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Bupivacaine Destabilizes Action Potential Duration in Cellular and Computational Models of Long QT Syndrome 1

Schwoerer, Alexander P. MD*; Zenouzi, Roman MD*; Ehmke, Heimo MD*; Friederich, Patrick MD

doi: 10.1213/ANE.0b013e3182323245
Anesthetic Pharmacology: Research Reports
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SDC

BACKGROUND: The effects of the local anesthetic bupivacaine on cardiac action potentials (APs) are mainly attributed to inhibition of cardiac Na+ channels. The relevance of its ability to also induce high-affinity blockade of human ether-à-gogo-related gene (hERG) channels is unclear. We investigated whether this interaction may functionally become more significant in cellular and computational models of long (L)QT syndromes.

METHODS: Left ventricular cardiomyocytes were isolated from adult guinea pig hearts, and bupivacaine-induced effects on APs were investigated using the patch-clamp technique. LQT-like states were pharmacologically induced by either blocking IKs (LQT1-like, 10 μmol/L chromanol 293B), or IKr (LQT2-like, 10 μmol/L E4031). Computational analysis of bupivacaine's effects was based on the Luo-Rudy dynamic model.

RESULTS: Bupivacaine induced dose-dependent AP shortening in control myocytes. However, in the presence of 1 to 30 μmol/L bupivacaine, a high variability in AP duration with AP prolongations of up to 40% was observed. This destabilizing effect on AP duration was significantly increased in LQT1-like but not in LQT2-like myocytes. Similarly, the incidence of AP prolongations in the presence of 3 μmol/L bupivacaine was significantly increased from 6% in control myocytes to 24% in LQT1-like but not in LQT2-like myocytes. Computational modeling supported the concept that this bupivacaine-induced AP instability and the AP prolongations in the control and LQT1-like myocytes were caused by inhibition of hERG channels.

CONCLUSIONS: This study provides evidence that bupivacaine induces inhibition of hERG channels, which is functionally silent under normal conditions but will become more relevant in LQT1-like states in which repolarization relies to a larger degree on hERG channels. Interactions with ion channels other than cardiac Na+ channels may, therefore, determine the net cardiac effects of bupivacaine when the normal balance of ionic currents is altered.

Published ahead of print October 14, 2011 Supplemental Digital Content is available in the text.

From the *Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg; and Department of Anaesthesiology, Bogenhausen Hospital, Academic Hospital of Technische Universitaet Muenchen, Munich, Germany.

Supported by departmental funding (Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf), by the European Society of Anaesthesiology (PF), and by the German Heart Foundation (APS).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Alexander P. Schwoerer, MD, Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Address e-mail to schwoerer@uke.de.

Accepted July 28, 2011

Published ahead of print October 14, 2011

Accidental intravascular injection of the long-acting local anesthetic bupivacaine can induce potentially lethal ventricular arrhythmias.1,2 Currently, there is no consensus on the molecular targets involved in these bupivacaine-induced severe arrhythmias.3 At micromolar concentrations, bupivacaine inhibits depolarizing cardiac currents such as the fast Na+ current (INa)4,5 and the L-type Ca2+ current (ICa,L).69 It is well accepted that the interaction with these currents may induce shortening of ventricular action potentials (APs).3 Furthermore, the blockade of INa is regarded as the simplest explanation for the generation of ventricular arrhythmias by bupivacaine.3 However, micromolar concentrations of bupivacaine also inhibit repolarizing currents, in particular the transient outward K+ current (Ito),10,11 and the rapid component of the delayed K+ current (IKr), which is mediated by human ether-à-gogo-related gene (hERG) channels.1216 The relevance of the interaction with these K+ currents is currently disputed.3 An interaction of bupivacaine with K+ currents that is unapparent under normal conditions may become functionally relevant when the electrophysiological properties of cardiac myocytes are altered, e.g., in inherited or acquired long (L)QT syndrome. We have previously reported that specific mutations underlying the LQT syndrome increase the bupivacaine sensitivity of K+ channels.15 The presence of an LQT syndrome may, therefore, constitute a specific risk factor for arrhythmias induced by bupivacaine intoxication.

