布比卡因抑制心肌线粒体中的酰基肉碱交换。

Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria.

作者信息

Weinberg G L, Palmer J W, VadeBoncouer T R, Zuechner M B, Edelman G, Hoppel C L

机构信息

Department of Anesthesiology, University of Illinois College of Medicine at Chicago, 60612, USA.

出版信息

Anesthesiology. 2000 Feb;92(2):523-8. doi: 10.1097/00000542-200002000-00036.

DOI:10.1097/00000542-200002000-00036

PMID:10691241

Abstract

BACKGROUND

The authors previously reported that secondary carnitine deficiency may sensitize the heart to bupivacaine-induced arrhythmias. In this study, the authors tested whether bupivacaine inhibits carnitine metabolism in cardiac mitochondria.

METHODS

Rat cardiac interfibrillar mitochondria were prepared using a differential centrifugation technique. Rates of adenosine diphosphate-stimulated (state III) and adenosine diphosphate-limited (state IV) oxygen consumption were measured using a Clark electrode, using lipid or nonlipid substrates with varying concentrations of a local anesthetic.

RESULTS

State III respiration supported by the nonlipid substrate pyruvate (plus malate) is minimally affected by bupivacaine concentrations up to 2 mM. Lower concentrations of bupivacaine inhibited respiration when the available substrates were palmitoylcarnitine or acetylcarnitine; bupivacaine concentration causing 50% reduction in respiration (IC50 +/- SD) was 0.78+/-0.17 mM and 0.37+/-0.03 mM for palmitoylcarnitine and acetylcarnitine, respectively. Respiration was equally inhibited by bupivacaine when the substrates were palmitoylcarnitine alone, or palmitoyl-CoA plus carnitine. Bupivacaine (IC50 = 0.26+/-0.06 mM) and etidocaine (IC50 = 0.30+/-0.12 mM) inhibit carnitine-stimulated pyruvate oxidation similarly, whereas the lidocaine IC50 is greater by a factor of roughly 5, (IC50 = 1.4+/-0.26 mM), and ropivacaine is intermediate, IC50 = 0.5+/-0.28 mM.

CONCLUSIONS

Bupivacaine inhibits mitochondrial state III respiration when acylcarnitines are the available substrate. The substrate specificity of this effect rules out bupivacaine inhibition of carnitine palmitoyl transferases I and II, carnitine acetyltransferase, and fatty acid beta-oxidation. The authors hypothesize that differential inhibition of carnitine-stimulated pyruvate oxidation by various local anesthetics supports the clinical relevance of inhibition of carnitine-acylcarnitine translocase by local anesthetics with a cardiotoxic profile.

摘要

背景

作者之前报道过继发性肉碱缺乏可能使心脏对布比卡因诱导的心律失常更敏感。在本研究中，作者测试了布比卡因是否抑制心脏线粒体中的肉碱代谢。

方法

采用差速离心技术制备大鼠心脏肌原纤维间线粒体。使用克拉克电极测量二磷酸腺苷刺激（状态III）和二磷酸腺苷限制（状态IV）的氧消耗率，使用含有不同浓度局部麻醉剂的脂质或非脂质底物。

结果

非脂质底物丙酮酸（加苹果酸）支持的状态III呼吸在布比卡因浓度高达2 mM时受影响最小。当可用底物为棕榈酰肉碱或乙酰肉碱时，较低浓度的布比卡因会抑制呼吸；导致呼吸降低50%的布比卡因浓度（IC50±标准差），棕榈酰肉碱为0.78±0.17 mM，乙酰肉碱为0.37±0.03 mM。当底物仅为棕榈酰肉碱或棕榈酰辅酶A加肉碱时，布比卡因对呼吸的抑制作用相同。布比卡因（IC50 = 0.26±0.06 mM）和依替卡因（IC50 = 0.30±0.12 mM）对肉碱刺激的丙酮酸氧化的抑制作用相似，而利多卡因的IC50大约大5倍（IC50 = 1.4±0.26 mM），罗哌卡因处于中间水平，IC50 = 0.5±0.28 mM。