Schaer G L, Hursey T L, Abrahams S L, Buddemeier K, Ennis B, Rodriguez E R, Hubbell J P, Moy J, Parrillo J E
Sections of Cardiology, Rush Medical College, Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill. 60612.
Circulation. 1994 Dec;90(6):2964-75. doi: 10.1161/01.cir.90.6.2964.
Reperfusion after prolonged coronary artery occlusion may be followed by additional myocardial necrosis persisting for hours to days. Potential mechanisms include neutrophil-mediated injury and compromised flow within the microcirculation of the reperfused myocardium. Poloxamer 188 is a nonionic surfactant with beneficial hemorheological and neutrophil-inhibitory properties. The purpose of the present study was to determine if poloxamer 188 is capable of reducing the myocardial injury associated with sustained reperfusion and to examine the effect of treatment duration.
Three groups of closed-chest dogs underwent 90 minutes of left anterior descending coronary artery occlusion (angioplasty balloon) and 72 hours of reperfusion. Poloxamer 188, formulated as RheothRx Injection (Burroughs Wellcome Co), was given as a 75 mg/kg IV bolus 15 minutes before reperfusion followed by a 150 mg.kg-1.h-1 continuous IV infusion for 4 hours (n = 13) or 48 hours (n = 13); control dogs (n = 12) received saline for 48 hours. The 48-hour infusion of poloxamer 188 resulted in a 42% reduction in infarct size (as a percent of the area at risk) compared with the control group (25.0 +/- 4.2% versus 43.3 +/- 4.3%, P D .01), whereas the 4-hour group demonstrated a 25% reduction in infarct size compared with the control group (32.4 +/- 4.3%, P = .08). ANCOVA demonstrated that the 48-hour infusion of poloxamer 188 reduced myocardial infarct size independent of differences in collateral blood flow (P = .002 versus control). A trend toward infarct size reduction was observed in the 4-hour infusion group (P = .098 versus control by ANCOVA). Plasma creatine phosphokinase concentration was lower in both poloxamer 188-treated groups (P < .05 versus control). Global left ventricular ejection fraction at 72 hours of reperfusion was improved in the 48-hour infusion group compared with the control group (43 +/- 3.1% versus 33 +/- 2.0%, P < .05), whereas ejection fraction in the 4-hour group was 37 +/- 1.3% (P = NS versus control). Regional ventricular function was also significantly better in the 48-hour infusion group compared with the control group. In vitro studies demonstrated that at concentrations comparable to those achieved in vivo, poloxamer 188 inhibited neutrophil chemotaxis. This finding may represent a beneficial mechanism of action.
A 48-hour infusion of poloxamer 188 reduced myocardial infarct size and improved left ventricular function in this dog model of 90 minutes of coronary artery occlusion and 72 hours of reperfusion. The finding that the 4-hour infusion of poloxamer 188 did not result in similar benefits suggests that additional reperfusion injury occurred between 4 and 48 hours.
长时间冠状动脉闭塞后的再灌注可能会伴随持续数小时至数天的额外心肌坏死。潜在机制包括中性粒细胞介导的损伤以及再灌注心肌微循环内的血流受损。泊洛沙姆188是一种具有有益血液流变学和中性粒细胞抑制特性的非离子表面活性剂。本研究的目的是确定泊洛沙姆188是否能够减轻与持续再灌注相关的心肌损伤，并研究治疗持续时间的影响。
三组开胸犬接受90分钟的左前降支冠状动脉闭塞（血管成形术球囊）和72小时的再灌注。泊洛沙姆188制成RheothRx注射液（百时美施贵宝公司），在再灌注前15分钟以75mg/kg静脉推注给药，随后以150mg·kg-1·h-1持续静脉输注4小时（n = 13）或48小时（n = 13）；对照犬（n = 12）接受48小时的生理盐水输注。与对照组相比，泊洛沙姆188输注48小时使梗死面积（占危险区域面积的百分比）减少了42%（25.0±4.2%对43.3±4.3%，P<0.01），而4小时组与对照组相比梗死面积减少了25%（32.4±4.3%，P = 0.08）。协方差分析表明，泊洛沙姆188输注48小时可减少心肌梗死面积，与侧支血流差异无关（与对照组相比P = 0.002）。在4小时输注组中观察到梗死面积有减小趋势（协方差分析与对照组相比P = 0.098）。两个泊洛沙姆188治疗组的血浆肌酸磷酸激酶浓度均较低（与对照组相比P<0.05）。与对照组相比，48小时输注组在再灌注72小时时的整体左心室射血分数有所改善（43±3.1%对33±2.0%，P<0.05），而4小时组的射血分数为37±1.3%（与对照组相比P = 无显著差异）。与对照组相比，48小时输注组的局部心室功能也明显更好。体外研究表明，在与体内达到的浓度相当的情况下，泊洛沙姆188抑制中性粒细胞趋化性。这一发现可能代表了一种有益的作用机制。
在这个90分钟冠状动脉闭塞和72小时再灌注的犬模型中，泊洛沙姆188输注48小时可减少心肌梗死面积并改善左心室功能。泊洛沙姆188输注4小时未产生类似益处这一发现表明，在4至48小时之间发生了额外的再灌注损伤。
