年龄对布比卡因心脏毒性的影响

背景新生儿和幼儿对消旋布比卡因，即布比卡因的心肌毒性是否敏感一直存有争议。有的研究表明新生儿能耐受比成年人更高的血浆布比卡因浓度，而不产生严重的心肌毒性。本课题比较了大鼠不同鼠龄对消旋布比卡因和左旋布比卡因的心肌毒性的影响，并研究了上述局麻药对细胞内钙离子浓度的调节作用。方法给机械通气的2、4、6、8和16周龄的大鼠分别输注消旋布比卡因或左旋布比卡因[输注速度4mg／（kg·min）]，当监测显示心电活动停止时，所用剂量即定为该鼠龄大鼠的致死剂量。在应用外消旋布比卡因或内消旋布比卡因和不用此类局麻药时，分别以离体乳头肌颤搐测定方法研究局麻药对心肌收缩效应的影响。以裸露的心室肌纤维研究两种局麻药对细胞内钙离子浓度的调节作用。结果2周龄大鼠消旋布比卡因和左旋布比卡因的致死剂量（分别为46．0±5．2mg／kg和91．3±4．9mg／kg）均高于16周龄大鼠（分别为22．7±1．3mg／kg和22．0±2．7mg／kg）。乳头肌颤搐呈剂量相关性减低，且幼龄鼠心肌与成龄鼠心肌之间有显著性差异。在成龄鼠心肌，给予外消旋布比卡因后肌颤搐较对照减低8．6％±0．8％，而给予消旋布比卡因后肌颤搐较对照减低18．1％±2．7％（1001xm）。左旋布比卡因具有〈10μm的正性肌力效应，但仅见于2周龄大鼠。在裸露的心室肌纤维，消旋布比卡因和左旋布比卡因均能促使咖啡因（1mmol／L）激活的肌浆网释放钙离子增多，增加幅度相似，而此效应在幼龄鼠比成龄鼠更为明显。在16周龄大鼠，消旋布比卡因组咖啡因引起的反应是最大效应的53．9％±1．7％，而左旋布比卡因组为最大效应的54．1％±3．2％。在2周龄大鼠，消旋布比卡因组咖啡因引起的反应是最大效应的81．1％±3．7％，左旋布比卡因组为最大效应的78．1％±4．5％。在上两个消旋布比卡因和左旋布比卡因实验鼠龄组，收缩蛋白对钙离子的敏感性呈现同等程度的增加。肌浆网摄取钙离子并不因鼠龄或应用局麻药而发生变化。结论细胞内肌浆网钙离子调节机制的差异可能是幼龄鼠对消旋布比卡因和左旋布比卡因心肌抑制易感性减低的原因。

BACKGROUND： The susceptibility of children and newborns to cardiotoxicity from racemic bupivacaine, RS（ ± ）-bupivacaine, is controversial. Some studies indicate that newborns can sustain higher bupivacaine plasma levels than adults, without severe toxicity. In this study, we compared the influence of age on cardiotoxicity from RS（ ± ）-bupivacaine and S （ - ）-bupivacaine in rats. The effects of these local anesthetics （LAs） on the regulation of intracellular Ca2＋ concentrations in cardiac fibers were also investigated. METHODS： The lethal dose was determined in ventilated male Wistar rats at 2, 4, 8, and 16 weeks of age by monitoring when cardiac electrical activity stopped after infusion of RS （ ± ）- bupivacaine and S（ -）-bupivacaine （4 mg kg-1 · min-1 ）. The effects on cardiac muscle contraction were investigated by in vitro measurement of papillary muscle twitches in the presence and absence of RS （ ± ）-bupivacaine or S（ - ）-bupivacaine. Skinned ventricular fibers were used to investigate the intracellular effects on Ca2＋ regulation induced by both LAs. RESULTS： The lethal dose for RS（ ± ） -bupivacaine and S（ - ） -bupivacaine in 2- week-old animals （46. 0 ±5.2 and 91.3 ±4.9 mg kg-1, respectively） was higher than in 16-week-old animals （22.7 ± 1.3 and 22.0 ±2.7 mg kg-1, respectively）. Papillary muscle twitches were reduced in a dose-dependent manner, with significant difference between young and adult hearts. In adults, the muscle twitches were reduced to 8.6% ± 0.8% of control by RS（ ± ）-bupivacaine, and to 18.1% bupivacaine had a positive inotropic effect at 〈10 μM, but 2.7% of control by S（ - ）-bupivacaine （ 100 μM）. S（ - ）- only in 2-week-old animals. In chemically skinned ventricular fibers, RS （ ± ）-bupivacaine and S （ - ）-bupivacaine induced similar increases in Ca2＋ release from the sarcoplasmic reticulum （SR） preactivated with caffeine （ 1 mM）, and this effect was greater in younger rats than adults. In 16-week- old rats, caffeine-induced tension was 53.9% ± 1.7% of the maximal fiber response with RS （ ± ）-bupivacaine, and 54. 1% ± 3.2% with S（ -）-bupivacaine. The caffeine response in 2-week-old rats was 81.1% ± 3.7% of the maximal response with RS （ ± ）-bupivacaine, and 78.1% ± 4.5% with S （ - ）-bupivacaine. The Ca2＋ sensitivity of contractile proteins was equally increased at both ages tested, with RS （ ± ）-bupivacaine or S （ - ）-bupivacaine. Ca2＋ uptake from the SR was not altered by the LA or by age. CONCLUSIONS： Differences in the mechanisms for regulating intracellular SR Ca2 ＋ may contribute to the decreased susceptibility of young animals to cardiodepression induced by RS （ ± ）-bupivacaine and S（ - ）-bupivacaine.