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Anesth Analg 2001;92:496-501
© 2001 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MEDICINE

Is Comparative Cardiotoxicity of S(-) and R(+) Bupivacaine Related to Enantiomer-Selective Inhibition of L-Type Ca2+ Channels?

Gisele Zapata-Sudo, MD, PhD*, Margarete M. Trachez, MD, PhD{dagger}, Roberto T. Sudo, MD, PhD*, and Thomas E. Nelson, PhD{ddagger}

*Departamento de Farmacologia Básica e Clinica, ICB, Universidade Federal do Rio de Janeiro; {dagger}Departamento de Anestesiologia, Universidade Federal Fluminense, Rio de Janeiro, Brazil; and {ddagger}Department of Anesthesiology, Wake Forest University School of Medicine, Winston Salem, North Carolina

Address correspondence and reprint requests to Dr. Gisele Zapata-Sudo, Departamento de Farmacologia Básica e Clínica, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude, Instituto de Ciencias Biomedicas, Bloco J, Sala 14, Rio de Janeiro, Brazil 21941-590. Address e-mail to gsudo{at}farmaco.ufrj.br


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Cardiac toxicity can occur after accidental intravascular injection of bupivacaine. Racemic bupivacaine can inhibit both cardiac Na+ and Ca2+ channels, but the contribution of these actions to cardiac depression is not totally understood. We tested whether the effect of R(+) bupivacaine on cardiac electrical activity in isolated hearts and on L-type Ca2+ channels (ICa-L) in isolated cardiac myocytes could be responsible for its increased cardiotoxicity compared with S(-) bupivacaine. Cardiac electrical activity of spontaneously beating isolated hearts was recorded before and after exposure to increasing concentrations of R(+) and S(-) bupivacaine. An increase of the PR interval (80%) and the QRS duration (370%) by 10µM R(+) bupivacaine (80% and 370%) was significantly higher than for S(-) bupivacaine (25% and 200%, respectively). R(+) but not S(-) bupivacaine produced severe arrhythmias at concentrations larger than 2.5µM. The intensity of ICa-L inhibition did not differ between bupivacaine isomers. At 0 mV, ICa-L was irreversibly reduced by 40.2% ± 8.8% and 51.4% ± 3.8% in the presence of 10µM R(+) and S(-) bupivacaine, respectively. The arrhythmogenic effect of R(+) bupivacaine could not be explained by stereoselectivity on the ICa-L inhibition. Thus, other mechanisms could contribute to the cardiac electrical and contractile dysfunction induced by R(+) bupivacaine.

Implications: Accidental intravascular injection of bupivacaine can induce toxic effects on the heart. We investigated the sensitivity of different bupivacaine structures’ actions on the Ca2+ conducting channels in rat ventricular cells and concluded that the increased toxicity of R(+) bupivacaine is not explained by actions on the Ca2+ channels’ inhibition.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Bupivacaine has an advantage over other local anesthetics because of its long-acting sensory anesthesia, but because of its high affinity for the myocardial Na+ channel, it can be cardiotoxic (1). The cardiac toxicity is related to a plasma concentration of 0.5–5 µg/mL (1.7–17µM) that can depress cardiac conduction (1–4) and contractility (5,6) consequent to an accidental intravascular injection. Electrophysiologic studies have shown that bupivacaine inhibits both Na+ (1) and L-type Ca2+ channels in cardiac cells (7,8), but the contribution of each component to cardiac arrhythmia or depressed contractility is still not completely understood. Stereoselective effects of bupivacaine isomers [R(+) and S(-) bupivacaine] have been extensively studied to determine which stereoisomer may have similar nerve block potency to the racemic mixture but less neuronal and cardiac toxicity. Basic and clinical studies demonstrated that even the duration of local anesthesia is similar for S(-) and R(+) bupivacaine (9), whereas R(+) bupivacaine induced more negative chronotropism (4) and arrhythmogenic effects than S(-) bupivacaine (10–12). The mechanisms by which R(+) bupivacaine is more cardiotoxic than S(-) bupivacaine are not completely known. The purpose of this study was to investigate the direct effects of R(+) and S(-) bupivacaine on the cardiac electrical activity (EKG) in isolated rat hearts and to determine whether differences in the sensitivity of their actions on the voltage-dependent Ca2+ channel (ICa-L) of rat ventricular myocytes explain the increased R(+) bupivacaine toxicity.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The Animal Care and Use Committee at Universidade Federal do Rio de Janeiro approved the protocol. After heparin IP injection (500 U), 30 male Wistar rats (250–350 g) were killed by cervical dislocation under ether anesthesia. The heart was rapidly removed, mounted to a Langendorff system through the aorta, and submersed into a chamber filled with Tyrode solution (composition below). EKG recordings were obtained through three glass pipette electrodes filled with 1M KCl solution positioned into the chamber. After 15 min of perfusion with Tyrode solution (8 mL/min), the heart was exposed to the bupivacaine enantiomers in incremental concentrations of from 0.5 to 10µM each for a duration of 5 min. EKG was recorded on a polygraph (Gould Polygraph Brush 2400; Gould Inc., Valley View, OH) before and 5 min after addition of each dose and at 30 min after washout.

