Biology Reference
In-Depth Information
thrombosis, the effect of cilostazol to protect against endothelial damage may
contribute substantially to its overall efficacy.
Effects on Lipid Metabolism
Hyperlipidemia is one of the risk factors for PAD, and it is interesting that cilostazol
has favorable effects on the plasma lipid profile. Following 12 weeks of cilostazol
treatment, plasma levels of triglycerides were decreased and high-density lipopro-
tein cholesterol and apolipoprotein A
1
were increased while remnant lipoprotein
concentrations were decreased in IC patients (Elam et al.
1998
; Wang et al.
2003
).
Furthermore, cilostazol seems to be particularly effective in improving lipid meta-
bolism in type 2 diabetes patients (Ikewaki et al.
2002
; Ishikawa et al.
1997
;
Mishima et al.
2000
; Takayoshi et al.
2001
; Tamai et al.
1992
; Watanabe et al.
1996
). However, there is insufficient information to determine whether these
beneficial effects are the result of cAMP-mediated mechanisms.
Protection Against Ischemia/Reperfusion Injury
Leg muscles in IC patients are expected to experience periods of ischemia during
walking/exercise. Thus, treatments that can reduce ischemia-induced tissue injury
may be beneficial. Preclinical studies have shown such protection by cilostazol in
cardiac muscle. Cilostazol reduced myocardial infarct size after ischemia and
reperfusion (Fukasawa et al.
2008
; Manickavasagam et al.
2007
). However, this
protection may not be related to PDE3 inhibition, as milrinone, a PDE3 inhibitor,
demonstrated no protection (Fukasawa et al.
2008
). Reduction of cerebral infarction
by cilostazol after stroke has also been reported in numerous studies (Choi et al.
2002
; Honda et al.
2006
; Ito et al.
2010
; Lee et al.
2004
; Wakida et al.
2006
; Yuzawa
et al.
2008
). However, the data also pointed to PDE3-independent mechanisms
being involved in the neuroprotection by cilostazol (Lee et al.
2004
; Wakida et al.
2006
). These mechanisms include an increase in adenosine levels (Manickavasagam
et al.
2007
), activation of calcium-activated potassium channels (Fukasawa et al.
2008
; Lee et al.
2004
) and metallothionein induction (Wakida et al.
2006
).
Nitric Oxide
Several studies have reported the ability of cilostazol to increase NO release from
endothelial cells (Nakamura et al.
2001
), through PDE3 inhibition (Hashimoto et al.
2006
). Similar effects have also been reported in other cell types and in vivo (Ikeda
et al.
1996
; Inada et al.
1999
; Manickavasagam et al.
2007
). This may be an
important part of cilostazol's action, since a reduction in NO availability impairs
vascular relaxation and accelerates the progression of atherosclerosis (Barton
and Haudenschild
2001
; Loscalzo
2001
; Traupe et al.
2003
). NO activates the
soluble (NO-sensitive) GC, thus increasing production of cGMP. Another possible
