Biology Reference
In-Depth Information
In contrast, cardiac myocytes express mainly Gi-coupled adenosine A
1
receptors,
activation of which reduces cAMP generation, thus limiting the inhibition of PDE3
in the heart. This unique feature may contribute to the safety profile of cilostazol
(see Sect.
4.1.5
).
4.1.3 Other Effects
In addition to its vasodilatory and inhibitory effects on platelet activation, other
beneficial effects of cilostazol, resulting from PDE3-depedent and -independent
actions, are discussed below.
Reduction of Restenosis
Proliferation and migration of VSMCs contribute to the growth of atherosclerotic
lesions and narrowing of the vascular lumen. In addition to numerous small
controlled studies (see Kambayashi and Liu
2007
), one large clinical study (The
Cilostazol for RESTenosis (CREST) trial) clearly demonstrated a reduction in
restenosis when cilostazol was administered (Douglas et al.
2005
). PDE3 inhibition
and increases in intracellular cAMP levels are likely the causes of inhibition of
restenosis since several studies have demonstrated PDE3 inhibitors can inhibit
VSMC proliferation (Indolfi et al.
2000
; Osinski and Schror
2000
; Zhao et al.
2008
). However, it remains to be determined whether the mechanism of cilostazol's
action actually slows the progression of atherosclerosis or inhibits VSMC prolifer-
ation in IC patients.
Effects on Endothelium
Two studies have shown that cilostazol can increase PGE
1
(Igawa et al.
1990
) and
PGI
2
(Ito et al.
2010
) release from vascular endothelial cells. These prostaglandins
can stimulate Gs to increase cAMP production and are thus likely to synergize with
PDE3 inhibitors as demonstrated by Igawa's study (Igawa et al.
1990
) on inhibition
of platelet activation. In addition, cilostazol has been shown to reduce both high-
glucose-mediated expression of adhesion molecules in endothelium (Omi et al.
2004
) and platelet-derived growth factor production (Mizutani et al.
1996
). Cilos-
tazol can also inhibit leukocyte adhesion to endothelium (Mori et al.
2007
; Omi
et al.
2004
). Protection of the endothelium by cilostazol has also been observed
following injury induced by ischemia (Iwama et al.
2007
) or lipopolysaccharide
(Kim et al.
2002
). It remains to be determined whether the protective effects of
cilostazol on the endothelium are due to PDE3-dependent or independent actions,
or both. One study has confirmed the involvement of cAMP-mediated signaling
pathways in the modulation of endothelial cells adhesive interactions by cilostazol
(Mori et al.
2007
). Since endothelium plays an important role in atherosclerosis and
