Phosphodiesterases as Targets for Intermittent Claudication - Phosphodiesterases as Drug Targets - page 219

PDE3
Inhibition

Adhesion molecule
in endothelium

Platelet Activation

Vasodilation VSMC Proliferation

Fig. 3 Major effects from PDE3 inhibition in the vascular system. Due to the wide expression of
PDE3 in the cardiovascular system, PDE3 inhibitors exert a plethora of beneficial effects targeting
different cells involved in the atherosclerosis pathway

observed in both milrinone-treated rats (Cheung et al. 2003 ) and PDE3B-null mice,
and consequently, fatty acid release was increased in these mice (Choi et al. 2006 ).
In contrast, cilostazol reduces plasma triglycerides (Elam et al. 1998 ; Nakamura
et al. 2003 ), suggesting that this effect may be mediated by a PDE3-independent
mechanism.
Figure 3 summarizes the effects of PDE3 inhibitors on cells involved in athero-
sclerosis. As discussed above, these effects may mitigate atherosclerosis-associated
diseases such as IC.

4 Pharmacotherapy for Claudication

Increasing walking distance by drug therapy has proved to be very challenging. As
summarized in the ACC/AHA 2005 practice guidelines (Hirsch et al. 2006 ),
vasodilators, including papaverine, prostaglandins (beraprost and iloprost), and
calcium-channel blockers, have not demonstrated clinical efficacy. Nutritional
supplements that exhibit vasodilatory or antioxidant properties, e.g., ginkgo biloba,
vitamin E, and L -arginine, have also failed in large clinical trials. Antiplatelet
agents, including aspirin and clopidogrel, which may reduce cardiovascular events,
do not increase walking distance. L -carnitine and propionyl- L -carnitine, which were
designed to facilitate the transfer of acyl groups from CoA into mitochondria and
improve energy utilization, were investigated in several small clinical studies
(Barker et al. 2001 ; Dal et al. 1999 ; Hiatt et al. 2001 ; Hiatt 2004 ). Although some
improvement in walking distance was observed, large clinical studies are lacking,
and neither drug is approved for this indication.
Currently, only cilostazol and pentoxifylline (for chemical structures, see Fig. 4 )
are approved to relieve symptoms associated with IC and increase walking distance.
A head-to-head comparison between cilostazol and pentoxifylline has demon-
strated the superior efficacy of cilostazol (Dawson et al. 2000 ). While both com-
pounds are PDE inhibitors, cilostazol shows greater selectivity for PDE3 than
pentoxifylline (Table 1 ). Both cilostazol and pentoxifylline inhibit adenosine