The LQT syndrome is characterized by polymorphic ventricular tachycardia known as Torsade de Pointes, which often leads to syncope and cardiac death.17 All currently known subtypes of LQT syndrome are caused by inherited or acquired alterations in the function of cardiac ion channels, which increase the duration of ventricular APs. This in turn is reflected in the prolongation of the QT interval in the electrocardiogram (Fig. 1). The most frequent inherited LQT syndromes, LQT1 and LQT2, are caused by mutations that lead to deficiencies in 1 of the 2 components of the repolarizing delayed K+ currents (Table 1). Mutations within the KCNQ1 gene that encode KvLQT1 (Kv7.1) channels lead to impairment of the slow component of the delayed K+ current (IKs) and underlie LQT1.18,19 LQT2 is caused by mutations in the KCNH2 gene that lead to impaired hERG (Kv11.1) channels that underlie the rapid component of the delayed K+ current (IKr).17,20 Moreover, mutations within accessory subunits of both channel complexes may also lead to reduced current densities of IKs and IKr, respectively, and underlie LQT5 and LQT6.

Figure 1

Figure 1

Table 1

Table 1

LQT-like states may also be acquired by a variety of frequently used drugs that inhibit K+ currents. For example, IKs may be inhibited by drugs such as thiopental, isoflurane, or sevoflurane, resulting in an LQT1-like state. IKr may be blocked, for example, by haloperidol, erythromycin, or ondansetron, yielding an LQT2-like state.2123 Indeed, because the hERG channels that underlie IKr are most susceptible to block by a variety of drugs, these channels are most frequently examined for possible drug interactions. Apart from these drug interactions, structural heart disease, hypothermia, or electrolyte disorders can also precipitate LQT-like states. Acquired LQT syndromes may, therefore, be expected to be more common than the inherited forms.

Regardless of the cause (inherited or acquired), the repolarization of myocytes lacking 1 of the 2 components of the delayed K+ current (IKs or IKr) strongly depends on the remaining component. We therefore hypothesized that an IKr blockade induced by bupivacaine has differential and subtype-specific consequences in myocytes exhibiting LQT-like states. In particular, inhibition of IKr by bupivacaine should have strong effects on the AP duration of LQT1-like myocytes where IKs is a priori impaired. In contrast, the inhibition of IKr should not affect APs of LQT2-like myocytes; in these cells, the effect of bupivacaine on the depolarizing Na+ and Ca2+ currents should prevail. Accordingly, the aim of the study was to investigate the effects of bupivacaine at toxicologically relevant concentrations on the AP duration of healthy cardiac myocytes and of myocytes with impaired repolarization. LQT1-like and LQT2-like states were pharmacologically induced in isolated guinea pig ventricular myocytes by specific inhibition of IKs and IKr, respectively, as previously described.24 Bupivacaine-induced effects were investigated using the patch-clamp technique. To further analyze the relevance of potential ion channel interactions of bupivacaine, we performed computer simulations based on the Luo-Rudy dynamic model.15,2426

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METHODS

Isolation of Cardiac Myocytes and Patch-Clamp Experiments

All animal experiments were conducted in accordance with institutional guidelines and were approved by local authorities (Ministry of Science and Health, Hamburg, Germany). Ventricular myocytes of adult, male, Dunkin-Hartley guinea pigs (385 ± 11 g body weight, n = 33; Charles River, Sulzfeld, Germany) were isolated as previously described.24 Briefly, guinea pigs were deeply anesthetized by thiopental-Na+ (200 mg/kg body weight) and hearts were excised and quickly placed into ice-cold Tyrode solution. To minimize cellular heterogeneity, myocytes were isolated from the center part of the midmyocardial layer of the left ventricle using a Langendorff apparatus. Myocytes were stored at room temperature in Tyrode solution and used for experiments within 8 hours. Only single, rod-shaped cells with clear cross-striation and no spontaneous contractions were used. The ruptured-patch whole-cell configuration was used as previously described with an EPC-9 amplifier controlled by the Pulse software (HEKA Elektronik, Lambrecht, Germany).24 Patch pipettes with a resistance of 4.2 ± 1.3 MΩ (n = 118) were pulled from borosilicate glass (GC150-15; Clark Electromedical Instruments, Reading, UK). Membrane capacitance was calculated using an automated procedure of the EPC-9 amplifier and averaged 135 ± 5 pF (n = 118). Membrane voltages were recorded in the zero-current clamp mode at a sampling rate of 5 kHz. Experiments were performed at 36.0°C ± 0.1°C (n = 118) using a temperature controlling system (TC-20 and HPT-2A; npi electronic, Tamm, Germany). Only experiments in which temperature changes were <0.5°C were included in the study.

