Biology Reference
In-Depth Information
4.1.6 Summary
Cilostazol has multiple activities; some are mediated through inhibition of PDE3,
while others are caused by different mechanisms. The inhibitory effect of cilostazol
on PDE3, together with its effects on signaling through adenosine, prostaglandins
and NO on platelets, VSMCs, and endothelium (Fig.
5
), likely contributes to its
overall benefits in IC patients. Nevertheless, the exact underlying mechanisms are
still unidentified. Direct measurement of blood flow after cilostazol treatment has
not been attempted in IC patients. Using ABI as an indirect evaluation of blood
supply to the leg, one study showed an improvement after several weeks of
treatment with cilostazol (Mohler et al.
2001
), while another study demonstrated
no effect (Dawson et al.
1998
). The increase in walking distance by cilostazol also
required weeks of treatment (Beebe et al.
1999
; Dawson et al.
1998
), suggesting
a
In the ischemic zone
Ischemia
CLZ
Blood
flow
Ado
NO
PG
thrombus
b
CLZ
Cyclic nucleotide-mediated
signal transduction
A
2A
PG
NO
G
s
AC
GC
Antiplatelet
VSMC Relaxation
Cytoprotection
cGMP
cAMP
CLZ
PDE3
5'-AMP
Fig. 5 Possible PDE-independent actions for cilostazol in the ischemic zone (a) and potential
actions relating to PDE3 inhibition in the affected cells (including VSMCs, platelets, and endo-
thelium) (b). A: Atherosclerosis results in the stenosis and narrowing of the artery. Thrombi can
also form downstream of the lesion site. In the IC patients, ischemia can be induced during
walking/exercise due to these pathological changes. Cilostazol can increase extracellular adeno-
sine (Ado), prostaglandin (PG) E
1
and I
2
, and nitric oxide (NO) concentration. B: By activating
Ado A
2A
and prostaglandin receptors, adenosine and prostaglandin(s) stimulate adenylyl cyclases
(AC) to generate cAMP, which can be further elevated by the inhibition of PDE3. NO stimulates
cellular soluble GC that generates cGMP. cAMP and cGMP both have anti-aggregatory effects on
platelets, promote vasodilation and have cytoprotective properties. These effects likely work in
concert to produce the clinical benefits of cilostazol in IC patients.
CLZ
cilostazol,
VSMC
vascular
smooth muscle cells,
Gs
stimulatory G-protein
