The protective effect of cilostazol on isolated rabbit femoral arteries under conditions of ischemia and reperfusion: the role of the nitric oxide pathway

Abstract

OBJECTIVES:The clinical significance of ischemia/reperfusion of the lower extremities demands further investigation to enable the development of more effective therapeutic alternatives. This study investigated the changes in the vascular reactivity of the rabbit femoral artery and nitric oxide metabolites under partial ischemia/reperfusion conditions following cilostazol administration.METHODS:Ischemia was induced using infrarenal aortic clamping. The animals were randomly divided into seven groups: Control 90 minutes, Ischemia/Reperfusion 90/60 minutes, Control 120 minutes, Ischemia/Reperfusion 120/90 minutes, Cilostazol, Cilostazol before Ischemia/Reperfusion 120/90 minutes, and Ischemia 120 minutes/Cilostazol/Reperfusion 90 minutes. Dose-response curves for sodium nitroprusside, acetylcholine, and the calcium ionophore A23187 were obtained in isolated femoral arteries. The levels of nitrites and nitrates in the plasma and skeletal muscle were determined using chemiluminescence.RESULTS:Acetylcholine- and A23187-induced relaxation was reduced in the Ischemia/Reperfusion 120/90 group, and treatment with cilostazol partially prevented this ischemia/reperfusion-induced endothelium impairment. Only cilostazol treatment increased plasma levels of nitrites and nitrates. An elevation in the levels of nitrites and nitrates was observed in muscle tissues in the Ischemia/Reperfusion 120/90, Cilostazol/Ischemia/Reperfusion, and Ischemia/Cilostazol/Reperfusion groups.CONCLUSION:Hind limb ischemia/reperfusion yielded an impaired endothelium-dependent relaxation of the femoral artery. Furthermore, cilostazol administration prior to ischemia exerted a protective effect on endothelium-dependent vascular reactivity under ischemia/reperfusion conditions.

The phosphodiesterase 3 inhibitor cilostazol does not stimulate growth of colorectal liver metastases after major hepatectomy

“…This may be due to the fact that cilostazol increases individual blood vessel perfusion due to its vasodilatory effects [31]. However, it may also be possible that tumors after cilostazol treatment require less blood supply for growth, because cilostazol can increase ischemic tolerance by upregulating phosphorylated casein kinase 2 (CK2), which may counteract hypoxic cell death [50,51]. Further, cilostazol has been shown to restore ATP release under hypoxic conditions [52], which may allow the metastatic tumors to survive with a reduced microvessel density.…”

Cilostazol enhances endothelium-dependent vasodilatation of intact endothelium in isolated rat aortic rings

“…[7,8] Recent studies have indicated that CIL is also associated with increased NO production in vascular cells. [9] Moreover, it has been shown to exert additional effects on the vascular endothelium and offer endothelial protection via the inhibition of apoptosis and neutrophil-endothelial cell adhesions. [10] The aim of this experimental study was to investigate the effect of chronic CIL treatment on the vascular reactivity of intact endothelium by examining the endothelium-dependent relaxation responses of isolated rat aortic rings in an organ bath.…”

“…Furthermore, CIL has recently been declared to improve the ischemia/reperfusion-associated defect in ACh-dependent relaxation in rat aortae and increase tissue nitrite and nitrate levels, which has been suggested to be mediated by eNOS phosphorylation. [9] In addition to the increased production of NO, CIL has also been found to trigger the release of PGI2, [26] which inhibits the release of noradrenaline from adrenergic nerve endings, thereby indirectly causing a vasodilator effect.…”

Effects of ischemic preconditioning and cilostazol on muscle ischemia-reperfusion injury in rats

“…But the protective role of this drug in acute IR injury of skeletal muscle is not yet established. Studies have indicated the protective role of this drug in skeletal muscle, through the effect on endothelium dependent vascular reactivity 19 , however, no decrease in muscle damage as a biomarker of serum myoglobin muscle and other histopathological changes and apoptosis using cilostazol was observed in IR muscle models 20.21 . The effects of IP associated with cilostazol treatment in muscle ischemia-reperfusion injury did not studied yet.…”