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Solutions and Chemicals

The modified Tyrode solution contained (in mmol/L): NaCl 138, KCl 4, MgCl2 1, NaH2PO4 0.33, glucose 10, HEPES 10, titrated to pH = 7.30 with NaOH. For patch-clamp experiments, 2 mmol/L CaCl2 was added. The pipette solution contained (in mmol/L): K-glutamate 120, KCl 10, MgCl2 2, EGTA 10, HEPES 10, Na2-ATP 2, titrated to pH = 7.20 with KOH. Chromanol 293B (Tocris, Bristol, UK) was dissolved in dimethyl sulfoxide (DMSO). The maximal concentration of DMSO in the bath solution was <0.1%. At these concentrations, DMSO alone had no effects on APs (data not shown). Bupivacaine (Sigma-Aldrich, Munich, Germany) and E4031 (Tocris) were dissolved in sterile water and then diluted in the bath solution.

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Experimental Protocol and Data Analysis

After establishment of the whole-cell configuration in the zero-current clamp mode, the AP threshold was determined. Throughout the entire experiment, APs were elicited at a frequency of 1 Hz using short (≤10 milliseconds) depolarizing current injections at 150% of the AP threshold. After an initial phase of pacing (control, 5 minutes), an LQT1-like or an LQT2-like state was induced by chromanol 293B (10 μmol/L) or E4031 (10 μmol/L), respectively.24,27,28 After steady-state conditions were reached (5 minutes), bupivacaine was washed in. For evaluation of AP characteristics, 30 consecutive APs from the end of each phase were exported using Pulsefit (HEKA Elektronik) and analyzed in IGOR (WaveMetrics, Lake Oswego, OR). Resting membrane potential, overshoot, AP amplitude, AP duration to a repolarization of 90% (APD90), and bath temperature were derived using custom made macros.

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Statistical Analysis

All data are presented as mean ± SEM, and n indicates the number of experiments. Statistical significance was calculated by repeated-measures 1-way analysis of variance followed by Bonferroni post hoc tests, by paired Student t test, or by χ2 tests using PRISM (GraphPad Software, Inc., San Diego, CA). Statistical significance was defined as P < 0.05.

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Computational Simulations of Cardiac APs

Computational simulations were conducted using a modified version of the Luo-Rudy dynamic model as previously described.15,2426 For modeling of LQT1 and LQT2, a severe phenotype with a 75% reduction in IKs and IKr, respectively, was assumed. For modeling of bupivacaine effects, a 50% inhibition of INa and ICa,L was implemented in the computational model.35,7,9,29 This was combined with different degrees of IKr blockade. Under steady-state conditions (2000 AP cycles), the AP duration of the last 10 cycles was identical, thus no standard errors are given.

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RESULTS

Effects of Bupivacaine on Ventricular APs

To determine the concentration-dependent effects of bupivacaine on APs of healthy ventricular myocytes (control), increasing concentrations of the local anesthetic were applied during continuous stimulation of cardiac myocytes. Figure 2A depicts representative APs of an isolated guinea pig ventricular myocyte before and after application of bupivacaine. Figure 2B and Table 2 summarize the effects of bupivacaine on the AP characteristics of all investigated cells. Concentrations of 0.01 to 10 μmol/L bupivacaine had no effect on the mean AP duration. APs were increasingly shortened by concentrations ≥30 μmol/L. Despite this clear concentration-dependent abbreviation of the average ventricular APs, bupivacaine at concentrations between 1 and 30 μmol/L had surprising heterogeneous effects on APs of individual myocytes. In this concentration range, bupivacaine induced AP shortenings as well as AP prolongation (defined as ≥5% decrease/increase in APD90 of the individual cell; Fig. 2B). Upon application of higher concentrations, only AP shortenings were observed, indicative of the prevailing blockade of depolarizing currents.

Figure 2

Figure 2

Table 2

Table 2

At 3 μmol/L (a concentration to be expected in local anesthetic intoxications),3 bupivacaine significantly shortened the mean AP duration by approximately 8% (Fig. 2C). Responses of the individual myocytes ranged from AP shortening by up to approximately 80 milliseconds to AP prolongations by up to approximately 30 milliseconds (Fig. 2D). The vast majority of individual myocytes displayed AP shortenings (22 of 32, 68% of all cells). In 8 experiments (25%), the AP duration was not affected and AP prolongations were recorded in 2 further cells (6%).

