Abstract
In this study, we evaluated the effect of therapeutic doses of cilostazol on human venous smooth muscle. Saphenous vein rings (two to four per patient sample) were suspended in tissue baths for isometric tension recordings. At the beginning of the experiment, optimal tension for isometric contraction was achieved for each ring in a stepwise fashion in the presence of norepinephrine (10−2 M). Norepinepherine was then added cumulatively in half-molar increments and isometric tension developed by the rings was measured, thereby obtaining a dose-response curve. Following washout and reequilibration, the rings were precontracted with a 30-50% submaximal dose of norepinepherine determined from the dose-response curve and allowed to contract until a stable plateau was reached. Cilostazol was then added in a cumulative manner (680-2,720 μg/L), and the tension generated was recorded. A total of 76 venous rings were tested, and all relaxed in the presence of cilostazol. The amount of relaxation increased as the concentration of cilostazol increased. Relaxation of 15 ± 1.9% (mean ± SEM) at low cilostazol doses (680 μg/L) to 37±3% at high cilostazol doses (2,720 μg/L) was demonstrated. A second finding of this study was demonstrated when the patient samples were divided according to the presence or absence of risk factors for arteriosclerosis. The specific risk factors examined included diabetes mellitus, smoking, hypercholesterolemia, and hypertension. The presence or absence of hypertension (n = 52) or hypercholesterolemia (n = 18) did not affect the amount of relaxation of the venous rings. Smokers (n = 46) had less relaxation 16 ± 2.4% (680 μg/L) to 41 ± 3.6% (2,720 μg/L) compared to nonsmokers (n = 53) who relaxed 22 ± 3.5% (680 μg/L) to 48 ± 5.7% (2720 μg/L). This did not reach statistical significance at any concentration cilostazol (p = 0.11-0.18). Diabetics (n = 53) did have statistically significantly less relaxation at every concentration of cilostazol compared to nondiabetics (n = 11, p < 0.05). All venous rings relaxed in the presence of cilostazol. Veins of nondiabetics relaxed statistically significantly more than those of diabetics. Smokers had less relaxation than non-smokers, but this was not statistically significant. We are the first to demonstrate that human venous smooth muscle cells undergo relaxation when exposed to therapeutic concentrations of cilostazol.
Similar content being viewed by others
References
M Criqui J Denenberg R Longer et al. (1997) ArticleTitleThe epidemiology of peripheral arterial disease: importance of identifying the population at risk Vasc Med 2 221–226 Occurrence Handle1:STN:280:DyaK1c7nvVSnsw%3D%3D Occurrence Handle9546971
TransAtlantic Inter-Society Consensus (TASC) Working Group. J Vasc Surg 2000;31:S5-S44, S54-S74, S77-S122
J Dormandy G Murray (1991) ArticleTitleThe fate of the claudicant—a prospective study of 1969 claudicants Eur J Vasc Surg 5 131–133 Occurrence Handle1:STN:280:By6B2czovFY%3D Occurrence Handle2037083
K Bloor (1961) ArticleTitleNatural history of atherosclerosis of the lower extremities Ann R Coll Surg Engl 28 36–51
J Dormandy L Heeck S Vig (1999) ArticleTitleThe natural history of claudication: risk to life and limb Semin Vasc Surg 12 123–37 Occurrence Handle1:STN:280:DC%2BD3c3jslSiug%3D%3D Occurrence Handle10777239
