Cilostazol improves endothelial function in acute cerebral ischemia patients: a double-blind placebo controlled trial with flow-mediated dilation technique

Seong-Joon Lee, Jin Soo Lee, Mun Hee Choi, Sung Eun Lee, Dong Hoon Shin, Ji Man Hong, Seong-Joon Lee, Jin Soo Lee, Mun Hee Choi, Sung Eun Lee, Dong Hoon Shin, Ji Man Hong

Abstract

Background: In order to evaluate the impact of cilostazol on endothelial function, we compared the changes of flow-mediated dilation (FMD) between aspirin and cilostazol groups in patients with acute cerebral ischemia.

Methods: Patients presenting with acute cerebral ischemic events were randomly assigned into aspirin (n = 40) or cilostazol (n = 40) group in a double-blinded manner. FMD was measured at baseline (T0) and 90 days (T1). We measured L-arginine at baseline (a precursor of biologically active nitric oxides). Serious and non-serious adverse events were described.

Results: Despite no difference in the baseline FMD values (p = 0.363), there was a significant increase of FMD values in cilostazol group (7.9 ± 2.4 to 8.9 ± 2.3%, p = 0.001) and not in aspirin group (8.5 ± 2.6 to 9.3 ± 2.8%, p = 0.108). In the multiple regression analysis performed in cilostazol group, serum L-arginine levels were inversely correlated with FMD at T1 (ß = -0.050, SE: 0.012, p < 0.001) with age, total cholesterol levels, and C-reactive protein as confounders. While T0 FMD values in both aspirin and cilostazol groups did not show any correlation with serum L-arginine levels, the correlation is restored in the cilostazol group at T1 (r = 0.467, p = 0.007), while such is not shown in the aspirin group. There was no difference of serious adverse events between the two groups (p = 0.235). Adverse events were more common in the cilostazol group (35/40 vs. 25/40, p = 0.010), due to frequent headaches (14/40 vs. 3/30, p = 0.003) which was well tolerated.

Conclusion: Cilostazol improved endothelial function in acute cerebral ischemia patients. It also restored an inverse correlation between 3-month FMD and baseline L-arginine levels.

Trial registration: NCT03116269 , 04/12/2017, retrospectively registered.

Keywords: Arginine; Cerebral infarction; Cilostazol; Endothelium; Transient ischemic attack.

Conflict of interest statement

Ethics approval and consent to participate

The institutional review board of Ajou University Hospital approved the protocol (AJIRB MED CT4 10–239) and all participants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
The FMD parameters on enrollment and at 3 months. A significant increase of FMD values in the cilostazol group is seen, while not in the aspirin group
Fig. 2
Fig. 2
Correlation between initial serum L-arginine levels and FMD at enrollment and at 3 months. Blue dots denote FMD at enrollment (T0), and red dots denote FMD at 3 months (T1). a In the aspirin group FMD values and L-arginine levels do not show correlation at T0 and at T1. b In the cilostazol group, T0 FMD values and L-arginine levels do not show correlation, but an inverse correlation between the two values is revealed at T1

