Neviere R R, Li F Y, Singh T, Myers M L, Sibbald W
AC Burton Vascular Biology Laboratory, Victoria Hospital Research Institute, and the University of Western Ontario, London, Canada.
Crit Care Med. 2000 May;28(5):1439-44. doi: 10.1097/00003246-200005000-00030.
To test whether or not endotoxin induces a dose-dependent reduction of myocardial contractile dysfunction after a standardized period of myocardial ischemia and reperfusion and whether nitric oxide is involved in this form of myocardial protection.
Prospective, randomized, controlled animal study.
University research laboratory.
Twenty-five male Sprague-Dawley rats.
After anesthesia, the left carotid artery was cannulated under sterile conditions and animals were allowed to recover from surgery for 12 hrs. Sterile saline or increasing doses (2.5, 5, or 10 mg/kg body weight) of endotoxin (Escherichia coli O26:B6; Sigma, Mississauga, Ontario, Canada) were given intravenously (1 mL over 5 mins). In some rats, diaspirin-crosslinked hemoglobin (200 mg/kg) was infused 6 hrs and 60 min before endotoxin infusion (10 mg/kg). Hearts were rapidly excised for retrograde perfusion through the ascending aorta (Langendorff apparatus) 6 hrs later. After baseline data collection, hearts were subjected to global ischemia (30 mins, 37 degrees C [98.6 degrees F]), followed by 30 mins of reperfusion.
Physiologic variables were recorded 6 hrs after saline and endotoxin infusion. Baseline myocardial systolic contractility and diastolic compliance were assessed, respectively, by left ventricular developed pressure (LVDP) and left ventricular (LV) volume-preload relationships. After 30 min of reperfusion, LVDP recovery and left ventricular end-diastolic pressure were measured. Endotoxin induced LV systolic contractile depression, irrespective of the dose of endotoxin administered. LV diastolic dysfunction varied between different doses of endotoxin administered. On reperfusion, endotoxin produced a dose-dependent improvement of postischemic LVDP recovery: 30+/-6% in sham, 78+/-9% in 2.5 mg/kg, 93+/-8% in 5 mg/kg, and 107+/-10% in 10 mg/kg endotoxin heart. In rats treated with 10 mg/kg endotoxin, diaspirin-crosslinked hemoglobin pretreatment abrogated endotoxin-induced postischemic LVDP recovery improvement (105+/-10% vs. 43+/-7%, p = .01).
Sublethal doses of endotoxin induce in a dose-dependent manner a delayed form of myocardial protection against ischemia. Although free-cell hemoglobin solution abrogates this endotoxin-induced cross-tolerance, we propose that possible mechanisms involved in this form of myocardial protection include nitric oxide pathway activation.
检测内毒素在标准化心肌缺血及再灌注一段时间后是否会引起心肌收缩功能障碍的剂量依赖性降低，以及一氧化氮是否参与这种心肌保护形式。
前瞻性、随机、对照动物研究。
大学研究实验室。
25只雄性斯普拉格-道利大鼠。
麻醉后，在无菌条件下插入左颈动脉，动物术后恢复12小时。静脉注射无菌生理盐水或递增剂量（2.5、5或10毫克/千克体重）的内毒素（大肠杆菌O26:B6；西格玛公司，加拿大安大略省密西沙加）（5分钟内注射1毫升）。在一些大鼠中，在注射内毒素（10毫克/千克）前6小时和60分钟输注双阿司匹林交联血红蛋白（200毫克/千克）。6小时后迅速取出心脏，通过升主动脉逆行灌注（Langendorff装置）。收集基线数据后，使心脏经历全心缺血（30分钟，37摄氏度[98.6华氏度]），随后再灌注30分钟。
在输注生理盐水和内毒素6小时后记录生理变量。分别通过左心室舒张末压（LVDP）和左心室（LV）容量-前负荷关系评估基线心肌收缩力和舒张顺应性。再灌注30分钟后，测量LVDP恢复情况和左心室舒张末压。无论给予何种剂量的内毒素，均会引起左心室收缩功能抑制。不同剂量内毒素引起的左心室舒张功能障碍有所不同。再灌注时，内毒素使缺血后LVDP恢复呈剂量依赖性改善：假手术组为30±6%，2.5毫克/千克组为78±9%，5毫克/千克组为93±8%，10毫克/千克内毒素组心脏为107±10%。在接受10毫克/千克内毒素治疗的大鼠中，双阿司匹林交联血红蛋白预处理消除了内毒素诱导的缺血后LVDP恢复改善（105±10%对43±7%，p = 0.01）。
亚致死剂量的内毒素以剂量依赖性方式诱导一种延迟性的心肌缺血保护形式。尽管游离细胞血红蛋白溶液消除了这种内毒素诱导的交叉耐受性，但我们认为这种心肌保护形式可能涉及的机制包括一氧化氮途径激活。