J Weitz J Byrne G Clagett et al. (1996) ArticleTitleDiagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review Circulation 94 3026–3049 Occurrence Handle1:STN:280:ByiD1MnhtlQ%3D Occurrence Handle8941154
W Kannel D McGee (1985) ArticleTitleUpdate on some emdemiological features of intermittent claudication J Am Geriatr Soc 33 13–18 Occurrence Handle1:STN:280:BiqD1c7gsFE%3D Occurrence Handle3965550
K Brockbank H Bank M Schmehl (1989) ArticleTitleIschemia and saphenous vein endothelial integrity Transpl. Proc 21 1384–1388 Occurrence Handle1:STN:280:BiaB38zit1Y%3D
K Brockbank M Davies S Fields (1993) ArticleTitleThe relationship of human saphenous vein smooth contractile responses to donor age and gender Vasc. Surg 29 15–21
J Torok F Krister M Mokrasova (1993) ArticleTitleEndothelium-dependent relaxation in rabbit aorta after cold storage Eur J Pharmacol 228 313–319 Occurrence Handle1:CAS:528:DyaK3sXitlWiurs%3D Occurrence Handle8482323
S Bramer W Forbes S Mallikaarjun (1999) ArticleTitleCilostazol pharmacokinetics after single and multiple oral doses in healthy males and patients with intermittent claudication resulting from peripheral arterial disease Clin Pharmaocokinet 37 IssueIDSupp. 2 1–11 Occurrence Handle1:CAS:528:DC%2BD3cXhs1Gns78%3D
T Tanaka T Ishikawa M Hagiwara et al. (1998) ArticleTitleEffects of cilostazol, a selective CAMP phosphodiesterase inhibitor on the contraction of vascular smooth muscle Pharmacology 36 313–320 Occurrence Handle10.1159/000138400
K Kawamura K Watanabe K Kimura (1985) ArticleTitleEffect of cilostazol, a new antithrombotic drug, on cerebral circulation Arzneimittelforschung 35 1149–1154 Occurrence Handle1:CAS:528:DyaL2MXltFGqu78%3D Occurrence Handle4074427
J Cone S Wang N Tandon et al. (1999) ArticleTitleComparison of the effects of cilostazol and milrinone on intracellular CAMP levels and cellular function in platelets and cardiac cells J Cardiovasc Pharmacol 34 497–504 Occurrence Handle1:CAS:528:DyaK1MXmt1ejtr4%3D Occurrence Handle10511123
D Dawson B Cutler M Meissner et al. (1998) ArticleTitleCilostazol has benefcial effects in treatment of intermittent claudication Circulation 98 678–686 Occurrence Handle1:CAS:528:DyaK1cXlslWltb4%3D Occurrence Handle9715861
Y Ikeda M Kikuchi H Murakami et al. (1987) ArticleTitleComparison of the inhibitory effects of cilostazol, acetylsalicylic acid and ticlopidine on platelet functions ex vivo: randomized, double-blind cross-over study Arzneimittleforschung 37 563–566 Occurrence Handle1:STN:280:BiiB1MfmvVc%3D
N Minami Y Suzuki M Yamamoto et al. (1997) ArticleTitleInhibition of shear stress-induced platelet aggregation by cilostazol, a specific inhibitor of cGMP-inhibited phosphodiesterase, in vitro and ex vivo Life Sci 61 383–389 Occurrence Handle10.1016/S0024-3205(97)00986-7 Occurrence Handle9244364
M Elam J Heckman J Grouse et al. (1998) ArticleTitleEffect of the novel antiplatelet agent, cilostazol, on plasma lipoproteins in patients with intermittent claudication Arterioscler. Thromb. Vasc. Biol. 18 1942–1947 Occurrence Handle1:CAS:528:DyaK1MXitVaqtw%3D%3D Occurrence Handle9848888
S Hayashi R Morishita H Mausushita et al. (2000) ArticleTitleCyclic AMP inhibited proliferation of human aortic vascular smooth-muscle cells, accompanied by induction of p53 and p21 Hypertension 35 237–243 Occurrence Handle1:CAS:528:DC%2BD3cXpt1aisg%3D%3D Occurrence Handle10642304