References

    1. Huang Y, Cheng Y, Wu J, Li Y, Xu E, Hong Z, Li Z, Zhang W, Ding M, Gao X, et al. Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. The Lancet Neurology. 2008;7(6):494–499. doi: 10.1016/S1474-4422(08)70094-2.
    1. Ikeda Y, Kikuchi M, Murakami H, Satoh K, Murata M, Watanabe K, Ando Y. Comparison of the inhibitory effects of cilostazol, acetylsalicylic acid and ticlopidine on platelet functions ex vivo. Randomized, double-blind cross-over study. Arzneimittelforschung. 1987;37(5):563–566.
    1. Tanaka T, Ishikawa T, Hagiwara M, Onoda K, Itoh H, Hidaka H. Effects of cilostazol, a selective cAMP phosphodiesterase inhibitor on the contraction of vascular smooth muscle. Pharmacology. 1988;36(5):313–320. doi: 10.1159/000138400.
    1. Ahn CW, Lee HC, Park SW, Song YD, Huh KB, Oh SJ, Kim YS, Choi YK, Kim JM, Lee TH. Decrease in carotid intima media thickness after 1 year of cilostazol treatment in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2001;52(1):45–53. doi: 10.1016/S0168-8227(00)00235-7.
    1. Park SW, Lee CW, Kim HS, Lee NH, Nah DY, Hong MK, Kim JJ, Park SJ. Effects of cilostazol on angiographic restenosis after coronary stent placement. Am J Cardiol. 2000;86(5):499–503. doi: 10.1016/S0002-9149(00)01001-8.
    1. Kwon SU, Cho YJ, Koo JS, Bae HJ, Lee YS, Hong KS, Lee JH, Kim JS. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke. 2005;36(4):782–786. doi: 10.1161/01.STR.0000157667.06542.b7.
    1. Takahashi S, Oida K, Fujiwara R, Maeda H, Hayashi S, Takai H, Tamai T, Nakai T, Miyabo S. Effect of cilostazol, a cyclic AMP phosphodiesterase inhibitor, on the proliferation of rat aortic smooth muscle cells in culture. J Cardiovasc Pharmacol. 1992;20(6):900–906. doi: 10.1097/00005344-199212000-00009.
    1. Wang T, Elam MB, Forbes WP, Zhong J, Nakajima K. Reduction of remnant lipoprotein cholesterol concentrations by cilostazol in patients with intermittent claudication. Atherosclerosis. 2003;171(2):337–342. doi: 10.1016/j.atherosclerosis.2003.08.017.
    1. Shin HK, Kim YK, Kim KY, Lee JH, Hong KW. Remnant lipoprotein particles induce apoptosis in endothelial cells by NAD(P)H oxidase-mediated production of superoxide and cytokines via lectin-like oxidized low-density lipoprotein receptor-1 activation: prevention by cilostazol. Circulation. 2004;109(8):1022–1028. doi: 10.1161/01.CIR.0000117403.64398.53.
    1. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340(8828):1111–1115. doi: 10.1016/0140-6736(92)93147-F.
    1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362(6423):801–809. doi: 10.1038/362801a0.
    1. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285–1295.
    1. Durante W. Role of arginase in vessel wall remodeling. Front Immunol. 2013;4:111. doi: 10.3389/fimmu.2013.00111.
    1. Katakami N, Kim YS, Kawamori R, Yamasaki Y. The phosphodiesterase inhibitor cilostazol induces regression of carotid atherosclerosis in subjects with type 2 diabetes mellitus: principal results of the diabetic atherosclerosis prevention by Cilostazol (DAPC) study: a randomized trial. Circulation. 2010;121(23):2584–2591. doi: 10.1161/CIRCULATIONAHA.109.892414.
    1. Shin DH, Lee JS, Hong JM, Kim SY. Cross-section imaging with M-mode as an alternative method for the measurement of brachial artery flow-mediated vasodilation. Journal of clinical ultrasound : JCU. 2013;41(3):158–163. doi: 10.1002/jcu.21972.
    1. Jauch EC, Saver JL, Adams HP, Jr, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW, Jr, Qureshi AI, Rosenfield K, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870–947. doi: 10.1161/STR.0b013e318284056a.
    1. Lee YS, Bae HJ, Kang DW, Lee SH, Yu K, Park JM, Cho YJ, Hong KS, Kim DE, Kwon SU, et al. Cilostazol in acute ischemic stroke treatment (CAIST trial): a randomized double-blind non-inferiority trial. Cerebrovasc Dis. 2011;32(1):65–71. doi: 10.1159/000327036.
    1. Fujita Y, Lin JX, Takahashi R, Tomimoto H. Cilostazol alleviates cerebral small-vessel pathology and white-matter lesions in stroke-prone spontaneously hypertensive rats. Brain Res. 2008;1203:170–176. doi: 10.1016/j.brainres.2008.01.103.
