Effect Of Cilostazol Research Articles

Cilostazol inhibits interleukin-1-induced ADAM17 expression through cAMP independent signaling in vascular smooth muscle cells.

Increased A disintegrin and metalloprotease 17 (ADAM17) expression in vascular smooth muscle cells (VSMC) is implicated in the development of cardiovascular diseases including atherosclerosis and hypertension. Although cilostazol, type III phosphodiesterase (PDE III) inhibitor, has recently been found to inhibit VSMC proliferation, the mechanisms remain largely unclear. Here, we hypothesized that cilostazol regulates the ADAM17 expression in VSMC. In cultured VSMC, interleukin (IL)-1α and IL-1β significantly increased ADAM17 expression. MEK inhibitor U0126, NF-κB inhibitor BAY-11-7085, and siRNA targeting p65/RelA significantly inhibited IL-1α or IL-β-induced ADAM17 expression. Cilostazol significantly inhibited IL-1α or IL-1β-induced extracellular signal-regulated kinase (ERK) phosphorylation and ADAM17 expression. Unexpectedly, cilostamide, dibutryl cAMP, and forskolin did not affect IL-1-induced ADAM17 expression. Our results clearly demonstrated that IL-1 induces ADAM17 expression through ERK/NF-κB activation in VSMCs. Moreover, the inhibitory effects of cilostazol on IL-1-induced ADAM17 expression may be independent of the cAMP signaling pathway in VSMC. These novel findings may provide important clues to understanding the expression mechanisms of ADAM17 and the inhibitory mechanisms of cilostazol in VSMC proliferation.

Meta-Analysis of Studies Evaluating the Effect of Cilostazol on Major Outcomes After Carotid Stenting

Purpose: To evaluate the effect of cilostazol on major outcomes after carotid artery stenting (CAS). Methods: A systematic literature review was conducted conforming to established criteria in order to identify articles published prior to May 2015 evaluating major post-CAS outcomes in patients treated with cilostazol vs patients not treated with cilostazol. Major outcomes included in-stent restenosis (ISR) within the observation period, the revascularization rate, major/minor bleeding, and the myocardial infarction/stroke/death rate (MI/stroke/death) at 30 days and within the observation period. Data were pooled for all studies containing adequate data for each outcome investigated; effect estimates are presented as the odds ratios (ORs) and 95 confidence intervals (CI). Results: Overall, 7 studies pertaining to 1297 patients were eligible. Heterogeneity was low among studies so a fixed-effect analysis was conducted. Six studies (n=1233) were compared for the ISR endpoint, showing a significantly lower ISR rate with cilostazol treatment after a mean follow-up of 20 months (OR 0.158, 95% CI 0.072 to 0.349, p<0.001). Five studies (n=649) were compared regarding 30-day MI/stroke/death (OR 0.724, 95% CI 0.293 to 1.789, p=0.484) and 3 studies (n=1076) were analyzed regarding MI/stroke/death within the entire follow-up period (OR 0.768, 95% CI 0.477 to 1.236, p=0.276); no significant difference was found between the groups. Data on bleeding rates and revascularization rates post ISR were inadequate to conduct further analysis. Conclusion: Cilostazol seems to decrease total ISR rates in patients undergoing CAS without affecting MI/stroke/death events, both in the early and late settings.

Abstract 13742: PDE3 Inhibitor, Cilostazol, Ameliorates Ischemic Hindlimb Through cAMP and PPARγ Activation

