Biology Reference
In-Depth Information
concentration cannot be accurately predicted (Thompson
1991
). Evidence derived
from studies of airway smooth muscle indicates that effects of theophylline in that
tissue are mediated through inhibition of PDEs 3-5 to cause increases in cAMP and
cGMP and activation of the respective signaling pathways (Cortijo et al.
1993
;
Rabe et al.
1995
). Effects of theophylline to blunt airway inflammation in COPD
occur below 10 mg/ml plasma (Hirano et al.
2006
; Kobayashi et al.
2004
) and are
therefore unlikely to act through PDE inhibition.
Cilostazol is somewhat selective as an inhibitor of the PDE3 family (IC
50
~0.5
m
M)
and is marketed for treatment of intermittent claudication (Kambayashi et al.
2003
);
it also reportedly inhibits PDE5 with nine-fold lower affinity (IC
50
~ 4.4
m
M)
(Sudo et al.
2000
) and antagonizes adenosine uptake at clinically relevant
concentrations (3
m
M). The inhibitory effect of cilostazol for both PDE3 and
adenosine uptake was not appreciated initially, but now this dual effect is suggested
to be a significant factor in the overall safety and efficacy of cilostazol compared to
PDE3 inhibitors that do not block adenosine uptake (Kambayashi et al.
2006
). Since
the clinically relevant concentration of cilostazol is also in the range of its IC
50
for PDE5, it is plausible that inhibition of PDE5 may account for a portion of
cilostazol's vasodilatory and antiaggregatory effects on vascular smooth muscle
and platelets, respectively, where PDE5 is abundant.
Dipyridamole, a PDE inhibitor that is approved for clinical use for prevention of
ischemic events following stroke, also has dual actions; it is a somewhat nonselec-
tive inhibitor of PDEs (PDE5 IC
50
~ 0.9
m
M, PDE7 IC
50
~ 0.6
m
M, PDE8 IC
50
~
9
m
M, PDE10 IC
50
~ 1.0
m
M, and PDE11 IC
50
~ 0.4
m
M) (Beavo and Brunton
2002
) and a relatively potent inhibitor of adenosine uptake (Klabunde
1983
;
Schaper
2005
). Although the antiaggregatory effects of dipyridamole in platelets
are largely attributed to its action to block adenosine uptake, its concentration in
plasma (1.7
m
g/L or ~3.5
m
M) is sufficient to block PDE5 as well (Serebruany et al.
2009
); the combined actions of this drug would decrease platelet aggregation.
Although the effects of the PDE5 inhibitors, vardenafil, sildenafil, and tadalafil
are thought to be mediated exclusively through inhibition of PDE5, differences in
the effects of vardenafil versus those of sildenafil and tadalafil in rabbit pulmonary
arteries and human platelets have been reported (Toque et al.
2008
). The evidence
in this report suggests that vardenafil, in addition to acting as a PDE5 inhibitor in
these tissues, may also block store-operated calcium channels. This possibility
warrants further study. A recent report indicates that
in vitro
sildenafil activates
several carbonic anhydrase isoenzymes (hCA I, hCA VB and hCA VI) with
K
a
values in the range of 1-7
m
M (Abdulkadir Coban et al.
2009
); this effect may be
mediated by the piperazine moiety in sildenafil since other carbonic anhydrases
activators contain a piperazine moiety. Whether this effect impacts the pharma-
cological actions of sildenafil is not known, but since plasma sildenafil (bound and
free) in a typical patient approaches 1
m
M, the possibility should not be entirely
dismissed. This effect emphasizes that a variety of molecular features of PDE inhi-
bitors may contribute to unanticipated interactions. Recently, Jeon et al. reported
that the anti-inflammatory action of vinpocetine, which has traditionally been
considered to be a PDE1-selective inhibitor, proceeds through a PDE-independent
