Biology Reference
In-Depth Information
(Clarke et al.
1994
). A combination of milrinone and sildenafil achieved a better
hemodynamic profile in a porcine model of acute PAH, with greater pulmonary
vasodilatation and increased contractility but without additional systemic vasodila-
tion (Lobato et al.
2006
). Furthermore, inhaled NO enhanced the dose-dependent
decrease in PVR by milrinone by a further 20% (Deb et al.
2000
). Inhalation of
nebulized milrinone can improve the hemodynamic profile in animal models of
PAH and patients with pulmonary hypertension secondary to congestive heart
failure, suggesting this may be a novel, effective pulmonary-selective strategy;
however, longer-term studies are required (Botha et al.
2009
; Hentschel et al.
2007
;
Lamarche et al.
2007
).
Inhibiting PDE3 increases cAMP, which decreases vasoconstriction and prolif-
eration through a number of mechanisms, although which are necessary and
sufficient for the beneficial effect of cAMP in PASMCs are not fully defined
(Koyama et al.
2001
; Rybalkin and Bornfeldt
1999
). cAMP, via PKA activation,
phosphorylates MLCK, leading to vasodilation of the PA and inhibits Raf-1
activation, thereby inhibiting ERK1/2 activation and PI3K, both of which attenuate
PASMC proliferation. In smooth muscle cells, cAMP blocks cell cycle progression
from G1 to S phase, inhibits cyclin-dependent kinase 4, and upregulates the cyclin-
dependent kinase 2 inhibitor, p27kip1(Koyama et al.
1996
). In PAH-PASMCs,
milrinone inhibited CCE ~50% (Murray et al.
2007
). Inhibitors of PDE3 open BK
Ca
channels in PAH-PASMCs, leading to membrane hyperpolarization, and also block
the vasoconstrictive response to PKC activation in isolated PAH-PA (Barman et al.
2003
; Zhu et al.
2008
). The latter effects were shown to be independent of PKA,
thereby highlighting a possible role for the other cAMP downstream mediators,
such as Epac, in cAMP-promoted vasodilation and antiproliferation. Epac, a gua-
nine nucleotide exchange factor for the low-molecular-weight G protein Rap-1, has
been shown to mediate a number of effects of cAMP; our unpublished data
show that PDE3 inhibition can activate Epac and that Epac activation decreases
proliferation of both control- and PAH-PASMCs. Of note, PDE3B can integrate
into a complex with Epac (Raymond et al.
2007
), suggesting that if such an interac-
tion occurs in PASMCs, increased cAMP that results from PDE3 inhibition might
preferentially enhance Epac-dependent functions.
The notion that specific PDE isoforms can regulate distinct “pools” of cAMP
could be key for the pharmacological actions of specific PDE inhibitors (Raymond
et al.
2007
). In addition, PKA-independent effects of PDE3 inhibitors conceivably
may be due to cross-activation by cAMP of PKG (which is known to occur in
numerous systems) or from cAMP-promoted increases in [cGMP]
i
as a conse-
quence of inhibition of its hydrolysis by interaction with dual-specificity PDEs
(Koyama et al.
2001
; Maurice
2005
; Zaccolo and Movsesian
2007
): such an idea is
worth further investigation in PAH-PASMCs. It can be hypothesized that a poten-
tial way to limit the detrimental effects of PDE3 inhibitors may be targeting drugs
to particular PDE3 isoforms (e.g., PDE3A or PDE3B), which based on their
different subcellular distribution and possibly different downstream mediators,
such inhibitors might have differential effects in the cell; currently, no such drugs
are available.