Peripheral arterial disease (PAD) is highly prevalent in the elderly and subjects with atherosclerotic risk factors. Approximately 2-4% of those affected with PAD commonly complain of intermittent claudication (IC) that is a strong indicator for the development of systemic atherosclerosis. Cilostazol (CSZ) has been shown to be of benefit in improving pain-free walking distance and quality of life in patients with IC. CSZ may be the most clinically effective pharmacologic option for IC. However, the underlying mechanism for amelioration of IC by CSZ remains largely unclear. Here, we demonstrate that CSZ increases expression of hepatocyte growth factor (HGF) in vascular smooth muscle cells (SMCs) via two distinct pathways, PPAR γ and cAMP pathway. Activation of PPAR γ and cAMP activates HGF promoter leading to increase in capillary density and improvement of perfusion in mouse ischemic hind limb model. Enhancement of angiogenesis by CSZ involves Akt/eNOS activation in endothelial cells by HGF secreted from SMCs. However, this process was essentially absent in aspirin treatment group and CSZ with HGF neutralizing antibody treatment group. As CSZ also increases HGF protein production in interstitial area of skeletal muscle where satellite cells reside, we postulated that CSZ stimulates myogenesis. To proof this hypothesis, BrdU was injected every day for 7days in mouse hind limb model, and animals were sacrificed at day 7 and 28. Embryonic form of myocyte heavy chain (eMHC), BrdU positive myocyte, and nuclear centralization was measured. As predicted, CSZ increases the number of newly formed myocyte in ischemic leg compared to control and Aspirin treated mouse. This beneficial effect of CSZ was blunted by the administration of HGF neutralizing antibody. Additionally, Heart specific HGF overexpression mouse in which serum level of HGF is 4-5 times higher than wild type mouse were generated to proof the role of HGF in angiogenesis and myogenesis. Similar to the data obtained from CSZ treated mouse, HGF Tg mouse ameliorates ischemic hind limb via both angiogenesis and myogenesis. Altogether, our date demonstrates that CSZ improves ischemic hind limb via angiogenesis and myogenesis. This results may account for the beneficial effect of CSZ in PAD patients with IC.

Serum Uric Acid Is Associated with Cerebral White Matter Hyperintensities in Patients with Acute Lacunar Infarction

The Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler (ECLIPse) study showed a significant decrease in transcranial Doppler pulsatility index (PI) with cilostazol treatment after 90 days of acute lacunar infarction. The aim of this analysis was to perform a subgroup analysis of the ECLIPse study to explore the relationship between serum uric acid (UA) and the volume of white matter hyperintensities (WMH) in patients with acute lacunar infarction. The ECLIPse was a multicenter, randomized, double-blind, placebo-controlled study conducted in Korea. For this subgroup analysis, WMH volume was measured for those subjects for whom FLAIR or T2-weighted images were available using semiautomated computerized software. Of the 203 patients in 8 hospitals in the ECLIPse study, 130 in 6 hospitals were entered for this subgroup analysis. The mean age was 64.7 ± 9.95 years, and 20.8% were women. The mean WMH volume was 11.57 cm(3) (.13 to 68.45, median 4.86) and mean serum UA was 5.2 mg/dL (1.5 to 8.9). Multiple linear regression analysis revealed that age (P < .001) and serum UA (P = .013) were significantly associated with WMH volume. Age-adjusted scatterplots showed that serum UA level was positively related to WMH volume in patients with acute lacunar infarction (r = 0.275, P = .003). This study showed that serum UA was associated with cerebral WMH in patients with acute lacunar infarction.

The effect of cilostazol on aura and migraine headache induction and peripheral vascular function

The effect of cilostazol on aura and migraine headache induction and peripheral vascular function

The Effect of Cilostazol on Arterial Stiffness in Patients Undergoing Percutaneous Coronary Intervention