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Effects of Bupivacaine on APs of Cellular LQT Models

The IKs blocker chromanol 293B and the IKr blocker E4031 were used to induce robust LQT1-like or LQT2-like states in isolated cardiac myocytes. Consistent with our previous results, chromanol 293B increased APD90 by 55.0 ± 6.0 milliseconds (n = 33; P < 0.001) and E4031 increased APD90 by 59.7 ± 16.0 milliseconds (n = 18; P < 0.001).24

Figure 3A depicts representative APs under control conditions, after induction of an LQT1-like state by blockade of IKs, and after additional application of 3 μmol/L bupivacaine. On average, 3 μmol/L bupivacaine had no significant effect on the mean APD90 in this LQT1 model (−8.6 ± 5.3 milliseconds, n = 33; Fig. 3B). As Figure 3C illustrates, the variance of the individual responses to 3 μmol/L bupivacaine was greatly augmented in these LQT1-like myocytes ranging from approximately 100-millisecond shortening to approximately 50-millisecond prolongation of the APD90. In contrast to the control myocytes, bupivacaine induced AP prolongations in nearly one-fourth of all myocytes (24%, 8 of 33; Fig. 3C). APs were shortened in 48% of the cells (16 of 33), and in the remaining 27% (9 of 33), APs were unaltered. In LQT2-like myocytes, 3 μmol/L bupivacaine significantly reduced the mean AP duration (Fig. 4, A and B) and resulted in a relatively homogeneous response in all myocytes (Fig. 4C). In only 1 myocyte (6%) was a relatively mild AP prolongation observed, which barely reached the threshold of ≥5% prolongation. The remaining cells either exhibited AP shortening (50%) or no change in AP duration (44%). The variance of effects, ranging from approximately 100-millisecond AP shortening to 13-millisecond AP prolongation, was smaller than in the LQT1-like myocytes.

Figure 3

Figure 3

Figure 4

Figure 4

Figure 5 summarizes the effects of 3 μmol/L bupivacaine on the APs of control myocytes and of both LQT models. The variance of individual responses to 3 μmol/L bupivacaine was significantly higher in the LQT1 model than in the other myocytes (Fig. 5A). Moreover, AP prolongations were observed significantly more often in the LQT1-like myocytes than in the control myocytes or in the LQT2-like myocytes (Fig. 5B).

Figure 5

Figure 5

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Computational Modeling of Bupivacaine Effects

The patch-clamp experiments demonstrated an increased instability of AP duration induced by bupivacaine and an increased incidence of AP prolongations in LQT1-like myocytes. To better understand the relevance of the K+ channel inhibition for these observations, we performed computer simulations based on the Luo-Rudy dynamic model. APs of cardiac myocytes of normal, LQT1, and LQT2 hearts were simulated as previously described (Fig. 6, data given in black).15,24

Figure 6

Figure 6

First, we hypothesized that the differential effects of bupivacaine on the APs of the cellular LQT models are ultimately determined by its interaction with IKr and not by an inhibition of INa and ICa,L. Assuming that bupivacaine inhibits only depolarizing currents (INa and ICa,L), the computer model predicts a relatively uniform AP shortening in all 3 types of cells (Fig. 6, “−IKr block,” blue data). Although the calculated degree of AP shortening in control myocytes (Fig. 6A) fits well to the mean AP shortening observed in the healthy cardiac myocytes (approximately 8%), a decrease of the AP duration was also predicted for LQT1 and LQT2 myocytes. Thus, the sole assumption of inhibition of depolarizing currents cannot explain the differential effects of bupivacaine observed in the cellular LQT models. We therefore implemented an additional IKr blockade in the computational models. Based on our previous publications,1316 we estimated that 3 μmol/L bupivacaine inhibits IKr to a similar degree as INa and ICa,L and assumed an IKr block by approximately 50% in the simulation (Fig. 6, “+IKr block,” red data). The modeling now predicted differential effects within the 3 cellular models. Despite the Na+ and Ca2+ block, the AP duration remained nearly unaffected in control and LQT2 myocytes (Fig. 6, A and C), whereas APs of LQT1 myocytes were prolonged by 13% (Fig. 6B). Thus, the concept that bupivacaine inhibits IKr in addition to INa and ICa,L yields results compatible with the subtype-specific effects observed in the patch-clamp experiments.

