Phosphodiesterases as Targets for Intermittent Claudication

Abstract

Intermittent claudication (IC) is one of the most frequent forms of lower extremity peripheral arterial disease (PAD) and is most commonly caused by arterial atherosclerosis. Its clinical manifestation includes fatigue, discomfort, or pain occurring in limb muscles due to exercise-induced ischemia, thus limiting the ability of IC patients to walk and exercise. In addition to lifestyle changes (diet, exercise, and smoking cessation), pharmacological treatments are needed. Pathologically, atherosclerotic lesions cause a mismatch in oxygen supply and metabolic demand in the leg muscles during walking/exercise. This subjects the muscles to repeated ischemia and reperfusion injury that can alter structure and oxidative metabolism, resulting in 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.

Pentoxifylline Protects the Small Intestine After Severe Ischemia and Reperfusion

“…22,23 Specifically, PTX downregulates inflammatory cytokines, such as TNF-α, IL1-β, and IL-6. Because of this, many intracellular down-stream molecules directly related to TNF-α or the other inflammatory cytokines, also demonstrate a diminished response to ischemia or inflammation.…”

“…22 Other demonstrated effects (eg, vasodilatation and inhibition of neutrophil adhesion) prompted its potential interest as a beneficial compound for various I/R conditions. 23 In this regard, in the late 1980s Waxman 24 and Coccia, 25 and a few years later, Flynn 26 and Sakio 27 and associates, among others, recognized the positive blood flow effects of PTX in hemorrhagic conditions. Mustafa in 1995 28 used PTX in a typical rat small bowel ischemic model as an anti-ischemic drug.…”

The effect of pentoxifylline on penile cavernosal tissues in ischemic priapism-induced rat model

“…Pentoxifylline decreases blood viscosity, improves erythrocyte flexibility, and increases microcirculatory flow and tissue oxygen concentration. This agent is used for the treatment of intermittent claudication, neuropathy, and stroke [25][26][27][28]. Pentoxifylline have also been studied as an anti-fibrotic agent in various fibrotic conditions, such as liver fibrosis, peritoneal fibrosis, and renal fibrosis [29][30][31].…”

Tailored Adjunctive Cilostazol Therapy Based on CYP2C19 Genotyping in Patients With Acute Myocardial Infarction ― The CALDERA-GENE Study ―

“…Cilostazol administered at clinically relevant concentrations also inhibits adenosine reuptake into erythrocytes, endothelial cells, muscle cells, and platelets, thereby increasing interstitial and circulatory adenosine levels. 32 Inhibitors of PDE3 are used clinically to increase cardiac contractility by raising the intracellular cAMP content in cardiac myocytes, and to reduce vascular resistance by increasing intracellular cGMP content in VSMCs. 33 In the present study, plasma BNP levels decreased significantly at 14 days post-PCI in the Carrier/DAPT+Cilostazol group compared with the other 2 groups.…”