ëª©ì : 동맥경직도의 증가는 심혈관질환의 위험인자로 잘 ì•Œë ¤ì ¸ 있다. 실로스타졸은 phosphodiesterase type 3 ì–µì œì œë¡œ, 혈관 확장 및 혈관 보호 효과를 보이는 í•­í˜ˆì†ŒíŒì œì´ë‹¤. 이에 본 ì €ìžë“¤ì€ 실로스타졸이 동맥경직도에 어떤 영향을 주는지 ì•Œì•„ë³´ê³ ìž 하였다. 방법: 허혈성심질환의 치료를 위하여 ê´€ìƒë™ë§¥ì¤‘ìž¬ìˆ ì„ 받은 환자 161ëª (남자 112ëª , í‰ê· 63세)을 ìˆœì°¨ì ìœ¼ë¡œ 본 연구에 등록하였다. baPWV, rAI, rAI75, cSBP와 cPP값을 ì¸¡ì • 하였다. ê¸°ì €ì¹˜ì™€ 30일 후 값을 얻어 변화량을 구하였다. 실로스타졸을 추가로 사용한 실로스타졸군과 표준치료를 받은 대조군으로 나누어 비교 분석하였다. ê²°ê³¼: 30일 경과 후 실로스타졸군에서 rAI와 cSBP, cPP가 í˜¸ì „ë˜ì—ˆë‹¤. 대조군은 이들 지표의 의미 있는 변화가 없었다. rAI75와 baPWV의 값은 두 군에서 차이가 없었다. rAI와 cSBP, cPP는 bSBP, bDBP, 심박수의 변화와 상관관계를 ë³´ì˜€ê³ , 실로스타졸의 사용 및 ë² íƒ€ì°¨ë‹¨ì œì˜ 사용과 ê´€ë ¨ 있었다. rAI, cSBP와 cPP에 대한 다변량분석에서 실로스타졸이 ë ë¦½ì  영향인자였다. ê²°ë¡ : ê´€ìƒë™ë§¥ì¤‘ìž¬ìˆ ì„ 받은 환자에서 실로스타졸의 추가 사용하여 30일 후 rAI와 cSBP, cPP가 í˜¸ì „ë˜ì—ˆë‹¤. rAI75와 baPWV의 í˜¸ì „ì€ 없었기 때문에 실로스타졸에 의한 심박수 증가에 의한 효과로 생각해 ë³¼ 수 있다. 중심 단어: 실로스타졸; 동맥경직도; Augmentation index

Cilostazol Upregulates Autophagy via SIRT1 Activation: Reducing Amyloid-β Peptide and APP-CTFβ Levels in Neuronal Cells.

Autophagy is a vital pathway for the removal of β-amyloid peptide (Aβ) and the aggregated proteins that cause Alzheimer’s disease (AD). We previously found that cilostazol induced SIRT1 expression and its activity in neuronal cells, and thus, we hypothesized that cilostazol might stimulate clearances of Aβ and C-terminal APP fragment β subunit (APP-CTFβ) by up-regulating autophagy.When N2a cells were exposed to soluble Aβ1–42, protein levels of beclin-1, autophagy-related protein5 (Atg5), and SIRT1 decreased significantly. Pretreatment with cilostazol (10–30 μM) or resveratrol (20 μM) prevented these Aβ1–42 evoked suppressions. LC3-II (a marker of mammalian autophagy) levels were significantly increased by cilostazol, and this increase was reduced by 3-methyladenine. To evoke endogenous Aβ overproduction, N2aSwe cells (N2a cells stably expressing human APP containing the Swedish mutation) were cultured in medium with or without tetracycline (Tet+ for 48 h and then placed in Tet- condition). Aβ and APP-CTFβ expressions were increased after 12~24 h in Tet- condition, and these increased expressions were significantly reduced by pretreating cilostazol. Cilostazol-induced reductions in the expressions of Aβ and APP-CTFβ were blocked by bafilomycin A1 (a blocker of autophagosome to lysosome fusion). After knockdown of the SIRT1 gene (to ~40% in SIRT1 protein), cilostazol failed to elevate the expressions of beclin-1, Atg5, and LC3-II, indicating that cilostazol increases these expressions by up-regulating SIRT1. Further, decreased cell viability induced by Aβ was prevented by cilostazol, and this inhibition was reversed by 3-methyladenine, indicating that the protective effect of cilostazol against Aβ induced neurotoxicity is, in part, ascribable to the induction of autophagy. In conclusion, cilostazol modulates autophagy by increasing the activation of SIRT1, and thereby enhances Aβ clearance and increases cell viability.

Increased expression of ATP-binding cassette transporter A1 (ABCA1) as a possible mechanism for the protective effect of cilostazol against hepatic steatosis