Next, we hypothesized that the increased instability of AP duration upon application of bupivacaine observed in the LQT1-like myocytes (compare Fig. 5A) can also be explained by an inhibition of IKr. We therefore investigated the consequence of increasing degrees of IKr block in the presence of a given 50% inhibition of INa and ICa,L in control, LQT1, and LQT2 myocytes in the computer model.

In control myocytes, inhibition of INa and ICa,L by 50% was associated with an AP shortening of approximately 10 milliseconds (Fig. 7A, “−IKr block”). In the presence of these ion channel inhibitions, AP prolongations were predicted when an IKr inhibition of ≥60%was assumed (arrow). A complete loss of IKr should be associated with an AP prolongation of approximately 30 milliseconds. Thus, the range of changes in AP duration caused by an IKr inhibition spans from approximately 10-millisecond shortening to approximately 40-millisecond prolongation. In LQT1 myocytes, the sole inhibition of the depolarizing currents was associated with an AP shortening of approximately 20 milliseconds (Fig. 7B, “−IKr block”). IKr inhibitions of only ≥35% were then associated with pronounced AP prolongations (arrow). Furthermore, blockade of >60% of IKr was associated with pronounced AP prolongations by approximately 75 milliseconds and resulted in APs that exceeded the interbeat interval of 250 milliseconds. Finally, in LQT2 myocytes, a 50% reduction in INa and ICa,L led to an AP shortening of approximately 10 milliseconds (Fig. 7A, “−IKr block”), and even a complete loss of the remaining IKr could not induce a relevant AP prolongation (Fig. 7C).

Figure 7

Figure 7

Similar to the previous set of simulation data, these calculations illustrate that different degrees of IKr blockade in the presence of a given INa and ICa,L inhibition may determine the net effect of bupivacaine on AP duration (shortening or prolongation). They also show that the bupivacaine-induced instability of the AP duration in LQT1-like myocytes can be explained with the complex interaction of bupivacaine with INa, ICa,L, and IKr.

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DISCUSSION

The duration of ventricular APs depends on a delicate balance between depolarizing and repolarizing currents. It is well established that bupivacaine inhibits the cardiac Na+ current (INa),4,5 the L-type Ca2+ current (ICa,L),69 and different K+ currents (Ito, IKr).1016 Although the relative contribution of each of these ion channel interactions during local anesthetic intoxications is unclear, the inhibition of the Na+ current is currently thought to cause the cardiac toxicity of bupivacaine.3 In agreement with the potent inhibition of INa and ICa,L, bupivacaine concentration- dependently shortened the mean AP duration of normal ventricular cardiac myocytes in this study. In contrast, the heterogeneous effects on AP duration of individual native cardiac myocytes observed in the presence of 1 to 30 μmol/L bupivacaine, in particular the AP prolongations, cannot be explained by an inhibition of the depolarizing currents alone. They are, however, compatible with a potent blockade of K+ currents. Previous studies have shown that bupivacaine potently inhibits Ito10,11 and IKr,1216 whereas IKs and IK1 are insensitive toward bupivacaine.15,30 Because Ito is absent in guinea pig cardiac myocytes, and the resting membrane potential was not affected by bupivacaine, IKr is the most likely target in the isolated cardiac myocytes. As illustrated by the computational modeling, the concept that bupivacaine inhibits IKr in combination with INa and ICa,L can explain the changes in AP durations (AP shortening as well as AP prolongation) observed in control myocytes. Furthermore, the observed interindividual variability seems to be determined by the degree of inhibition of each ionic current and the relative contribution of these currents to the AP. It is conceivable that these vary from cell to cell and may be modulated, for example, by the expressed ion channel repertoire and cellular metabolism. The observation that bupivacaine only rarely induced AP prolongations in control cardiac myocytes suggests a predominant interaction of bupivacaine with depolarizing currents, which leads to a net AP shortening in most cells. However, it does not necessarily imply that in cells that show a net AP shortening, bupivacaine does not inhibit K+ channels. Rather, the AP prolonging effects of K+ channel inhibition may be small compared with the overwhelming impact of Na+ and Ca2+ channel inhibition on AP duration. The K+ channel interaction may therefore simply be unapparent.

