; Sun et al. 2009b ). PKG activation in PASMCs, via inhibition of
PDE5, activates calcium pumps, inhibits voltage-gated and receptor operated Ca 2+
channels and inhibits BK Ca channels, all of which contribute to reduction in intra-
cellular [Ca 2+ ] i , uncoupling of the contractile apparatus by activating myosin light
chain phosphatase (MLCP) and hyperpolarization of the membrane (Archer et al.
1994 ; Koyama et al. 2001 ; Lu et al. 2010 ; Pauvert et al. 2004 ; Rybalkin and
Bornfeldt 1999 ; Wang et al. 2009 ). Sildenafil downregulates the increased expres-
sion of TRPC1 and TRPC6 in PAH-PASMCs, thereby decreasing capacitative
calcium entry (CCE) and inhibiting proliferation by ET-1 and 5-HT; inhibition of
NFAT translocation and activation by sildenafil may be key for the decrease in
TRPC expression (Lu et al. 2010 ; Pauvert et al. 2004 ; Wang et al. 2009 ). In parallel,
PDE5 inhibition can also suppress RhoA activation and attenuate MMP2 produc-
tion, mechanisms that contribute to decreased pulmonary vascular remodeling (Sun
et al. 2009b ). Inhibition of RhoA prevents ROCK-dependent inhibition of MLCP,
thereby upregulating MKP-1 that can also decrease phosphorylation of ERK1/2 and
suppress PASMC proliferation (Guilluy et al. 2005 ). In vascular smooth muscle
cells, sildenafil activates RGS2 (the regulator of G-protein-coupled signaling 2) to
suppress Gq-mediated contraction; if such an effect occurs in PASMCs, it could
contribute to the blunting of ET-1 or 5-HT signaling by PDE5 inhibition (Lu et al.
2010 ; Pauvert et al. 2004 ; Takimoto et al. 2009 ; Wang et al. 2009 ). Many studies
imply that some of the beneficial effects of PDE5-inhibitors are, at least in part,
mediated by an increase in cAMP, which results from an inhibition of PDE3
(a cGMP-inhibited PDE) by the increased levels of cGMP, as will be discussed
below (Koyama et al. 2001 ; Zaccolo and Movsesian 2007 ). However, we find that
the acute stimulation of PAH-PASMCs with zaprinast does not increase the blunting
of agonist-induced cAMP accumulation in these cells (Fig. 2b ).
Role of PDE3 in Pulmonary Vasculature
PDE3 is a major PDE in the lung and both PDE3A and PDE3B are expressed in
human and rat PASMCs (Murray et al. 2002 , 2007 ; Palmer and Maurice 2000 ). The
mRNA and protein expression and activity of PDE3 is increased in animal models
of PAH and PAH-PASMCs (PDE3A and PDE3B, Fig. 1b, c ) and after exposure of
PASMCs to chronic hypoxia (which, in particular, enhances expression of PDE3A
(Murray et al. 2002 , 2007 ; Wagner et al. 1997 ). Elevated PDE3 activity, at least
in part, would explain reduced [cAMP] i in both isolated lung from the chronic-
hypoxic rat and agonist-induced cAMP accumulation in PAH-PASMCs; PDE3
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