Adult Wistar rats of either sex (200–250 g) were anesthetized with ether and then killed by cervical dislocation. After rapid excision, the heart was mounted in a modified Langendorff system and retrogradely perfused with oxygenated (95% oxygen, 5% CO2) nominally 0-Ca Tyrode solution at 33°C–35°C. Ventricular myocytes were enzymatically isolated after 8 min perfusion with Tyrode solution containing 120 U/mL collagenase type II (Worthington Biochemical, Lakewood, NJ) and 0.2 U/mL protease type XIV (Sigma Chemical Co, St. Louis, MO). The enzymes were washed out by perfusion with Tyrode solution containing 0.2mM CaCl2. Patch pipettes were prepared with capillary glass (1.2-mm outer diameter) and had resistance of 5–7 M{Omega} when filled with internal solution (composition below). Recordings of Ca2+ currents were obtained by using the whole cell configuration of the patch clamp technique (13) through an EPC-7 patch clamp amplifier (List Electronics, Darmstadt, Germany). Voltage pulses were generated by pClamp software, a digital interface (Axon Instruments, Foster City, CA), and a computer. Currents were expressed relative to cell capacitance, and the current-voltage relationship was determined through increasing depolarization from a holding potential of -40 mV to potentials ranging from -30 to +40 mV. Single ventricular cell experiments were performed at 20°C–22°C.

For EKG recording, the solution was composed of the following, in mM: NaCl, 120; KCl, 5.4; MgCl2, 1.2; CaCl2, 1.25; NaH2PO4, 2.0; NaHCO3, 27; Na2SO4, 2.2; and glucose, 11. It was equilibrated with 95% oxygen and 5% CO2. The pH was adjusted to 7.4 ± 0.02 at 37°C. For ventricular cells, the isolation solution contained the following, in mM: NaCl, 132; KCl, 4; MgCl2, 1.2; HEPES, 5; and glucose, 5. The pH was adjusted to 7.2 ± 0.02 with NaOH. Internal solution contained the following, in mM: CsCl, 125; tetraethylammonium, 25; MgCl2, 1; HEPES, 5; and EGTA, 10. The pH was adjusted to 7.4 ± 0.02. Cesium and tetraethylammonium were included in the internal solution to inhibit potassium current.

Racemic bupivacaine and its enantiomers were received from Cristalia Pharmaceutical and Chemical Products Co. (Itapira, Brazil) with >97% purity and were dissolved in distilled water at a stock concentration of 10mM.

Current amplitudes were normalized to cell capacitance (pA/pF) and presented as mean ± SEM. For statistical analysis, the data were compared within drug by an unpaired Student’s t-test. For differences between the drugs, means were compared in a one-way analysis of variance. For the frequency analysis, the {chi}2 and Fisher’s exact tests were used, and the difference was considered significant when P < 0.05.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Electrical activity of spontaneously beating isolated hearts was observed before and after treatment with R(+) or S(-) bupivacaine in a Langendorff system. Figure 1 shows a representative EKG tracing, in which R(+) bupivacaine produced two effects: it increased the PR interval and the QRS duration in a dose-dependent manner. As a consequence of one or a combination of these effects, a threshold for developing severe arrhythmia was reached at 10µM R(+) bupivacaine. Only a partial recovery to a normal pattern of EKG was observed after 30 min of washout with Tyrode drug-free solution. Infusion of S(-) bupivacaine also increased the PR interval and the QRS duration but did not trigger multifocal ventricular premature systole (Fig. 1). At concentrations ranging from 0.5 to 5µM, R(+) and S(-) bupivacaine decreased heart rate (HR) equally, but at 10µM, R(+) bupivacaine reduced HR about 30% of control compared with 18% for S(-) bupivacaine ( Fig. 2A). A change in the PR interval was also more evident in the presence of 10µM R(+) bupivacaine. R(+) bupivacaine increased the PR interval by 80%, compared with 25% for S(-) bupivacaine (Fig. 2, A and B). At concentrations <10µM, R(+) bupivacaine increased QRS duration much more than did S(-) bupivacaine (Fig. 2C).



