Biology Reference
In-Depth Information
inhibition increases beraprost (a stable analogue of prostacyclin)-induced cAMP
accumulation from 6
1pmol/mginPAH-PASMCs(Fig.
2b
)
(MacLean et al.
1996
,
1997
; Murray et al.
2007
). Increased PDE3 activity con-
tributes to the decrease response to cAMP-elevating agents, such as isoproterenol
and forskolin, in vasodilating the PA from chronic hypoxic rats and decreasing
proliferation of PAH-PASMCs (Murray et al.
2007
; Pyne et al.
2007
; Schermuly
et al.
2005
). The PDE3 inhibitor milrinone decreases proliferation in PAH-
PASMCs to a similar degree as does PDE5 inhibition (Fig.
2a
). PDE3 appears
important in maintaining the SMC phenotype in PASMCs, such that PDE3 activity
and PDE3A expression are reduced in synthetic/activated cells (Dunkerley et al.
2002
). PDE3 inhibitors, such as milrinone or SCA40, relax preconstricted PA rings
from both control- and PAH-rats, providing evidence that PDE3 activity may help
maintain the low tone of the pulmonary circulation (Jeffery and Wanstall
1998
;
Pyne et al.
2007
; Wagner et al.
1997
). Figure
2c, d
show that SK9483 promotes
relaxation of both the main and first branch PA preconstricted with phenylephrine.
Importantly, the effects of the PDE3 inhibitors are not compromised in PAH.
In animal models of PAH, amrinone, cilostamide, milrinone, and cilostazol (Pletal)
have all been shown to decrease mPAP and PVR and even reverse remodeling of
the PA (Clarke et al.
1994
; Phillips et al.
2005
; Sun et al.
2009a
). Cilostazol (Pletal),
which is FDA approved for intermittent claudication, partially reverses PAH in
animal models of the disease and acts synergistically with bone marrow-derived
endothelial progenitor cells to inhibit the inflammatory response that is seen in such
models (Sun et al.
2009a
; Thompson et al.
2002
). Although PDE3 inhibitors
effectively lower PA wedge pressure and mPAP, because they have positive
inotropic and vasodilatory actions in the systemic circulation, they were deemed
an unsuitable option for treating PAH. In addition, based on results of clinical trials
for heart failure that showed PDE3 inhibitors increased mortality by around 30%
(Packer et al.
1991
), there has been a reluctance to consider their use in PAH.
However, PDE3 is being “revisited” as a possible target for PAH because PDE3
inhibition may have therapeutic potential either in combination with approved
drugs such as prostacyclin and its analogues or even PDE5 inhibitors (allowing
the use of lower doses with less cardiovascular side effects), by altering the route
of administration or only using the PDE3 inhibitors in a subset of patients. Combi-
nation therapy for PAH with PDE3 inhibitors can produce potent and selective
pulmonary vasodilation; the coapplication of subthreshold doses of PDE3 inhibitors
amplify prostacyclin, isoproterenol, and forskolin-induced vasodilation of isolated
PA from chronic-hypoxic rats, and attenuate PASMC proliferation (Phillips et al.
2005
; Schermuly et al.
2001
; Wagner et al.
1997
). Distal pulmonary artery muscu-
larization in the chronic-hypoxic rat is inhibited by the combination of iloprost
and cilostamide (more than either agent alone), providing a rationale for their
coadministration in reversing pulmonary vascular remodeling.
A similar interaction has been observed with PDE3 and PDE5 inhibitors,
such that “a low dose” of each type of inhibitor yielded ~4 and 8% reduction
of elevated PVR, respectively; however, together they reduced PVR by ~40%,
implying a synergistic effect of their coadministration in reducing elevated PVR
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