氯克罗孟的抗缺血作用与其抗血小板活性的解离。

Dissociation of the anti-ischaemic effects of cloricromene from its anti-platelet activity.

作者信息

Lidbury P S, Cirillo R, Vane J R

机构信息

William Harvey Research Institute, St Bartholomew's Hospital Medical College, London.

出版信息

Br J Pharmacol. 1993 Sep;110(1):275-80. doi: 10.1111/j.1476-5381.1993.tb13805.x.

DOI:10.1111/j.1476-5381.1993.tb13805.x

PMID:8220889

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2176012/

Abstract

Cloricromene is a non-anticoagulant coumarin derivative with anti-platelet and anti-leukocyte properties, which has beneficial effects in various models of ischaemia and shock. 2. We have assessed the effects of cloricromene on (a) ex vivo platelet aggregation, and (b) infarct size using a model of myocardial ischaemia in the anaesthetized rabbit. 3. Cloricromene (1-1000 micrograms kg-1 min-1 for 15 min) induced a dose-dependent inhibition of ex vivo platelet aggregation, causing only a minimal increase in heart rate and no change in mean arterial blood pressure. The inhibitory activity was considerably stronger when platelet aggregation was induced by collagen than by ADP. 4. Cloricromene inhibited ex vivo platelet aggregation in rabbits pretreated with indomethacin (5 mg kg-1) and this inhibition persisted for 30-60 min. 5. The model of myocardial ischaemia involved 1 h occlusion of the first antero-lateral branch of the left coronary artery followed by 2 h of reperfusion. Infusion of cloricromene (30 or 300 micrograms kg-1 min-1), ibuprofen (80 micrograms kg-1 min-1) or vehicle began 15 min prior to occlusion, and continued throughout the experiment. 6. While area at risk was similar for all groups studied, cloricromene (30 or 300 micrograms kg-1 min-1) or ibuprofen caused a reduction in infarct size, and decreased myeloperoxidase activity in the tissue of the infarcted myocardium. 7. Cloricromene at 300 micrograms kg-1 min-1 also reduced the occlusion-induced elevation of the ST-segment of the rabbit electrocardiogram, and inhibited platelet aggregation ex vivo. Ibuprofen or cloricromene at 30 fg kg-1 min-1 had no effect on either the ST-elevation or platelet reactivity.8. Thus, cloricromene exhibits a cardioprotective activity via an inhibition of leukocyte infiltration, in the presence (300 microg kg-l min-1) or absence (30 microg kg-1 min-1) of inhibition of platelet activity ex vivo.The anti-aggregatory activity of cloricromene acts via a mechanism that is either different from, or in addition to, inhibition of cyclo-oxygenase, and is of long duration.

摘要

氯克罗孟是一种具有抗血小板和抗白细胞特性的非抗凝香豆素衍生物，在多种缺血和休克模型中具有有益作用。2. 我们使用麻醉兔的心肌缺血模型评估了氯克罗孟对（a）体外血小板聚集和（b）梗死面积的影响。3. 氯克罗孟（1 - 1000微克·千克⁻¹·分钟⁻¹，持续15分钟）可剂量依赖性地抑制体外血小板聚集，仅使心率略有增加，平均动脉血压无变化。当由胶原诱导血小板聚集时，其抑制活性比由二磷酸腺苷诱导时强得多。4. 氯克罗孟可抑制用吲哚美辛（5毫克·千克⁻¹）预处理的兔的体外血小板聚集，且这种抑制持续30 - 60分钟。5. 心肌缺血模型包括左冠状动脉第一前外侧分支闭塞1小时，随后再灌注2小时。在闭塞前15分钟开始输注氯克罗孟（30或300微克·千克⁻¹·分钟⁻¹）、布洛芬（80微克·千克⁻¹·分钟⁻¹）或赋形剂，并在整个实验过程中持续输注。6. 虽然所有研究组的危险区域相似，但氯克罗孟（30或300微克·千克⁻¹·分钟⁻¹）或布洛芬可使梗死面积减小，并降低梗死心肌组织中的髓过氧化物酶活性。7. 300微克·千克⁻¹·分钟⁻¹的氯克罗孟还可降低闭塞诱导的兔心电图ST段抬高，并抑制体外血小板聚集。30微克·千克⁻¹·分钟⁻¹的布洛芬或氯克罗孟对ST段抬高或血小板反应性均无影响。8. 因此，无论体外是否抑制血小板活性（300微克·千克⁻¹·分钟⁻¹或30微克·千克⁻¹·分钟⁻¹），氯克罗孟均可通过抑制白细胞浸润发挥心脏保护作用。氯克罗孟的抗聚集活性通过一种不同于或除抑制环氧化酶之外的机制起作用，且持续时间长。