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  		Figure 1. Representative electrocardiogram recordings of isolated hearts mounted in a modified Langendorff system in the absence (control and 30 min after washout) or presence of 2.5, 5.0, or 10µM R(+) and S(-)bupivacaine. Drugs were perfused at a rate of 8 mL/min during 5 min for each concentration.

 


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  		Figure 2. A, Effects of R(+) and S(-) bupivacaine on heart rate; B, on PR interval; and C, on QRS duration obtained from electrocardiogram recording from isolated heart. The data represent mean ± SEM (n = 15 experiments per drug). * P < 0.05 relative to S(-)bupivacaine.

 
A significant difference in the incidence of arrhythmias was observed between bupivacaine enantiomers in a range of clinically used concentrations ( Fig. 3). Table 1 shows different types of arrhythmias classified in four groups. Changes in the EKG rhythm were not caused by concentrations <2.5µM. First- and second-degree atrioventricular (AV) block was the most frequent EKG alteration observed with both isomers; however, the incidence was different between the drugs (Table 1). At 2.5µM, the AV block was present in 60% (9 of 15) and 13% (2 of 15) in hearts treated with R(+) bupivacaine and S(-) bupivacaine, respectively. At this concentration, ventricular tachycardia (VT) occurred in one heart treated with R(+) bupivacaine. The incidence of AV block increased to 66% of the hearts for R(+) bupivacaine and 33% for S(-) bupivacaine when the concentration was increased to 5µM. R(+) bupivacaine 5µM produced severe arrhythmias in three hearts (one multifocal ventricular premature systole [MVPS] and 2 VT). Two MVPS, two VTs, and two ventricular fibrillations (VFs) occurred with R(+) bupivacaine at 10µM. Even at this large concentration, S(-) bupivacaine caused MVPS in only one experiment. The recovery of arrhythmias measured 30 min after perfusion with drug-free Tyrode solution was dependent on stereoisomers and concentration. At 2.5µM, complete restoration of cardiac activity was observed in all experiments with S(-) bupivacaine. Six of 10 hearts exposed to R(+) bupivacaine that developed arrhythmias had a return to normal EKG pattern. The percentage of recovery decreased as the drug concentration increased. Recovery of cardiac activity was not observed after VF induced by R(+) bupivacaine in two experiments.



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  		Figure 3. Incidence of different types of arrhythmias observed after 5 min of exposure to 2.5, 5, and 10µM S(-) or R(+) bupivacaine (n = 15). *P < 0.05 relative to R(+) bupivacaine.

 

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  		Table 1. Incidence and Type of Arrhythmias Induced by Increasing Concentrations of Bupivacaine Isomers
 
