Longridge D J, Follenfant M J, Ford A J
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
Cardiovasc Res. 1991 Mar;25(3):184-91. doi: 10.1093/cvr/25.3.184.
The aim was to evaluate the thrombolytic efficacy of recombinant double chain tissue plasminogen activator (Duteplase, t-PA) given as a single intravenous bolus versus an infusion in a canine model of coronary arterial occlusion/reperfusion.
Coronary arterial thrombi were induced by a copper coil (placed under fluoroscopic control) in the left anterior descending coronary artery of anaesthetised dogs. Following 90 min thrombotic occlusion, animals were randomly assigned to one of two treatment groups: group 1 = t-PA infused intravenously at 0.6 x 10(6) IU.kg-1.h-1, or group 2 = t-PA (0.6 x 10(6) IU.kg-1) by intravenous bolus over 6 min. Both groups received concurrent heparin (six 1000 IU boluses, + 100 IU.kg-1.h-1) throughout t-PA administration and the 2 h reperfusion period.
16 beagle dogs of either sex were used, weight 9.2-20.3 kg.
Radiolabelled microspheres were injected to assess microvascular coronary flow at various time points throughout the experimental period. Infarct related vessel patency (IRVP) was assessed arteriographically every 5 min. Infarct size was assessed histochemically at the end of the reperfusion period. IRVP was achieved within 42.9 (SEM 7.4) min and 43.1(7.0) min for infusion and bolus groups respectively; 60 min patency rates were 88% for both groups. t-PA restored full microvascular flow to ischaemic subendocardial and subepicardial regions in both groups compared to initial preocclusion regional blood flow. Extent of reactive hyperaemia was greater in infusion than bolus treatment animals: infusion group 1.18(0.15) v bolus group 0.72(0.14) ml.min-1.g-1 (subepicardial). Degree of microvascular reocclusion at 120 min reperfusion was similar for both groups despite aggressive anticoagulation throughout: infusion group 0.33(0.08) v bolus group 0.42(0.11) ml.min-1.g-1 (subendocardial). Areas of the myocardium at risk (R), absolute infarct size (I), and infarct risk ratio (I/R) were similar for both groups: R = 33.9(1.5) v 30.9(1.9)%; I = 15.9(3.1) v 13.3(3.1)%; I/R = 46.3(8.4) 42.1(9.2)%. Degree of systemic fibrinogenolysis was similar for both groups: infusion 1.65(0.40) to 0.67(0.07) g.litre-1 v bolus 1.68(0.15) to 0.96(0.12) g.litre-1.
Single bolus administration of t-PA showed equivalent efficacy to infusion dosing in respect of IRVP, microvascular reperfusion, and microvascular reocclusion. As a result the degree of tissue necrosis (I/R ratio) was no different when comparing the two dosing regimens. Similar degrees of systemic fibrinogenolysis were observed for both treatment groups.
旨在评估重组双链组织型纤溶酶原激活剂（杜替普酶，t-PA）单次静脉推注与静脉输注在犬冠状动脉闭塞/再灌注模型中的溶栓效果。
在麻醉犬的左前降支冠状动脉中通过铜线圈（在荧光镜控制下放置）诱导冠状动脉血栓形成。在血栓闭塞90分钟后，将动物随机分为两个治疗组之一：第1组 = 以0.6×10⁶IU·kg⁻¹·h⁻¹的速度静脉输注t-PA，或第2组 = 在6分钟内静脉推注t-PA（0.6×10⁶IU·kg⁻¹）。在整个t-PA给药期间和2小时再灌注期，两组均同时接受肝素治疗（六次1000IU推注，+ 100IU·kg⁻¹·h⁻¹）。
使用16只雌雄不限的比格犬，体重9.2 - 20.3kg。
在整个实验期间的不同时间点注射放射性微球以评估冠状动脉微血管血流。每隔5分钟通过血管造影评估梗死相关血管通畅情况（IRVP）。在再灌注期结束时通过组织化学评估梗死面积。输注组和推注组分别在42.9（标准误7.4）分钟和43.1（7.0）分钟内实现IRVP；两组60分钟时的通畅率均为88%。与初始闭塞前区域血流相比，t-PA使两组缺血性心内膜下和心外膜下区域的微血管血流完全恢复。输注组的反应性充血程度高于推注组动物：输注组1.18（0.15）对推注组0.72（0.14）ml·min⁻¹·g⁻¹（心外膜下）。尽管在整个过程中积极抗凝，但两组在再灌注120分钟时的微血管再闭塞程度相似：输注组0.33（0.08）对推注组0.42（0.11）ml·min⁻¹·g⁻¹（心内膜下）。两组的心肌危险区面积（R）、绝对梗死面积（I）和梗死危险比（I/R）相似：R = 33.9（1.5）对30.9（1.9）%；I = 15.9（3.1）对13.3（3.1）%；I/R = 46.3（8.4）对42.1（9.2）%。两组的全身纤维蛋白原溶解程度相似：输注组从1.65（0.40）降至0.67（0.07）g·L⁻¹，推注组从1.68（0.15）降至0.96（0.12）g·L⁻¹。
在IRVP、微血管再灌注和微血管再闭塞方面，t-PA单次推注给药显示出与输注给药等效的疗效。因此，比较两种给药方案时，组织坏死程度（I/R比）没有差异。两个治疗组观察到相似程度的全身纤维蛋白原溶解。
