Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: A placebo-controlled study in rats

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• 作者：Grzegorz Grzesk^a ; ^b ; Marek Kozinski^b ; ^{marekkozinski@wp.pl} ; Eliano Pio Navarese^b ; ^c ; Marek Krzyzanowski^a ; Elzbieta Grzesk^d ; Aldona Kubica^e ; Jolanta Maria Siller-Matula^f ; Fausto Castriota^c ; Jacek Kubica^b
• 关键词：ticagrelor ; prasugrel ; clopidogrel ; off-target effect ; vascular smooth muscle cells ; platelets
• 刊名：Thrombosis Research
• 出版年：2012
• 期刊代码：247_00493848
• 类别：med
• 出版时间：July, 2012
• 卷：130
• 期：1
• 页码：65-69
• 文件大小：310 K

摘要

Introduction

Off-target effects of novel antiplatelet agents due to their potential clinical benefits are currently an area of intensive investigation. We aimed to compare the effects of different P2Y₁₂ antagonists on the reactivity of vascular smooth muscle cells.

Materials and methods

Wistar rats (n = 30) were pretreated with an investigated drug or placebo. Clopidogrel (50 mg/kg, n = 7), prasugrel (10 mg/kg, n = 7), ticagrelor (10 mg/kg, n = 7) or placebo (n = 9) were administered orally 12 and 2 hours before experiments. Constrictions of rat tail arteries induced with a stable analogue of adenosine diphosphate (2-MeS-ADP), phenylephrine and arginine vasopressin were measured as an increase in perfusion pressure. Effects of ticagrelor were assessed in the presence of ticagrelor (1 渭M/L) added to the perfusion solution as this drug reversibly inhibits the P2Y₁₂ receptor.

Results

Pretreatment with clopidogrel and prasugrel did not inhibit 2-MeS-ADP-induced contraction while ticagrelor did. Experiments employing endothelium-deprived arteries provided similar results. Clopidogrel and prasugrel did not influence concentration-response curves in the presence of neither phenylephrine nor arginine vasopressin. The curves obtained for both vasopressors in the presence of ticagrelor and 2-MeS-ADP were shifted to the right with a significant reduction in the maximal response.

Conclusions

Oral administration of ticagrelor, in contrast to clopidogrel and prasugrel, prevents adenosine diphosphate-induced contraction of vascular smooth muscle cells in a rat model. Both the clinical significance and detailed mechanism of our findings warrant further investigation.