Because cardiac activity could also be affected by ionic permeability on channels such as Na+, Ca2+, and K+, we tested the hypothesis that the reduction of ICa-L could contribute to the increased toxicity of R(+) bupivacaine. Figure 4 shows a representative example of the whole-cell voltage-clamp tracings of inward Ca2+ currents recorded from rat ventricular myocytes at different membrane potentials in the absence and presence of 5µM R(+) (Fig. 4A) or S(-) bupivacaine (Fig. 4B). We observed two different effects of both tested drugs: one related to inhibition of the peak ICa-L, and the second related to the prolonged time course of ICa-L in the presence of the isomers. The inhibition of ICa-L induced by bupivacaine isomers was irreversible in all tested concentrations (not shown). The average values of ICa-L were plotted versus membrane potential from -40 to +40 mV before and after treatment of R(+) and S(-) bupivacaine (n = 5 for each condition) (Fig. 4). In both control and drug-treated myocytes, the ICa-L activation threshold was approximately -25 mV, and the maximal current was about 0 mV. Upon perfusion of each isomer (5µM), ICa-L was significantly (P < 0.01) reduced at potentials >-10 mV, and the major decrease was at test potential near 0 mV. At 0 mV, ICa-L was irreversibly reduced 20.4% ± 7.84% (n = 5) and 57.4% ± 12.0% (n = 5) from control in the presence of 5µM (1.62 µg/mL) R(+) and S(-) bupivacaine, respectively ( Fig. 5). The ICa-L was not affected by R(+) bupivacaine at test potentials <-10 mV or >+10 mV; however, S(-) bupivacaine significantly reduced ICa-L at potentials >+10 mV (Fig. 5). As a consequence, the reversal potential was shifted to a more negative value, and an outward current was observed at +40 mV in the presence of S(-) bupivacaine. The 50% inhibition, estimated from the dose-response curve, was 5.0 and 2.5µM for R(+) and S(-) bupivacaine, respectively. Maximal reduction (57.1% ± 4.9%) was produced at 20µM R(+) bupivacaine, and maximal effect of S(-) bupivacaine was observed at 10µM, with a decrease of 51.4% ± 3.8%. The inactivation of ICa-L was fit to a biexponential function that gave two time constants of inactivation ({lambda}1 and {lambda}2). The {lambda}2 was not significantly affected in the presence of either isomer. However, the fast component decay of ICa-L ({lambda}1) was increased from 15.4 ± 0.7 ms to 35.7 ± 0.9 ms (P < 0.05) and 27.8 ± 4.7 ms (P < 0.05) at 2.5 and 5µM R(+) bupivacaine and from 20.8 ± 4.4 ms to 26.8 ± 1.7 ms (P < 0.05) and 30.0 ± 3.7 ms (P < 0.05) for S(-) bupivacaine. At 10µM, a significant increase of {lambda}1 was observed only for S(-) bupivacaine (36.9 ± 8.7 ms, P < 0.05).



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  		Figure 4. Representative whole-cell inward Ca2+ currents recorded from ventricular myocytes before and after exposure to 5µM R(+) and S(-) bupivacaine. Currents were obtained by 300 ms depolarizing voltage steps from a holding potential of -40 mV to test potentials from -30 to +40 mV. Current-voltage relationships for the peak inward currents in the absence (open circles) or presence (filled circles) of (A) 5µM R(+) and (B) S(-) bupivacaine. The peak currents were normalized to the cell capacitance (pA/pF). Data represent mean ± SEM of five cells. There were significant differences (P < 0.05) between control and presence of R(+) or S(-) bupivacaine at 0 mV.

 


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  		Figure 5. Inhibitory effect of bupivacaine enantiomers on L-type Ca2+ channels. Concentration dependency of current reduction evoked at 0 mV. Data at each concentration were mean ± SEM of five cells.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Electrophysiologic studies have demonstrated that the racemic mixture of bupivacaine induces alterations in the genesis and conduction of cardiac action potentials predisposing to reentry ventricular arrhythmias (14–19). Those arrhythmias could be responsible for the cardiac arrest after intravascular injection of bupivacaine (20,21). Experiments were performed in two different models to clarify previous reports that S(-) bupivacaine is less cardiotoxic than R(+) bupivacaine. In the EKG of isolated rat hearts, we showed that HR was reduced by both optical isomeric forms of bupivacaine in a concentration-dependent manner, with a difference between them only at 10 micromolar. If depression of cell automatism is an important mechanism related to cardiac arrest observed during accidental injection of bupivacaine, then we should expect a more pronounced effect on HR. However, HR was reduced only by 18% for S(-) bupivacaine and 30% for R(+) bupivacaine. Graf et al. (4) did not find any difference on HR, and consequently no alteration in automatism, that could explain the difference in toxicity between the isomers. In another study, verapamil and nimodipine, drugs that reduce cardiac automatism, were effective in decreasing cardiac toxicity induced by racemic bupivacaine (22). If arrhythmias induced by bupivacaine isomers are not related to alterations on automatism, a possible alternative mechanism could be a stereoselective activation of reentry phenomena. By placing bipolar electrodes in the atria and ventricle of isolated guinea pig hearts, Graf et al. (4) demonstrated an enantiomer-specific delay of AV conduction associated with a second-degree AV dissociation. We found that R(+) bupivacaine was more toxic than S(-) bupivacaine, because the PR interval and the QRS duration increased about 80% and 300% of control, respectively. Increased toxicity could be confirmed because severe arrhythmias were more frequent when the hearts were treated with R(+) bupivacaine. We observed that S(-) bupivacaine at 2.5 micromolar caused arrhythmias in <20% of 15 hearts, whereas a frequent incidence (>65%) was found with R(+)bupivacaine. Neither VT nor complete cardiac arrest occurred with S(-) bupivacaine, even at 10 micromolar. In a recent study, racemic bupivacaine and S(-) bupivacaine were directly infused into the left anterior descending coronary artery of anesthetized swine (23), and QRS and QTc intervals widened and progressed to a VF in all tested animals.

