Graf B M, Martin E, Bosnjak Z J, Stowe D F
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Anesthesiology. 1997 Feb;86(2):410-9. doi: 10.1097/00000542-199702000-00016.
The local anesthetic bupivacaine is an equal mixture of two optically active isomers known to exert different cardiotoxic profiles in vivo. Enantiomer-specific forms of bupivacaine may have differential effects on cardiovascular function, specifically on cardiac electrophysiology. The authors' aim was to determine if there were any direct functional differences in the cardiac effects of bupivacaine isomers. The isolated heart was used to avoid possible indirect cardiac effects of bupivacaine, such as autonomic nervous and hormonal influences, as well as preload and afterload factors.
The hearts of 12 ketamine-anesthetized guinea pigs were perfused with Krebs-Ringer's solution (97% oxygen, 3% carbon dioxide) at constant perfusion pressure using the Langendorff technique. Atrial and ventricular bipolar electrodes were placed to measure heart rate (HR) and atrioventricular (AV) conduction time. Left ventricular pressure (LVP), coronary flow, and inflow and outflow oxygen tensions were also measured. Oxygen delivery, oxygen consumption (MVO2), and percentage of oxygen extraction were calculated. Each heart was perfused with increasing randomized concentrations (0.5, 1, 5, 10 microM) of both isomers and the racemate of bupivacaine.
Racemic and isomeric bupivacaine equally and dose dependently decreased cardiac function. At 10 microM bupivacaine these changes were HR, -17 +/- 2%; LVP, -50 +/- 3%; coronary flow, -20 +/- 4%; and MVO2, -46 +/- 4%. The (+) isomer significantly prolonged AV conduction compared with the racemate and the (-) isomer at all concentrations. At 10 microM, AV time was 54 +/- 6% longer with the (+) isomer and 30 +/- 4% longer with the (+/-) racemate than with the (-) isomer. The greater delay in AV time with the (+) than the racemate or (-) isomer led to a second-degree AV dissociation in 10 of 12 of hearts treated with (+) bupivacaine.
This study shows that bupivacaine has an enatiomer-specific effect to delay AV conduction and to produce second-degree AV dissociation in the isolated perfused heart. This suggests that bupivacaine isomers probably have differential effects on one or more ion-specific channels regulating AV conduction. Other measured direct cardiac effects of bupivacaine appear to be independent of the isomeric form.
局部麻醉药布比卡因是两种旋光异构体的等量混合物，已知这两种异构体在体内具有不同的心脏毒性特征。布比卡因的对映体特异性形式可能对心血管功能有不同影响，特别是对心脏电生理。作者的目的是确定布比卡因异构体的心脏效应是否存在任何直接功能差异。使用离体心脏以避免布比卡因可能的间接心脏效应，如自主神经和激素影响，以及前负荷和后负荷因素。
采用Langendorff技术，在12只氯胺酮麻醉的豚鼠心脏上，以恒定灌注压力用Krebs-Ringer溶液（97%氧气，3%二氧化碳）进行灌注。放置心房和心室双极电极以测量心率（HR）和房室（AV）传导时间。还测量左心室压力（LVP）冠状动脉血流量以及流入和流出氧张力。计算氧输送、氧消耗（MVO2）和氧摄取百分比。每个心脏用布比卡因的两种异构体及其外消旋体递增的随机浓度（0.5、1、5、10微摩尔）进行灌注。
外消旋和异构体布比卡因均同等程度且剂量依赖性地降低心脏功能。在布比卡因浓度为10微摩尔时，这些变化为心率降低-17±2%；左心室压力降低-50±3%；冠状动脉血流量降低-20±4%；氧消耗降低-46±4%。在所有浓度下，（+）异构体与外消旋体和（-）异构体相比，显著延长房室传导。在10微摩尔时，（+）异构体的房室时间比（-）异构体长54±6%，外消旋体（±）比（-）异构体长30±4%。（+）异构体的房室时间延迟比外消旋体或（-）异构体更大，导致12只接受（+）布比卡因治疗的心脏中有10只出现二度房室传导阻滞。
本研究表明，布比卡因在离体灌注心脏中具有对映体特异性效应，可延迟房室传导并产生二度房室传导阻滞。这表明布比卡因异构体可能对调节房室传导的一种或多种离子特异性通道有不同影响。布比卡因其他测量的直接心脏效应似乎与异构体形式无关。