Interestingly, differential and subtype-specific effects of bupivacaine were observed in the cellular LQT models. In control and LQT2-like myocytes, 3 μmol/L bupivacaine significantly reduced the mean AP duration. In contrast, bupivacaine did not affect the mean length of the APs in the LQT1-like myocytes but caused a 4-fold increase in the incidence of AP prolongations. This subtype-specific effect on the mean AP duration can also not be explained by the assumption that bupivacaine only inhibits depolarizing currents. Relatively uniform AP shortening should then be expected in both cellular models of LQT syndrome. In LQT1 myocytes, IKs is markedly reduced, and the repolarization depends to a much larger degree on IKr than in control myocytes. Accordingly, a blockade of IKr by bupivacaine has a more pronounced impact on AP duration in the LQT1-like myocytes than in control myocytes. However, in LQT2-like myocytes, which already lack a substantial degree of IKr, the consequences of a further IKr blockade are relatively small.

In all 3 investigated cell types, heterogeneous responses with AP shortenings as well as AP prolongations induced by bupivacaine were observed. This may be explained by different degrees of IKr blockade. As the modeling illustrates, in the presence of a strong INa and ICa,L inhibition, the interaction of bupivacaine with IKr may determine the net effect of bupivacaine on the AP duration. At low degrees of IKr inhibition, the impact of bupivacaine on INa and ICa,L prevails, resulting in a pronounced AP shortening. At increasing degrees of IKr inhibition, the net effect of these ion channel interactions on AP duration is shifted toward AP prolongations. Thus, it is conceivable that the observed variability depends on the degree of the different ion channel interactions and their relative contribution to the AP. The increase in AP instability in LQT1-like but not in LQT2-like myocytes may result from the decreased electrophysiological stability of these cells. In the presence of a pronounced inhibition of INa and ICa,L, the threshold of IKr blockade necessary for induction of AP prolongation was found to be reduced from 60% to 35% in LQT1 myocytes. Also, the potential degree of AP prolongations caused by IKr blockade may be greater in these cells. However, AP prolongations should be relatively mild in LQT2 myocytes. Indeed, even a complete loss of IKr should not induce AP prolongations ≥5% in the presence of 50% inhibition of depolarizing currents in these myocytes. This is compatible with the results of the patch-clamp experiments. Here, bupivacaine predominantly abbreviated ventricular APs of LQT2-like myocytes and only a single AP prolongation was observed, which was relatively modest and barely exceeded the threshold of 5%. Thus, the concept that bupivacaine inhibits IKr in combination with INa and ICa,L and that this interaction determines the net effect of bupivacaine on the AP duration is in good accordance with the results from the cellular LQT models.

Taken together, the results presented in this study show that bupivacaine at concentrations that may become relevant during intoxications (1–30 μmol/L)3 induces highly variable changes in AP duration (AP shortenings as well as AP prolongations) in single ventricular cardiac myocytes. The variance of the individual responses was specifically increased in LQT1-like myocytes in which repolarization depends on a large degree on IKr. In addition, the incidence of the AP prolongations was significantly enhanced by a factor of 4 in these cells. These observations are fully concordant with the concept that bupivacaine inhibits IKr as well as INa and ICa,L in cardiac myocytes. The inhibition of IKr seems to be functionally silent in most healthy myocytes. However, it may become relevant under specific alterations of cardiac electrophysiology, in particular when IKs is impaired. In these cells, the complex ion channel interactions of bupivacaine further destabilize the APs resulting in an increased electrophysiological instability. The current results, therefore, strongly suggest that the interactions of bupivacaine with ionic currents other than INa or ICaL may determine the net effects on cardiac electrophysiology observed in our study. Inhibitory effects on cardiac K+ channels (in particular on IKr) may thus become critically important when the normal balance of ion channel activity is specifically altered. This frequently is the case in inherited or acquired LQT1.

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DISCLOSURES

Name: Alexander P. Schwoerer, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Alexander P. Schwoerer has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Roman Zenouzi, MD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Roman Zenouzi has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Heimo Ehmke, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Heimo Ehmke has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Patrick Friederich, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Patrick Friederich has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Marcel E. Durieux, MD, PhD.

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