ObjectiveCilostazol, a phosphodiesterase 3, has been widely used in patients with arterial disease and is known to have additional beneficial effects on dyslipidemia. However, the effect of cilostazol on hepatic steatosis has not been fully elucidated. We investigated the effect of cilostazol on hepatic ABCA1 expression and hepatic steatosis in diet-induced obesity mice model. MethodsHepatic ABCA1 expression and lipid accumulation were analyzed in HepG2 cell lines treated with cilostazol. Male C57BL/6 mice were randomly divided into three groups: (1) fed normal chow diet with vehicle; (2) fed high-fat diet (HFD) with vehicle; (3) fed HFD with cilostazol. Cilostazol (30mg/kg) was orally administered once daily for 9weeks. ResultsCilostazol significantly enhanced ABCA1 expression and restored ABCA1 expression reduced by palmitate in HepG2 cells. Cilostazol treatment ameliorated lipid accumulation induced by palmitate, and this effect was diminished when ABCA1 or LRP1 was silenced by small interference RNA. After silencing of LRP1, ABCA1 expression was decreased in HepG2 cells. Cilostazol significantly enhanced hepatic ABCA1 expression and decreased hepatic fat in HFD-fed mice. Hepatic expression of cleaved caspase-3 and PARP1 was also decreased in HFD-fed mice treated with cilostazol. ConclusionsCilostazol ameliorated hepatic steatosis and increased ABCA1 expression in the hepatocytes. Enhancing ABCA1 expression with cilostazol represents a potential therapeutic avenue for treatment of hepatic steatosis.

Protective effect of cilostazol against doxorubicin-induced cardiomyopathy in mice

Doxorubicin (Dox) is an effective anti-cancer drug, but its use is limited because of its adverse effect of inducing irreversible dilated cardiomyopathy. Cilostazol (Cilo), a potent phosphodiesterase III inhibitor, has been reported to have an anti-inflammatory effect. Here, we investigated whether Cilo has a protective effect against Dox-induced cardiomyopathy (DIC). Mice were randomly divided into four groups: saline control, Dox (15mg/kg), Dox (15mg/kg) plus Cilo (50mg/kg), and Cilo (50mg/kg). The results showed that the coadministration of Dox and Cilo significantly enhanced left-ventricular systolic function compared with Dox alone. In addition, Cilo treatment significantly reduced Dox-induced perivascular fibrosis, collagen concentration, and connective growth factor expression in the heart. Also, Cilo administration markedly reduced Dox-induced levels of serum B-type natriuretic peptide, dysferlin, high-mobility group protein B1, Toll-like receptor 4, nuclear factor-κB p65, and cyclooxygenase-2. Furthermore, Cilo treatment significantly reduced Dox-induced oxidative stress by lowering the translocation of Nrf2 into the nucleus and the expression of NQO1, heme oxygenase 1, and superoxide dismutase-1. Our results suggest that Cilo may be a potential antifibrotic, antioxidative, and anti-inflammatory drug for DIC.

Cilostazol Induces PGI2 Production via Activation of the Downstream Epac-1/Rap1 Signaling Cascade to Increase Intracellular Calcium by PLCε and to Activate p44/42 MAPK in Human Aortic Endothelial Cells.

BackgroundCilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is known as an anti-platelet drug and acts directly on platelets. Cilostazol has been shown to exhibit vascular protection in ischemic diseases. Although vascular endothelium-derived prostaglandin I2 (PGI2) plays an important role in vascular protection, it is unknown whether cilostazol directly stimulates PGI2 synthesis in endothelial cells. Here, we elucidate the mechanism of cilostazol-induced PGI2 stimulation in endothelial cells.Methods and ResultsHuman aortic endothelial cells (HAECs) were stimulated with cilostazol and PGI2 accumulation in the culture media was measured. Cilostazol increased PGI2 synthesis via the arachidonic acid pathway. Cilostazol-induced intracellular calcium also promoted PGI2 synthesis via the inositol 1,4,5-trisphosphate receptor. Using RNAi, silencing of PDE3B abolished the induction effect of cilostazol on PGI2 synthesis and intracellular cAMP accumulation. Inhibition of the exchange protein, which was directly activated by cyclic AMP 1 (Epac-1) and its downstream signal the Ras-like small GTPase (Rap-1), abolished cilostazol-induced PGI2 synthesis, but this did not take place via protein kinase A (PKA). Inhibition of downstream signaling, such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) γ, and phospholipase C (PLC) ε, suppressed cilostazol-induced PGI2 synthesis.ConclusionsThe PDE3/Epac-1/Rap-1 signaling pathway plays an important role in cilostazol-induced PGI2 synthesis. Namely, stimulation of HAECs with cilostazol induces intracellular calcium elevation via the Rap-1/PLCε/IP3 pathway, along with MAPK activation via direct activation by Epac-1/Rap-1 and indirect activation by Epac-1/Rap-1/PI3Kγ, resulting in synergistically induced PGI2 synthesis.

