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Comparison of the effects of mepivacaine and lidocaine on rat myocardium

David, J.-S.*; Amour, J.; Duracher, C.*; Ferretti, C.*; Precloux, P.; Petit, P.*; Riou, B.; Gueugniaud, P.-Y.*

European Journal of Anaesthesiology: February 2007 - Volume 24 - Issue 2 - p 190–197
doi: 10.1017/S0265021506001359
Original Article
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Background and objective: To compare the inotropic and lusitropic effect of lidocaine and mepivacaine on rat papillary muscle.

Methods: Effects of lidocaine and mepivacaine (10−8−10−3 M) were studied in rat left ventricular papillary muscles in vitro at a calcium concentration of 1 mmol, under low (isotony) and high (isometric) loads.

Results: Lidocaine induced a significant negative inotropic effect in isotonic and isometric conditions whereas mepivacaine did not. Mepivacaine only induced a negative inotropic effect when added as a bolus for the highest concentration and this effect was significantly more pronounced with lidocaine than with mepivacaine (active force at 10−3 M: 63 ± 10 vs. 84 ± 10% of baseline, P < 0.05). Increasing calcium concentration resulted in a greater positive inotropic effect in the control (199 ± 11% of baseline) and mepivacaine groups (197 ± 22% of baseline) when compared to the lidocaine group (163 ± 19% of baseline, P < 0.05 vs. lidocaine and control groups), suggesting an impairment on intracellular Ca2+ handling by lidocaine. A negative lusitropic effect under low load was observed only for mepivacaine and suggested an impairment of sarcoplasmic reticulum function. Lidocaine and mepivacaine did not modify postrest potentiation but significantly depressed the force–frequency relationship.

Conclusions: The negative inotropic and lusitropic effects induced by lidocaine were more important than that of mepivacaine and may involve an impairment of intracellular Ca2+ handling.

*Laboratoire d'Anesthésiologie, Equipe d'Accueil 1896, Département d'Anesthésie-Réanimation-SAMU, Centre Hospitalier Universitaire (CHU) Edouard Herriot and Service d'Anesthésie-Réanimation, CHU Lyon-Sud, Hospices Civils de Lyon (HCL), Université Claude Bernard, Lyon, France

Laboratoire d'Anesthésiologie, Equipe d'Accueil 3975, Département d'Anesthésie-Réanimation et Service d'Accueil des Urgences, CHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Pierre et Marie Curie, Paris, France

Service d'Anesthésie-Réanimation, Hôpital d'Instruction des Armées Desgenettes, Lyon, France

Correspondence to: Jean-Stéphane David, Département d'Anesthésie-Réanimation-SAMU, Hôpital Edouard Herriot, 3 Place d'Arsonval, 69437 Lyon Cedex 03, France. E-mail: js-david@univ-lyon1.fr; Tel: +33 4 72 11 75 88; Fax: +33 4 72 11 75 89

Accepted for publication 31 July 2006

First published online 29 August 2006

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Introduction

Lidocaine and mepivacaine are short-acting local anaesthetics widely used for local anaesthesia [1,2]. Although lidocaine is one of the least toxic local anaesthetics, limitations to its use include systemic toxic reactions and lack of optimal intraoperative analgesia whereas mepivacaine ensured better intraoperative analgesia [2]. Cardiotoxicity of local anaesthetics may be related to their electrophysiological and direct myocardial depressant effects [3,4] because it has been shown that lidocaine and mepivacaine may act at different level of the cardiomyocyte including sodium channels [5,6], sarcoplasmic reticulum (SR) [7], Na+–Ca2+ exchanger [8], potassium [9] or calcium channels [9–11]. Mepivacaine and lidocaine also have different affinity for sodium and potassium channels. For example, it has been shown that half-maximal tonic inhibiting concentrations as obtained from concentration-effects curves for Na+ current block were smaller for mepivacaine whereas these concentrations were greater for lidocaine for voltage-dependent K+ current block [6]. However, the mechanism by which lidocaine and mepivacaine impair myocardial contractility is not completely understood and an effect on the relaxation process has only been described for lidocaine [12]. Therefore, the aim of this study was to compare the effect of lidocaine and mepivacaine on contraction (inotropy) and relaxation (lusitropy) in isolated rat cardiac papillary muscles and to describe the mechanisms by which they impaired intrinsic myocardial properties.

