Effects of cilostazol on angiographic restenosis after coronary stent placement. 

Reference: Am J Cardiol 2000;86(5):499-503.

This study evaluates the impact of cilostazol on post-stenting restenosis. Cilostazol is a potent
antiplatelet agent with antiproliferative properties. Few data are available about the effect of cilostazol on poststenting restenosis. Four hundred nine patients (494 lesions) who were scheduled for elective stenting were randomized to receive aspirin plus ticlopidine (group I, n = 201, 240 lesions) or aspirin plus cilostazol (group II, n = 208, 254 lesions), starting 2 days before stenting. Ticlopidine was given for 1 month and cilostazol for 6 months. Follow-up angiography was performed at 6 months, and clinical evaluation at regular intervals. Baseline characteristics were similar between the 2 groups. The procedural success rate was 99.6% in group I and 100% in group II. There were no cases of stent thrombosis after stenting. Angiographic follow-up was performed in 380 of the 494 eligible lesions and the angiographic restenosis rate was 27% in group I and 22.9% in group II (p = NS). However, diffuse type in-stent restenosis was more common in group I than in group II (54.2% vs 26.8%, respectively, p <0.05). In diabetic patients, the angiographic restenosis rate was 50% in group I and 21.7% in group II (p <0.05). Clinical events during follow-up did not differ between the 2 groups. In conclusion, aspirin plus cilostazol seems to be an effective antithrombotic regimen with comparable results to aspirin plus ticlopidine, but it does not reduce the overall angiographic restenosis rate after elective coronary stenting.

Cilostazol, a selective type III phosphodiesterase inhibitor, decreases triglyceride and increases HDL cholesterol levels by increasing lipoprotein lipase activity in rats. 

Reference: Atherosclerosis 2000;152(2):299-305.

Cilostazol, a selective type III phosphodiesterase inhibitor, has antiplatelet and vasodilating effects. In this study, the effects of cilostazol on lipid metabolism and lipoprotein lipase (LPL) activity were
studied in rats. Cilostazol was administered orally at doses of 30 or 100 mg/kg twice a day for 1-2
weeks to rats. Cilostazol decreased the serum triglyceride level in normolipidemic rats. The serum
triglyceride level was reduced and HDL cholesterol level was increased by cilostazol in streptozotocin (STZ)-induced diabetic rats. The disappearance of exogenous triglyceride was accelerated by cilostazol in normolipidemic rats. Cilostazol increased post-heparin plasma LPL activity but had no effect on hepatic triglyceride lipase activity in STZ-induced diabetic rats. Cilostazol also increased LPL activity in the heart in STZ-induced diabetic rats. These findings suggest that an increase in LPL activity is responsible for the serum triglyceride lowering and HDL cholesterol elevating effects of cilostazol in rats.

Inhibition of adenosine uptake and augmentation of ischemia-induced increase of interstitial adenosine by cilostazol, an agent to treat intermittent claudication. 

Reference: J Cardiovasc Pharmacol 2000;36(3):351-60.

Cilostazol (Pletal), a quinolinone derivative with a cyclic nucleotide phosphodiesterase type 3 (PDE3) inhibitory activity, was recently approved by the Food and Drug Administration for treatment of symptoms of intermittent claudication (IC). However, the underlying mechanisms of action are not
entirely clear. In this study, we showed that cilostazol inhibited adenosine uptake into cardiac
ventricular myocytes, coronary artery smooth muscle, and endothelial cells with a median effective
concentration (EC50) approximately 10 microM. In vivo, cilostazol increased cardiac interstitial
adenosine levels after a 2-min ischemia in rabbit hearts (329 +/- 92% increase vs. 102 +/- 29%
ischemia alone). The combination of cilostazol and 2-min ischemia reduced infarction from
subsequent 30-min regional ischemia and 3 h of reperfusion (infarct size was 18 +/- 4% vs. 53 +/- 3% in the hearts with 2-min ischemia alone or 48 +/- 2% in the hearts treated with cilostazol alone). In
contrast, milrinone had no effect on either adenosine uptake or interstitial adenosine levels. These
data show that cilostazol, unlike milrinone, inhibits adenosine uptake, and thus potentiates
adenosine accumulation from a 2-min ischemia. Future studies are needed to investigate the role of
adenosine in the treatment of IC by cilostazol.

EXISTENCE OF A beta3-ADRENOCEPTOR AND ITS FUNCTIONAL ROLE IN THE HUMAN URETER. 

Reference: J Urol 2000;164(4):1364-70

PURPOSE: We tried to determine the beta-adrenoceptor (AR) subtypes distributed in the human
ureter and to clarify their functional role in ureteral relaxation. 

MATERIALS AND METHODS: 1)Effects of beta-AR agonists on either spontaneous or KCl-induced contractions of the human ureter and the antagonism by beta-AR antagonists on isoprenaline (a non-selective beta-AR agonist)-induced effects were evaluated in vitro. 2) Displacement by beta-AR antagonists of [3H]-dihydroalprenolol binding to a membrane preparation derived from human ureteral smooth muscle was evaluated. 3) A reverse transcription polymerase chain reaction assay was performed to determine the expression of the mRNA for beta1-, beta2- and beta3-ARs in human ureteral smooth muscle. 

RESULTS: 1) Isoprenaline and procaterol (a beta2-AR agonist) concentration-dependently suppressed both spontaneous and KCl-induced contractions of the human ureter. The beta3-AR agonists, CGP-12177A and CL-316243, also suppressed these ureteral contractions, but dobutamine (a beta1-AR agonist) had little relaxing effect. The rank order of relaxing potency for the catecholamines was isoprenaline > adrenaline > noradrenaline. ICI-118,551 (a beta2-AR antagonist) only partially antagonized the isoprenaline-induced relaxation. 2) Propranolol (a non-selective beta-AR antagonist) and ICI-118,551 concentration-dependently displaced [3H]-dihydroalprenolol binding to the membrane with Ki values of 1.5 x 10-9 M and 6.3 x 10-9 M, respectively, while metoprolol (a beta1-AR antagonist) was less effective in this assay. 3) beta1-, beta2- and beta3-AR mRNAs were all expressed in human ureteral smooth muscle.

 CONCLUSION: The present results provide the first evidence that the beta3-AR subtype is distributed in human ureteral smooth muscle and that it, and beta2-AR, mediate the ureteral relaxation induced by adrenergic stimulation.