Biology Reference
In-Depth Information
progressed to phase II clinical trials may suggest that systemic exposure and/
or cardiovascular toxicity of PDE3/PDE4 inhibitors can be minimized. Indeed,
because of synergy in target cells, it is logical to predict that proportionally lower
doses of dual-selective inhibitors will be required to elicit the same degree of
therapeutic benefit relative to a PDE4 inhibitor alone as a monotherapy. Selectively
targeting the respiratory tree through formulation and/or route of administration are
validated means of gaining tissue-specific drug delivery. In addition, exploiting the
fact that in PDE3 isoforms are encoded by two genes (PDE3A and PDE3B; Bender
and Beavo
2006
) could also offer a more novel approach to reduce cardiovascular
adverse events (Thompson et al.
2007
). In this respect, baseline cardiovascular
function (blood pressure, heart rate (HR), left ventricular pressure (LVP), and
cardiac contractility) and adenosine diphosphate- and collagen-induced platelet
aggregation in vitro were unaffected in
pde3b
-deficient mice when compared
to wild-type animals. In contrast, mice lacking
pde3a
had an elevated HR and
LVP was significantly reduced (Sun et al.
2007
). Moreover, the PDE3 inhibitor,
cilostamide, did not change any of the aforementioned hemodynamic parameters
in
pde3a
knockout mice, whereas in wild-type mice and animals deficient in
pde3b
, HR and cardiac contractility and BP and LVP were significantly increased
and decreased, respectively (Sun et al.
2007
). Clearly, these data show that, in
mice, PDE3A is the major regulator of several cardiovascular parameters. What is
unknown are the PDE3 isoenzymes that, when inhibited, promote bronchodilation
and enhance the anti-inflammatory effect of PDE4 inhibitors. Indeed, human
airway smooth muscle cells express mRNA for both PDE3 isoforms (authors'
unpublished observations) and the expression of these variants across proinflam-
matory and immune cells has not been cataloged. Nevertheless, subtype-selective
compounds have been described including 4 and 5 (Fig.
1
) fromMerck and ICOS,
respectively, that are
30-fold selective for the PDE3B isoform (Edmondson
et al.
2003
; Snyder et al.
2002
). Thus, tools are beginning to emerge with which
to tease out, pharmacologically, the functional effects mediated by inhibition of
PDE3A and PDE3B.
>
2.3
Inhibition of PDE4 and PDE5
Chronic generalized alveolar hypoxia occurs in diseases associated with decreased
ventilation including COPD. Accordingly, many patients with COPD have coex-
isting PH, although the exact prevalence is unclear (see Jyothula and Safdar
2009
).
This condition is thought to be multifactorial due to complex interactions involving
hypoxic pulmonary vasoconstriction (HPV), pulmonary and systemic inflamma-
tion, a loss of pulmonary capillaries, and, potentially, hyperinflation, which may
cause mechanical injury (reviewed in Chaouat et al.
2008
; Jyothula and Safdar
2009
). Although the increase in pulmonary artery pressure (Ppa) is usually mild to
moderate, some individuals suffer from right heart failure secondary to severe PH.
In addition, there can be extensive remodeling of the pulmonary vasculature in