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Methods

We used adult Wistar rats weighing 250–300 g. Care of the animals conformed to the recommendations of the Helsinki Declaration and the study was performed in accordance with the regulations of the official edict of the French Ministry of Agriculture.

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Experimental protocol

After brief anaesthesia with intraperitoneal pentobarbital, the hearts were quickly removed from adult male Wistar rats (Iffa Credo, L'Arbresles, France) weighing 250–300 g. Left ventricular papillary muscles were carefully excised and suspended vertically in a 200-mL jacketed reservoir with Krebs–Henseleit bicarbonate buffer solution (118 mmol NaCl, 4.7 mmol KCl, 1.2 mmol MgSO4, 1.1 mmol KH2 PO4, 25 mmol NaHCO3, 2.5 mmol CaCl2 and 4.5 mmol glucose) maintained at 29°C with a thermostatic water circulator (Polystat 5HP; Bioblock, Illkirch, France) with continuous monitoring of the solution temperature using a temperature probe (Pt100; Bioblock). Preparations were field stimulated at 12 pulses/min by two platinum electrodes with rectangular wave pulses lasting 5 ms just above threshold. The bathing solution was bubbled with 95% oxygen and 5% carbon dioxide, resulting in a pH of 7.4 [13].

After a 60-min stabilization period at the initial muscle length at the apex of the length-active isometric tension curve (Lmax), papillary muscles recovered their optimal mechanical performance which remained stable for several hours. The extracellular calcium concentration ([Ca2+]o) was decreased from 2.5 to 1 or 0.5 mmol because rat myocardial contractility is nearly maximum at 2.5 mmol making more difficult the observation of a potential positive inotropic effect [13]. Inotropic and lusitropic responses of cumulative concentrations (10−8−10−3 M, n = 8 in each group) of lidocaine HCL 5% (Xylocard®; Astra-Zeneca, Nanterre, France) and mepivacaine HCL 2% (Carbocaine®; Astra-Zeneca) were determined at a [Ca2+]o of 1 mmol. The inotropic and lusitropic responses were recorded 10 min after each dose was added to the bathing solution. To mimic the effect of a massive systemic uptake, we studied the effect of 10−3 M (bolus dose) of mepivacaine or lidocaine in a separate group of eight muscles.

In order to determine the mechanism by which local anaesthetics induced negative inotropic effects, we studied the effects of local anaesthetics on the contractile response after increasing extracellular calcium concentration (to test their effects on myofilament machinery) [14], on force–frequency relationship (FFR) (to test their effects on intracellular calcium handling and excitation–contraction coupling) [15] or after rest (to test their effect on postrest potentiation, mainly related to SR storage and release capacity) [13,16]. Effect of increased concentrations of [Ca2+]o (0.5–1 mmol by step of 0.1 mmol, contact time of 10 min) on inotropic responses force was studied in the presence of 10−4 M of lidocaine or mepivacaine (n = 6 in each group). We chose a concentration of 10−4 M because at a [Ca2+]o of 0.5 mmol and with greater concentrations of lidocaine, the muscles ceased to contract. An FFR was determined at a [Ca2+]o of 1 mmol (n = 6 in each group), in the presence of 10−3 M of lidocaine or mepivacaine. Following this, frequency of stimulation was increased from 0.1 to 5 Hz (0.1, 0.2, 0.5, 1, 2, 3, 4 and 5 Hz). We reduced the [Ca2+]o at 1 mmol to minimize the phenomenon of calcium overload during FFR [17]. In addition, we studied postrest potentiation in the presence of 10−4 M of local anaesthetic (n = 6 in each group) and at a [Ca2+]o of 0.5 mmol because it is more easily elicited at a low [Ca2+]o. During rest in the rat myocardium, SR accumulates calcium above and beyond that accumulated during regular stimulation, and the first beat after the rest interval (B1) is stronger than the beat before the rest interval (B0) [18]. The study of postrest potentiation contraction may provide some insight into SR function in a biochemically intact preparation [15].

Throughout the study we ensured that the highest concentration of local anaesthetics (i.e. 10−3 M) did not modify the concentration of ionized calcium: 1.00 ± 0.01 mmol L−1 for mepivacaine and 1.03 ± 0.19 mmol L−1 for lidocaine vs. 1.03 ± 0.00 mmol L−1 in the control group by directly measuring its concentration (Modular P900; Roche Diagnostics, Meylan, France).