Stimulation of angiogenesis by cilostazol accelerates fracture healing in mice.

Cilostazol, a selective phosphodiesterase-3 inhibitor, is known to control cyclic adenosine monophosphate (c-AMP) and to stimulate angiogenesis through upregulation of pro-angiogenic factors. There is no information, however, whether cilostazol affects fracture healing. We, therefore, studied the effect of cilostazol on callus formation and biomechanics during fracture repair. Bone healing was analyzed in a murine femur fracture stabilized with an intramedullary screw. Radiological, biomechanical, histomorphometric, histochemical, and protein biochemical analyses were performed at 2 and 5 weeks after fracture. Twenty-five mice received 30 mg/kg body weight cilostazol p.o. daily. Controls (n=24) received equivalent amounts of vehicle. In cilostazol-treated animals radiological analysis at 2 weeks showed an improved healing with an accelerated osseous bridging compared to controls. This was associated with a significantly higher amount of bony tissue and a smaller amount of cartilage tissue within the callus. Western blot analysis showed a higher expression of cysteine-rich protein 61 (CYR61), bone morphogenetic protein (BMP)-4, and receptor activator of NF-kappaB ligand (RANKL). At 5 weeks, improved fracture healing after cilostazol treatment was indicated by biomechanical analyses, demonstrating a significant higher bending stiffness compared to controls. Thus, cilostazol improves fracture healing by accelerating both bone formation and callus remodeling.

New therapeutic effects of cilostazol in patients with ischemic disorders.

Cilostazol (CIL) is effective for the treatment of patients with peripheral arterial disease (PAD). CIL is an orally administered drug with multiple effects, including anti-platelets aggregation, favorable functions on plasmatic lipids and vasodilator ones, but how these effects might be related to improvement in patients walking affected by PAD is not fully understood. The latest data demonstrate that nitric oxide (NO) is induced by CIL through endothelial nitric oxide synthase (eNOS) activation via a cyclic-AMP (cAMP)/ protein kinase A (PKA)- and PI3K/Akt- dependent mechanism. This mechanism is also responsible for the vasodilatation dependent on endothelium which characterized patients receiving CIL. Other investigators have found that CIL notably reduces the exercise-induced host-inflammatory response in PAD patients, and consequently it improves lipid hydroperoxides and cell-adhesion molecule levels. We recently reported that CIL is able to cause neoangiogenesis in vivo by stimulating the production of proangiogenic proteins, such as vascular endothelial growth factor (VEGF), that increase levels of Endothelial progenitor cells (EPCs) and the formation of new blood vessels. The mechanisms of action of this drug are several and are not clear and established. The objective of the present review is to analyze the existing data about the therapeutic effects of CIL, with the purpose of providing practical indications about this topic for the management of subjects affected by ischemic disorders.

Cilostazol inhibits plasmacytoid dendritic cell activation and antigen presentation.

BackgroundCilostazol, an anti-platelet drug for treating coronary heart disease, has been reported to modulate immune cell functions. Plasmacytoid dendritic cells (pDCs) have been found to participate in the progression of atherosclerosis mainly through interferon α (IFN-α) production. Whether cilostazol influences pDCs activation is still not clear. In this study, we aimed to investigate the effects of cilostazol on cell activation and antigen presentation of pDCs in vitro in this study.MethodsPeripheral blood mononuclear cells isolated by Ficoll centrifugation and pDCs sorted by flow cytometry were used in this study. After pretreated with cilostazol for 2 h, cells were stimulated with CpG-A, R848 or virus for 6 h or 20 h, or stimulated with CpG-B for 48 h and then co-cultured with naïve T cell for five days. Cytokines in supernatant and intracellular cytokines were analyzed by ELISA or flow cytometry respectively.ResultsOur data indicated that cilostazol could inhibit IFN-α and tumor necrosis factor α (TNF-α) production from pDCs in a dose-dependent manner. In addition, the ability of priming naïve T cells of pDCs was also impaired by cilostazol. The inhibitory effect was not due to cell killing since the viability of pDCs did not change upon cilostazol treatment.ConclusionCilostazol inhibits pDCs cell activation and antigen presentation in vitro, which may explain how cilostazol protects against atherosclerosis.

