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two approved pharmacological agents in the USA that are indicated for relief of
IC symptoms and increased walking distance: cilostazol and pentoxifylline, with
cilostazol demonstrating superiority over pentoxifylline. The mechanisms underly-
ing their effects are not entirely clear, but both compounds have the property of
inhibiting phosphodiesterases (PDEs), albeit with different isoform selectivity and
potency. In this chapter, we use cilostazol as an example to discuss the potential
utilization and limitation of PDE inhibitors in the treatment of IC. We hope that this
will serve as a primer for future drug development in IC, and PAD in general, in the
search for improved drugs that can both reduce cardiovascular risk and improve
exercise capacity and quality of life.
2 Cells Contributing to Atherosclerosis
Since the root cause of PAD, including IC, is atherosclerosis, it is important to
understand the pathology of this process as summarized in Fig. 2 . The major players
include endothelium, macrophages, platelets,
lipid, and smooth muscle cells.
thrombus
Turbulent flow
Laminar flow
Smooth muscle cell
Endothelial cell
Activated platelet
Foam cell
Macrophage
Subendothelial extracellular matrix
Fig. 2 Major players of arterial atherosclerosis. Endothelial damage is likely to be the initiating
event in plaque formation arising as a result of chemical forces such as oxidized low-density
lipoprotein, which can increase oxygen free radical production (Galle et al. 2000 ) and induce
endothelial cell apoptosis (Dimmeler et al. 1997 ). Damaged endothelium leads to the activation
and attachment of platelets, monocytes, and T lymphocytes at the site of the injury. Inflammatory
cytokines and growth factors, released by these cells as well as smooth muscle cells of the vascular
wall, promote the migration of monocytes and leukocytes into the subendothelial space. Macro-
phages, generated by differentiation of monocytes, then ingest oxidized lipid to form foam cells
and fatty streaks. Proliferating VSMCs along with the continuing influx and propagation of
macrophages converts fatty streaks to more advanced lesions and ultimately to a fibrous plaque
that protrudes into the arterial lumen. Arterial atherosclerosis also produces favorable conditions
for thrombosis to occur. Platelets may be attracted to the dysfunctional endothelium expressing
high levels of adhesion molecules or directly interact with subendothelial thrombogenic extracel-
lular matrix proteins. Hemodynamics also favor the formation of thrombi downstream of the
protruding plaque due to the low shear and turbulent flow (Nesbitt et al. 2009 )
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