Phosphodiesterases as Targets for Intermittent Claudication - Phosphodiesterases as Drug Targets - page 221

walking distances on the treadmill and improved quality of life in comparison with
placebo (see review by (Kambayashi and Liu 2007 )). This led to the approval of
cilostazol in the USA, and subsequently several EU countries, for the relief of
symptoms of IC and improvement in walking distance.
4.1.2 Mechanisms of Cilostazol
Cilostazol is a 2-oxo-quinoline derivative that was synthesized in 1983 by Otsuka
Pharmaceutical Company, Tokushima, Japan (Nishi et al. 1985 ) as a PDE3 inhibitor.
The biological effects of cilostazol that may potentially be relevant to the treatment
of IC are discussed below. However, the exact mechanisms underlying the observed
benefits have not yet been fully elucidated.
Antiplatelet and Vasodilatory Effects
The antiplatelet effect of cilostazol has been reviewed extensively elsewhere
(Goto 2005 ; Kambayashi and Liu 2007 ). Cyclic AMP-mediated effects inhibit the
common pathways of platelet activation, and so inhibition by cilostazol has a broad-
spectrum of effects irrespective of the platelet activator that is used: ADP, collagen,
epinephrine, arachidonic acid, thrombin receptor activating peptide, and shear
stress-induced platelet activation.
Compared to the substantial research that has been conducted on the antiplatelet
effects of cilostazol, its effects on vasodilation have been less well investigated.
Studies have shown that cilostazol has broad vasodilatory effects, but with variable
magnitude in different vascular beds. Vasodilation was reported to be most potent
in femoral arteries (Kimura et al. 1985 ). In a recent investigation, we reported that
cilostazol was able to increase tissue blood flow in working leg muscle, while
having no effect on resting muscle (Fong et al. 2010 ).
Additional Mechanism: Inhibition of Adenosine Uptake
In addition to PDE3 inhibition, we found that cilostazol inhibits adenosine uptake
and increases interstitial and circulatory adenosine levels in ischemic tissue
(Liu et al. 2000 ; Manickavasagam et al. 2007 ; Sun et al. 2002 ; Wang et al. 2001 ).
A later study confirmed this observation by showing that cilostazol can increase
tissue adenosine levels during ischemia (Manickavasagam et al. 2007 ). Adenosine
possesses a wide range of biological activities that are mediated via the activation of
G-protein-coupled adenosine receptors. In platelets and VSMCs, Gs-coupled aden-
osine A 2 receptors dominate, and their stimulation increases intracellular cAMP.
Thus, cilostazol can both increase the production and inhibit the breakdown of cAMP
in platelets and VSMCs resulting in a sustained increase in the level of intracellular
cAMP (Kambayashi et al. 2003 ;KambayashiandLiu 2007 ; Liu et al. 2001 ).