    1. Oida K, Ebata K, Kanehara H, Suzuki J, Miyamori I. Effect of cilostazol on impaired vasodilatory response of the brachial artery to ischemia in smokers. J Atheroscler Thromb. 2003;10(2):93–98. doi: 10.5551/jat.10.93.
    1. Kim KS, Park HS, Jung IS, Park JH, Ahn KT, Jin SA, Park YK, Kim JH, Lee JH, Choi SW, et al. Endothelial dysfunction in the smokers can be improved with oral cilostazol treatment. Journal of cardiovascular ultrasound. 2011;19(1):21–25. doi: 10.4250/jcu.2011.19.1.21.
    1. Jeong IS, Park JH, Jin SA, Kim JH, Lee JH, Choi SW, Jeong JO, Seong IW. Oral sarpogrelate can improve endothelial dysfunction as effectively as oral cilostazol, with fewer headaches, in active young male smokers. Heart Vessel. 2013;28(5):578–582. doi: 10.1007/s00380-012-0282-1.
    1. Ikeda U, Ikeda M, Kano S, Kanbe T, Shimada K. Effect of cilostazol, a cAMP phosphodiesterase inhibitor, on nitric oxide production by vascular smooth muscle cells. Eur J Pharmacol. 1996;314(1–2):197–202. doi: 10.1016/S0014-2999(96)00551-1.
    1. Nakamura T, Houchi H, Minami A, Sakamoto S, Tsuchiya K, Niwa Y, Minakuchi K, Nakaya Y. Endothelium-dependent relaxation by cilostazol, a phosphodiesteras III inhibitor, on rat thoracic aorta. Life Sci. 2001;69(15):1709–1715. doi: 10.1016/S0024-3205(01)01258-9.
    1. Rajagopalan S, Pfenninger D, Somers E, Kehrer C, Chakrabarti A, Mukherjee D, Brook R, Kaplan MJ. Effects of cilostazol in patients with Raynaud's syndrome. Am J Cardiol. 2003;92(11):1310–1315. doi: 10.1016/j.amjcard.2003.08.013.
    1. Mori H, Maeda A, Wakabayashi K, Sato T, Sasai M, Tashiro K, Iso Y, Ebato M, Suzuki H. The effect of Cilostazol on endothelial function as assessed by flow-mediated dilation in patients with coronary artery disease. J Atheroscler Thromb. 2016;23(10):1168–1177. doi: 10.5551/jat.32912.
    1. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86(1):228–234. doi: 10.1172/JCI114688.
    1. Bragulat E, de la Sierra A, Antonio MT, Coca A. Endothelial dysfunction in salt-sensitive essential hypertension. Hypertension. 2001;37(2 Pt 2):444–448. doi: 10.1161/01.HYP.37.2.444.
    1. Watts GF, Playford DA. Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis. Atherosclerosis. 1998;141(1):17–30. doi: 10.1016/S0021-9150(98)00170-1.
    1. Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis? Circulation. 2004;109(21 Suppl 1):II27–II33.
    1. Boger RH. The pharmacodynamics of L-arginine. J Nutr. 2007;137(6 Suppl 2):1650S–1655S.
    1. Perticone F, Sciacqua A, Maio R, Perticone M, Maas R, Boger RH, Tripepi G, Sesti G, Zoccali C. Asymmetric dimethylarginine, L-arginine, and endothelial dysfunction in essential hypertension. J Am Coll Cardiol. 2005;46(3):518–523. doi: 10.1016/j.jacc.2005.04.040.
    1. Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frolich J, et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet. 2001;358(9299):2113–2117. doi: 10.1016/S0140-6736(01)07217-8.
    1. Boger RH, Bode-Boger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation. 1998;98(18):1842–1847. doi: 10.1161/01.CIR.98.18.1842.
    1. Hashimoto A, Miyakoda G, Hirose Y, Mori T. Activation of endothelial nitric oxide synthase by cilostazol via a cAMP/protein kinase A- and phosphatidylinositol 3-kinase/Akt-dependent mechanism. Atherosclerosis. 2006;189(2):350–357. doi: 10.1016/j.atherosclerosis.2006.01.022.
    1. Bode-Boger SM, Muke J, Surdacki A, Brabant G, Boger RH, Frolich JC. Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med. 2003;8(2):77–81. doi: 10.1191/1358863x03vm474oa.
    1. Bode-Boger SM, Scalera F, Ignarro LJ. The L-arginine paradox: importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacol Ther. 2007;114(3):295–306. doi: 10.1016/j.pharmthera.2007.03.002.
    1. Frick M, Alber HF, Hugel H, Schwarzacher SP, Pachinger O, Weidinger F. Short- and long-term changes of flow-mediated vasodilation in patients under statin therapy. Clin Cardiol. 2002;25(6):291–294. doi: 10.1002/clc.4960250610.

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