Effect of Cilostazol on The Pharmacodynamics of Cyp3a and Non-Cyp3a-Dependent Statins

Effect of Cilostazol on The Pharmacodynamics of Cyp3a and Non-Cyp3a-Dependent Statins

Effect of cilostazol on neointimal hyperplasia in iliac arteries of pigs after transluminal angioplasty

to evaluate whether systemic administration of cilostazol reduces neointimal hyperplasia in iliac arteries of pigs submitted to balloon catheter angioplasty. twenty pigs underwent angioplasty with a 6x40 mm balloon catheter in the right common iliac artery, guided by Doppler ultrasound. The animals were randomized into two groups: group 1 (n=10), which received 50mg cilostazol twice a day, and group 2 (n=10), control. After 30 days, the animals were killed and the iliac arteries prepared for histological analysis. The histological sections were digitized and analyzed by digital morphometry. Statistical analysis was performed using the Student t and Mann-Whitney tests. when comparing the iliac arteries submitted to angioplasty with those not subjected to angioplasty, there was significant neointimal hyperplasia (0.228 versus 0.119 mm2; p=0.0001). In arteries undergoing angioplasty, there was no difference between group 1 (cilostazol) and group 2 (control) as for the lumen area (2.277 versus 2.575 mm2; p=0.08), the tunica intima (0.219 versus 0.237 mm2; p=0.64), the tunica media (2.262 vs. 2.393 mm2; p=0.53) and the neointimal occlusion percentage (8.857 vs. 9.257 %; p=0.82). the use of cilostazol 50mg administered in two daily doses did not reduce neointimal hyperplasia in iliac arteries of pigs submitted to balloon angioplasty catheter.

Cilostazol attenuates ovariectomy-induced bone loss by inhibiting osteoclastogenesis.

BackgroundCilostazol has been reported to alleviate the metabolic syndrome induced by increased intracellular adenosine 3’,5’-cyclic monophosphate (cAMP) levels, which is also associated with osteoclast (OC) differentiation. We hypothesized that bone loss might be attenuated via an action on OC by cilostazol.Methodology and Principal FindingsTo test this idea, we investigated the effect of cilostazol on ovariectomy (OVX)-induced bone loss in mice and on OC differentiation in vitro, using μCT and tartrate-resistant acid phosphatase staining, respectively. Cilostazol prevented from OVX-induced bone loss and decreased oxidative stress in vivo. It also decreased the number and activity of OC in vitro. The effect of cilostazol on reactive oxygen species (ROS) occurred via protein kinase A (PKA) and cAMP-regulated guanine nucleotide exchange factor 1, two major effectors of cAMP. Knockdown of NADPH oxidase using siRNA of p47phox attenuated the inhibitory effect of cilostazol on OC formation, suggesting that decreased OC formation by cilostazol was partly due to impaired ROS generation. Cilostazol enhanced phosphorylation of nuclear factor of activated T cells, cytoplasmic 1 (NFAT2) at PKA phosphorylation sites, preventing its nuclear translocation to result in reduced receptor activator of nuclear factor-κB ligand-induced NFAT2 expression and decreased binding of nuclear factor-κB-DNA, finally leading to reduced levels of two transcription factors required for OC differentiation.Conclusions/SignificanceOur data highlight the therapeutic potential of cilostazol for attenuating bone loss and oxidative stress caused by loss of ovarian function.

An experimental study of the effect of pre-operative administration of cilostazol on random skin flap survival in rats: double blinded randomized controlled trial.