E Shimizu Y Kobayashi Y Oki et al. (1999) ArticleTitleOPC-13013, a cyclic nucleotide phosphodiesterase type III inhibitor, inhibits cell proliferation and transdifferentiation of cultured rat hepatic stellate cells Life Sci 64 2081–2088 Occurrence Handle1:CAS:528:DyaK1MXjt12msLk%3D Occurrence Handle10372650
S Takahashi K Oida R Fujiwara et al. (1992) ArticleTitleEffect of cilostazol, a cyclic AMP phosphodiesterase inhibitor, on the proliferation of rat aortic smooth muscle cells in culture J Cardiovasc Pharmacol 3 587–599
N Ishizaka J Taguchi Y Kimura et al. (1999) ArticleTitleEffects of a single local administration of cilostazol on neointimal formation in balloon-injured rat carotid artery Atherosclerosis 142 41–46 Occurrence Handle1:CAS:528:DyaK1cXnt1arsLY%3D Occurrence Handle9920504
Y Kubota K Kichikawa H Uchida et al. (1995) ArticleTitlePharmacologic treatment of intimal hyperplasia after metallic stent placement in the peripheral arteries. An experimental study Invest. Radiol. 30 532–537 Occurrence Handle1:CAS:528:DyaK2MXpsl2ksLs%3D Occurrence Handle8537210
K Kozuma K Hara M Yamasaki et al. (2001) ArticleTitleEffects of cilostazol on late lumen loss and repeat revascularization after Palmas-Schatz coronary stent implantation Am Heart J 141 124–130 Occurrence Handle11136497 Occurrence Handle1:CAS:528:DC%2BD3MXlt1Clug%3D%3D
T Kunishima H Musha F Eto et al. (1997) ArticleTitleA randomized trial of aspirin versus cilostazol therapy after successful coronary stent implantation Clin. Ther 19 1058–1066 Occurrence Handle1:CAS:528:DyaK2sXns1ygsLw%3D Occurrence Handle9385493
M Ochiai K Eto S Takeshita et al. (1999) ArticleTitleImpact of cilostazol on clinical and angiographic outcome after primary stenting for acute myocardial infarction Am J Cardiol 84 1074–1076 Occurrence Handle1:CAS:528:DyaK1MXnvVGms74%3D Occurrence Handle10569666
M Ochiai T Isshiki S Takeshita et al. (1997) ArticleTitleUse of cilostazol, a novel antiplatelet agent, in a post-Palmaz-Schatz stenting regimen Am J Cardiol 79 1471–1474 Occurrence Handle1:CAS:528:DyaK2sXktF2jsLo%3D Occurrence Handle9185635
E Tsuchikane A Fukuhara T Kobayashi et al. (1999) ArticleTitleImpact of cilostazol on restenosis after percutaneous coronary balloon angioplasty Circulation 100 21–26 Occurrence Handle1:CAS:528:DyaK1MXksFyltbY%3D Occurrence Handle10393676
N Hertzer E Beven J Young et al. (1984) ArticleTitleCoronary artery disease in peripheral vascular patients. A classification of 1000 coronary angiograms and results of surgical management Ann Surg 199 223–233 Occurrence Handle1:STN:280:BiuC38jgs1Y%3D Occurrence Handle6696538
J Dormandy M Mahir J Ascada et al. (1989) ArticleTitleFate of the patient with chronic leg ischemia J Cardiovasc Surg 30 50–57 Occurrence Handle1:STN:280:BiaC2svpsVE%3D
M Bots A Hofman D Grobbee (1994) ArticleTitleCommon carotid intima-media thickness and lower extremity atherosclerosis: the Rotterdam Study Arterlosclei Thromb 14 1885–1891 Occurrence Handle1:STN:280:ByqD2s7pvVc%3D
P Allan P Mowbray A Lee et al. (1997) ArticleTitleRelationship between carotid intima-media thickness and symptomatic and asymptomatic peripheral arterial disease: the Edinburgh Artery Study Stroke 28 348–353 Occurrence Handle1:STN:280:ByiC1MzgvFI%3D Occurrence Handle9040688
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Becker, R.W., Lusis, E., Sohn, R.L. et al. Effects of Cilostazol on Human Venous Smooth Muscle. Ann Vasc Surg 19, 393–397 (2005). https://doi.org/10.1007/s10016-005-0012-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10016-005-0012-6