Lack of total recovery from cardiotoxicity is one of the most important disadvantages of racemic bupivacaine in comparison with other amide-type local anesthetics. Complete recovery from AV block after exposure of hearts to S(-) bupivacaine occurred in 100% (2.5 micromolar), 60% (five micromolar) and 44.4% (10 micromolar) after 30 minutes’ washout with drug-free Tyrode solution. With R(+) bupivacaine, the percentage of complete AV block recovery was reduced to 55%, 40%, and 33.3% for the equivalent drug concentrations. The concentration dependence for irreversibility or long duration of the cardiotoxic effects of R(+) bupivacaine is not related to a difference in tissue lipid solubility. Rutten et al. (24) did not find any difference in cardiac tissue affinity among the isomers after IV infusion in sheep.

One possible explanation for the longer effect of R(+) bupivacaine could be the increased rate of binding to the inactivated state of Na+ channels (12). The difference in the blockade of cardiac conduction induced by isomers was first explained by stereoselective binding to the Na+ channel. Valenzuela et al. (12) demonstrated that binding of bupivacaine displayed stereoselectivity for the inactivated Na+ channels but not for the activated or open-state Na+ channels. The interaction of R(+) bupivacaine with inactive Na+ channels was faster and more potent in comparison with S(-) bupivacaine (12). Its selective action on the inactivate state of Na+ channels could therefore be one possible explanation for the increased potency of R(+) bupivacaine to induce cardiac arrhythmias in comparison with the S(-) form of bupivacaine. Inhibition of K+ channels with consequent action potential prolongation could indirectly exacerbate Na+ channels block. A sevenfold higher potency of R(+) bupivacaine in comparison with S(-) bupivacaine to block K+ channels was demonstrated in cardiac K+ channel cloned from human ventricle (hKv1.5) (25).

Inhibition of L-type Ca2+ channels has been implicated in cardiac depression induced by bupivacaine (>20 micromolar) (7,9). We hypothesized that an enantiomer-specific blockade, in addition to inhibition of Na+ channel, could be important for explaining the increased cardiotoxic (arrhythmias) effect of R(+) bupivacaine in comparison with S(-) bupivacaine. However, although both isomers reduced the peak ICa-L, the extension of this effect was slightly more for S(-) bupivacaine. Therefore, the more arrhythmogenic effect of R(+) bupivacaine is probably related to an enantiomer-specific binding to Na+ or K+ channels, but not as a consequence of interaction with ICa-L.

We are uncertain about the contribution of ICa-L blockade in the total cardiac toxicity induced by bupivacaine at clinical concentrations. Cardiac depression induced by local anesthetics seems to be correlated with reduction of intracellular Ca2+ concentration by inactivation of L-type Ca2+ channels (9). From the experiments that used voltage-clamp measurements, Rossner and Freese (8) also showed ICa-L inhibition by racemic mixture of bupivacaine in hamster cardiomyocytes and suggested that the local anesthetic predisposed the channels to the inactivated state. In our study, the maximal reduction of Ca2+ channel activity was <60%, reaching a plateau at concentration >20 micromolar with both isomers. We did not investigate how much of the cardiac contractility reduction induced by bupivacaine isomers could be explained by the inhibition of ICa-L.

Besides the effect on L-type Ca2+ channels, depression of cardiac contractility induced by bupivacaine could also be related to inhibition of Ca2+ release from the sarcoplasmic reticulum, as suggested by Lynch (26). Komai and Lokuta (27) have demonstrated that racemic bupivacaine increases the ryanodine binding to RYR1 (skeletal muscle isoform) and decreases to RyR2 (cardiac muscle isoform). However, large concentrations (>1 millimolar) of bupivacaine were required to modify the ryanodine binding.

In conclusion, an enantiomer-specific blockade of ICa-L does not explain the higher cardiac arrhythmogenic effect observed with R(+) bupivacaine in comparison with S(-) bupivacaine. The difference on the inhibition of cardiac conduction could be related to a direct enantiomer-specific blockade on Na+ channels or as a indirect consequence of the blockade of K+ channels.


   Acknowledgments
 
Supported by Cristalia, CNPq, CAPES, and FUJB.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication October 23, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press