BackgroundInsufficient arterial blood flow is the one cause of flap necrosis. Cilostazol is an inhibitor of phosphodiesterase III and increases cyclic AMP level in vascular smooth muscle cell causing vasodilation. Therefore, effect of cilostazol is expected to improve the viability of the flap.MethodsDouble blinded randomized controlled trial was conducted. The study was to compare the survival of dorsal rat flaps between preoperative cilostazol supplemented diet and regular diet. The flap survival area was measured using PixArea Image software on post operative day 1,3,5 and 7. Fluorescein injection was performed to evaluate the exactly area of flap survival on postoperative day 7 and morphology of arterioles and venules were examined by histopathologic examination.ResultsA statistical significance was found in the percentage of area of flap survival between cilostazol supplemented diet and control group on postoperative day 3, 5 and 7 (p < 0.05). Fluorescein injection showed the higher area of flap survival in cilostazol group than the control group (p < 0.05). Histopathologic examination showed dilation of vessels in the cilostazol group.ConclusionPreoperative cilostazol in rats can enhance skin flap survival.Electronic supplementary materialThe online version of this article (doi:10.1186/s13022-015-0011-4) contains supplementary material, which is available to authorized users.

Serum uric acid is positively associated with cerebral white matter hyperintensities in patients with acute lacunar infarction: Subgroup analysis of the Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler (ECLIPse) study (P1.046)

Serum uric acid is positively associated with cerebral white matter hyperintensities in patients with acute lacunar infarction: Subgroup analysis of the Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler (ECLIPse) study (P1.046)

Retraction note: Systematic study of cilostazol on secondary stroke prevention: a meta-analysis.

To study the efficacy and safety of cilostazol on ischemic stroke prevention and treatment, systematic reviews of related clinical randomized controlled trials were analyzed. We searched the main databases for eligible trials including literature from January 1966 to November 2012 in MEDLINE, reports from 1980 to November 2012 in EMBASE, and all the studies published in EBSCO, Springer, Ovid, and Cochrane library citations. We also searched for keywords, including cilostazol and aspirin. RewMan 5.0 software was used to conduct the meta-analysis. Our search yielded five eligible trials. The effects of cilostazol and aspirin on ischemic stroke prevention and treatment were almost equal (combined odds ratio (OR) 0.78, 95% confidence interval (CI) (0.59, 1.04)). Additionally, both magnetic resonance angiography (MRA) and transcranial Doppler (TCD) examination showed that cilostazol could significantly decrease the incidence of intracranial artery stenosis exacerbation (MRA: combined OR 0.22, 95% CI (0.07, 0.68); TCD: combined OR 0.17, 95% CI (0.05, 0.51)). In terms of adverse reactions, there were slightly fewer incidences of major bleeding with cilostazol than with aspirin (combined OR 0.38, 95% CI (0.24, 0.60)), and there was no difference in the number of heart palpitations between cilostazol and aspirin. However, the incidence of gastrointestinal disorders, dizziness, and headaches caused by cilostazol was greater. Cilostazol might be a more effective and safer alternative to aspirin for patients with ischemic stroke. Further studies are required to confirm whether cilostazol is a suitable therapeutic option for secondary stroke prevention in larger cohorts of patients with ischemic stroke.

Cilostazol induces vasodilation through the activation of Ca2 +-activated K+ channels in aortic smooth muscle

We investigated the vasorelaxant effect of cilostazol and related signaling pathways in phenylephrine (Phe)-induced pre-contracted aortic rings. Cilostazol induced vasorelaxation in a concentration-dependent manner when aortic rings were pre-contracted with Phe. Application of the voltage-dependent K+ (Kv) channel inhibitor 4-AP, the ATP-sensitive K+ (KATP) channel inhibitor glibenclamide, and the inwardly rectifying K+ (Kir) channel inhibitor Ba2+ did not alter the vasorelaxant effect of cilostazol; however, pre- and post-treatment with the big-conductance Ca2+-activated K+ (BKCa) channel inhibitor paxilline inhibited the vasorelaxant effect of cilostazol. This vasorelaxant effect of cilostazol was reduced in the presence of an adenylyl cyclase or a protein kinase A (PKA) inhibitor, but not a protein kinase G inhibitor. Inside-out single channel recordings revealed that cilostazol induced the activation of BKCa channel activity. The vasorelaxant effect of cilostazol was not affected by removal of the endothelium. In addition, application of a nitric oxide synthase inhibitor and a small-conductance Ca2+-activated K+ (SKCa) channel inhibitor did not affect cilostazol-induced vasorelaxation. We conclude that cilostazol induced vasorelaxation of the aorta through activation of BKCa channel via a PKA-dependent signaling mechanism independent of endothelium.