Biology Reference
In-Depth Information
insufficient utilization of oxygen supply. Despite extensive research efforts, cilostazol
and pentoxifylline are the only drugs indicated for relieving the symptoms of IC,
with cilostazol demonstrating significant improvement in walking distance and
quality of life in these patients. Originally developed as a PDE3 inhibitor, cilostazol
was later found to have several other pharmacological actions, and its success has
been attributed to its multifactorial actions on platelets, endothelium, smooth
muscle, and lipid profiles. Using cilostazol as an example, we discuss the rationales
and pitfalls of targeting PDEs in IC, and potential strategies for the development of
new and more effective pharmacological treatments.
Keywords Adenosine
Atherosclerosis
Cilostazol
Intermittent claudication
Peripheral arterial disease
Phosphodiesterase
Abbreviation List
ABI Ankle-brachial index
AC Adenylyl cyclase
ADP Adenosine diphosphate
GC Guanylyl cyclase
Gi Inhibitory G-protein
GP Glycoprotein
Gs Stimulatory G-protein
IC Intermittent cladication
NO Nitric oxide
PAD Peripheral arterial disease
PDE Phosphodiesterease
TXA
2
Thromboxane A
2
VSMC Vascular smooth muscle cell
1 Overview of Intermittent Claudication
Peripheral arterial disease (PAD) is a common manifestation of systemic athero-
sclerosis. Age, cigarette smoking, and diabetes mellitus are the major risk factors,
along with hyperlipidemia, hypertension, and hyperhomocysteinemia. Many people
with this disease are asymptomatic, but about one third of patients with PAD of
the lower extremities have intermittent claudication (IC) (Hiatt
2001
). IC limits the
ability to walk and perform daily activities and severely affects the quality of life
of patients. The severity of claudication progresses slowly, and patients may eventu-
ally develop critical limb ischemia, with substantial risk of limb loss.
