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二磷酸腺苷(ADP)在介导犬冠状动脉狭窄和内皮损伤时体内血小板聚集及血流周期性变化中起重要作用。

ADP plays an important role in mediating platelet aggregation and cyclic flow variations in vivo in stenosed and endothelium-injured canine coronary arteries.

作者信息

Yao S K, Ober J C, McNatt J, Benedict C R, Rosolowsky M, Anderson H V, Cui K, Maffrand J P, Campbell W B, Buja L M

机构信息

Department of Internal Medicine, University of Texas Medical School, Houston.

出版信息

Circ Res. 1992 Jan;70(1):39-48. doi: 10.1161/01.res.70.1.39.

Abstract

The goal of this study was to test the hypotheses that endogenous ADP plays an important role in vivo in mediating platelet aggregation and cyclic coronary artery blood flow variations (CFVs) in stenosed and endothelium-injured coronary arteries in an experimental canine model. Anesthetized animals were studied and coronary blood flow velocities monitored by a pulsed Doppler flow probe positioned around the left anterior descending coronary artery. CFVs were established by an external constrictor positioned at sites with injured endothelium. Apyrase, an ADP-removing enzyme, was infused into the left anterior descending coronary artery (0.3-1.8 units/min) 30 minutes or 2 hours after the establishment of CFVs. Complete abolition of CFVs was achieved in 81% (13/16) of dogs with 30-minute CFVs and in 83% (five of six) of dogs with 2-hour CFVs. In other dogs, a potent inhibitor of ADP-induced platelet aggregation, clopidogrel, was administered as a 10 mg/kg i.v. bolus and a 2.5 mg/kg/hr infusion 30 minutes and 3 hours after the establishment of CFVs. This treatment resulted in complete abolition of CFVs in 14 dogs (100%) with either 30-minute or 3-hour CFVs. Epinephrine was infused into some dogs after CFVs had ceased as a result of either apyrase or clopidogrel administration and into some dogs in whom SQ29548, a thromboxane A2 receptor antagonist, had been given when apyrase failed to abolish CFVs. Epinephrine restored CFVs in all dogs treated with apyrase alone, 67% (four of six) of dogs treated with the combination of apyrase and SQ29548, and 29% (two of seven) of dogs treated with clopidogrel. The plasma epinephrine levels required for CFV restoration were 20 times higher than baseline values in dogs receiving apyrase alone, 100 times higher when a combination of apyrase and SQ29548 had been given, and more than 5,000 times higher in dogs receiving clopidogrel. In vitro studies showed that apyrase only inhibited ADP-induced platelet aggregation, whereas clopidogrel not only inhibited ADP-induced platelet aggregation, but also reduced platelet aggregation induced by the thromboxane mimetic U46619 and serotonin. These data suggest that 1) ADP is an important mediator of platelet aggregation and CFVs in vivo and 2) combined inhibition of thromboxane A2 and ADP's effects provides marked protection against CFVs in experimentally stenosed and endothelium-injured canine coronary arteries. These data and our previous observations are consistent with the possibility that specific antagonists of thromboxane A2, serotonin, and ADP, alone and together, may provide substantial protection against platelet aggregation leading to CFVs at sites of endothelial injury and coronary artery stenosis.

摘要

本研究的目的是在实验犬模型中检验以下假设

内源性二磷酸腺苷(ADP)在体内介导狭窄和内皮损伤冠状动脉中的血小板聚集及冠状动脉血流周期性变化(CFV)方面发挥重要作用。对麻醉动物进行研究,通过置于左前降支冠状动脉周围的脉冲多普勒血流探头监测冠状动脉血流速度。通过位于内皮损伤部位的外部收缩器建立CFV。在建立CFV后30分钟或2小时,将一种ADP去除酶——腺苷三磷酸双磷酸酶注入左前降支冠状动脉(0.3 - 1.8单位/分钟)。在CFV持续30分钟的犬中,81%(13/16)的犬CFV完全消失;在CFV持续2小时的犬中,83%(6只中的5只)的犬CFV完全消失。在其他犬中,在建立CFV后30分钟和3小时,给予一种强效的ADP诱导血小板聚集抑制剂氯吡格雷,静脉推注剂量为10 mg/kg,输注剂量为2.5 mg/kg/小时。该治疗使14只(100%)CFV持续30分钟或3小时的犬的CFV完全消失。在因给予腺苷三磷酸双磷酸酶或氯吡格雷导致CFV停止后,向部分犬输注肾上腺素;在腺苷三磷酸双磷酸酶未能消除CFV时,向部分已给予血栓素A2受体拮抗剂SQ29548的犬输注肾上腺素。单独给予腺苷三磷酸双磷酸酶治疗的所有犬、给予腺苷三磷酸双磷酸酶和SQ29548联合治疗的犬中的67%(6只中的4只)以及给予氯吡格雷治疗的犬中的29%(7只中的2只),肾上腺素使CFV恢复。在单独接受腺苷三磷酸双磷酸酶治疗的犬中,恢复CFV所需的血浆肾上腺素水平比基线值高20倍;在给予腺苷三磷酸双磷酸酶和SQ29548联合治疗的犬中,该水平比基线值高100倍;在接受氯吡格雷治疗的犬中,该水平比基线值高5000倍以上。体外研究表明,腺苷三磷酸双磷酸酶仅抑制ADP诱导的血小板聚集,而氯吡格雷不仅抑制ADP诱导的血小板聚集,还减少血栓素类似物U46619和5-羟色胺诱导的血小板聚集。这些数据表明:1)ADP是体内血小板聚集和CFV的重要介质;2)联合抑制血栓素A2和ADP的作用可显著保护实验性狭窄和内皮损伤的犬冠状动脉免受CFV影响。这些数据以及我们之前的观察结果与以下可能性一致:血栓素A2、5-羟色胺和ADP的特异性拮抗剂单独或联合使用,可能为防止导致内皮损伤和冠状动脉狭窄部位CFV的血小板聚集提供实质性保护。

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