Zmudka K, Dubiel J, Vanhaecke J, Flameng W, De Geest H
Department of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium.
Cardiovasc Drugs Ther. 1994 Jun;8(3):479-87. doi: 10.1007/BF00877926.
To study the effects of oral pretreatment with metoprolol over 3 days on hemodynamics, left ventricular function, regional myocardial blood flow, and infarct size in an anesthetized dog model of thrombotic occlusion of the anterior descending coronary artery treated with thrombolysis.
Ten dogs received 200 mg metoprolol (Selozok) orally and 8 dogs received placebo for 3 days twice daily and 1 hour before the experiment. Under general anesthesia, thrombotic occlusion was provoked by the copper-coil technique. Intracardiac pressures and their derivatives, cardiac output (thermodilution method), regional coronary blood flow (microspheres), global and regional left ventricular function (ventriculography), and infarct size (triphenyltetrazolium staining) were measured. Measurements were performed during control, after 60 minutes of occlusion, and after 30 and 90 minutes of reperfusion. Thrombolysis was performed in all dogs 60 minutes after occlusion by intravenous infusion of 10 micrograms/kg/min of rt-PA for 30 minutes.
During control cardiac output was lower, total peripheral resistance higher, and Tau and the left ventricular isovolumic relaxation time greater in the metoprolol group. During occlusion and after reperfusion, there were no significant hemodynamic differences between both groups. Blood flow to the area at risk and circumflex territory during occlusion were, respectively, 12.8 +/- 5.80 ml/100 g/min versus 9.65 +/- 8.35 ml/100 g/min (p > 0.05) and 42.58 +/- 7.86 ml/100 g/min versus 61.52 +/- 20.43 ml/100 g/min (p = 0.01) in the metoprolol- and placebo-treated dogs. The ratios of flow area at risk/circumflex territories in the epicardial, midmyocardial, and endocardial layers were, respectively, 0.44 +/- 0.20, 0.19 +/- 0.09, and 0.20 +/- 0.13 in the metoprolol- versus 0.24 +/- 0.16, 0.08 +/- 0.06, and 0.06 +/- 0.07 (p > or = 0.04) in the placebo-treated dogs. The ratio of flow endocardium/epicardium was higher (p > or = 0.02) in the active treatment group during the control period, both in the area at risk and circumflex territory; this was also the case in the circumflex territory at the end of the experiment (p = 0.003). Thirty minutes after occlusion, blood flow to the three layers of the area at risk rose to 2-3 times control values in both groups; a significant increase above control values also occurred in the circumflex territory. After 90 minutes reperfusion, blood flow to both territories was similar in both groups but was comparable to the control; however, in necrotic tissue of the subendocardial layer of both groups, flow fell below control values (p < 0.05). End-systolic volume rose from 21.2 +/- 7.4 ml to 36.1 +/- 11.5 ml (p < 0.05), end-diastolic volume remained constant (46.0 +/- 13.8 vs. 47.9 +/- 12.1 ml; p > 0.05), and ejection fraction fell from 53.9 +/- 8.3% to 25.8 +/- 10.2% (p < 0.05) at the end of the experiment in the metoprolol group. Respective figures for the placebo group were 19.4 +/- 7.9 versus 27.9 +/- 10.9 (p < 0.05), 38.5 +/- 13.0 versus 42.1 +/- 11.0 (p > 0.05), and 50.6 +/- 5.7 versus 35.5 +/- 11.7 (p < 0.05). Fractional shortening of the chords analyzed was similar in both groups during the control period; it fell significantly at the end of the experiment in three chords of the metoprolol group and in five chords of the placebo group. The apical chord in the placebo, but not in the metoprolol, dogs was dyskinetic: fractional shortening was -0.86 +/- 9.7 versus 7.5 +/- 13.5% (p > 0.05). The area at risk was 41.6 +/- 10.6 cm2 in metoprolol- and 40.5 +/- 7.2 cm2 in placebo-treated dogs (p > 0.05); the infarct size, expressed as a percentage of the area at risk, was 29.0 +/- 22.5% and 45.3 +/- 23.6% (p = 0.02), respectively.
Oral pretreatment with metoprolol limited infarct size and improved regional left ventricular function, probably due to its negative chronotropic and inotropic effects, and also due to an enhancement of collateral flow fr
研究在接受溶栓治疗的前降支冠状动脉血栓闭塞麻醉犬模型中，连续3天口服美托洛尔预处理对血流动力学、左心室功能、局部心肌血流和梗死面积的影响。
10只犬口服200mg美托洛尔（倍他乐克），8只犬口服安慰剂，均为每日2次，连续3天，并在实验前1小时给药。在全身麻醉下，采用铜圈技术诱发血栓闭塞。测量心内压力及其导数、心输出量（热稀释法）、局部冠状动脉血流（微球法）、整体和局部左心室功能（心室造影）以及梗死面积（三苯基四氮唑染色）。在对照期、闭塞60分钟后、再灌注30分钟和90分钟后进行测量。所有犬在闭塞60分钟后通过静脉输注10μg/kg/min的重组组织型纤溶酶原激活剂（rt-PA）30分钟进行溶栓。
对照期美托洛尔组的心输出量较低，总外周阻力较高，Tau和左心室等容舒张时间较长。在闭塞期间和再灌注后，两组间血流动力学无显著差异。在美托洛尔治疗组和安慰剂治疗组中，闭塞期间梗死相关区域和回旋支区域的血流分别为12.8±5.80ml/100g/min对9.65±8.35ml/100g/min（p>0.05）和42.58±7.86ml/100g/min对61.52±20.43ml/100g/min（p=0.01）。美托洛尔治疗组和安慰剂治疗组在心外膜、心肌中层和心内膜层梗死相关区域/回旋支区域的血流比值分别为0.44±0.20、0.19±0.09和0.20±0.13对0.24±0.16、0.08±0.06和0.06±0.07（p≥0.04）。在对照期，活性治疗组在梗死相关区域和回旋支区域的心内膜/心外膜血流比值较高（p≥0.02）；在实验结束时，回旋支区域也是如此（p=0.003）。闭塞30分钟后，两组梗死相关区域三层的血流均升至对照值的2 - 3倍；回旋支区域也出现了显著高于对照值的增加。再灌注90分钟后，两组两个区域的血流相似，但与对照值相当；然而，两组心内膜下层坏死组织中的血流均低于对照值（p<0.05）。在美托洛尔组实验结束时，收缩末期容积从21.2±7.4ml升至36.1±11.5ml（p<0.05），舒张末期容积保持不变（46.0±13.8对47.9±12.1ml；p>0.05），射血分数从53.9±8.3%降至25.8±10.2%（p<0.05）。安慰剂组的相应数值分别为：19.4±7.9对27.9±10.9（p<0.05），38.5±13.0对42.1±11.0（p>0.05），50.6±5.7对35.5±11.7（p<0.05）。在对照期，两组分析的弦的缩短分数相似；在实验结束时，美托洛尔组的三根弦和安慰剂组的五根弦的缩短分数显著下降。安慰剂组犬的心尖弦出现运动障碍，而美托洛尔组未出现：缩短分数为-0.86±9.7对7.5±13.5%（p>0.05）。美托洛尔治疗组和安慰剂治疗组的梗死相关区域面积分别为41.6±10.6cm²和40.5±7.2cm²（p>0.05）；梗死面积占梗死相关区域面积的百分比分别为29.0±22.5%和45.3±23.6%（p=0.02）。
美托洛尔口服预处理限制了梗死面积并改善了局部左心室功能，这可能归因于其负性变时和变力作用，也归因于侧支血流的增强。