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Electromagnetic lever system and recording

The electromagnetic lever system has been previously described [13]. Briefly, the load applied to the muscle was determined using a servomechanism-controlled current through the coil of an electromagnet. Muscular shortening induced a displacement of the lever, which modulated the light intensity of a photoelectric transducer. All analyses were made from digital records of force and length obtained using a computer as previously described [13].

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Mechanical parameters

Conventional mechanical variables at Lmax were calculated from three twitches. The first twitch was isotonic and was loaded with the preload corresponding to Lmax. The second twitch was abruptly clamped to zero load just after the electrical stimulus with a critical damping to slow the first and rapid shortening overshoot resulting from the recoil of series-passive elastic components. The third twitch was fully isometric at Lmax. We determined the maximum unloaded shortening velocity (Vmax) using the zero-load technique, maximum shortening (maxVc) and lengthening (maxVr) velocities of the twitch with preload only. In addition, maximum isometric active force normalized per cross-sectional area (AF) as well as the peaks of the positive (+dF dt−1) and the negative (−dF dt−1) force derivatives at Lmax normalized per cross-sectional area from the isometric twitch were recorded. Because changes in the contraction phase induce coordinated changes in the relaxation phase, indexes of contraction–relaxation coupling have been developed to study lusitropy [19]. R1 coefficient = maxVc/maxVr studied the coupling between contraction and relaxation under low load and thus lusitropy, in a manner that is independent of inotropic changes. R1 tests SR uptake function [18,19]. R2 coefficient = (+dF dt−1/−dF dt−1) studied the coupling between contraction and relaxation under high load and thus lusitropy, in a manner that is less dependent on inotropic changes [18]. When the muscle contracts isometrically, sarcomeres shorten very little [20]. Because of the higher sensitivity of myofilament for calcium [21], the time course of relaxation is determined by calcium unbinding from troponin C rather than by calcium sequestration by the SR. Thus R2 reflects myofilament calcium sensitivity [19]. R2 is less modified by major inotropic changes induced by decreasing [Ca2+]o than +dF dt−1 and −dF dt−1. Because +dF dt−1 is depressed more than −dF dt−1, the resulting decrease in R2 reflects a positive lusitropic effect. The slight decrease in R2 as [Ca2+]o is decreased, is consistent with the fact that calcium per se modulates myofilament calcium sensitivity, according to the cooperativity concept [22]. The parameters R1 and R2, which evaluate lusitropy under low and high load respectively, have been used empirically for many years but have been validated only recently [23].

At the end of the study, the muscle cross-sectional area was calculated from the length and weight of papillary muscle, assuming a density of 1. Because there are important differences in baseline values from one muscle to another, inotropic responses were expressed as a percentage of baseline values (i.e. after exposure to local anaesthetics), as previously reported [14,24].

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Statistical analysis

Data are expressed as mean percent of baseline ± SD. Comparison of two means was performed using the t -test. Comparison of several means was performed using analysis of variance and the Newman–Keuls multiple-comparison test. Baseline values between groups were compared using analysis of variance. All probability values were two-tailed, and a P value <0.05 was required to reject the null hypothesis. Statistical analysis was performed with NCSS 2004 software (Statistical Solutions Ltd., Cork, Ireland) and graphic made with Origin 5.0 (Microcal Software Inc., Northampton, MA).

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Results

We studied 62 left ventricular papillary muscles. The mean Lmax was 6.3 ± 1.7 mm, the mean cross-sectional area was 0.45 ± 0.20 mm2, the mean ratio of resting force to total force was 0.12 ± 0.04, the mean R1 was 0.68 ± 0.11, at a [Ca2+]o of 2.5 mmol. A decrease in contractility was observed as [Ca2+]o was decreased from 2.5 to 1 or 0.5 mmol. At a [Ca2+]o of 1 mmol, Vmax and AF decreased respectively to 84 ± 8% and 76 ± 12% of baseline and at a [Ca2+]o of 0.5 mmol, Vmax and AF decreased respectively to 58 ± 11% and 45 ± 13% of baseline. These results were consistent with those previously reported [18].

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Inotropic effects

Lidocaine induced a marked negative inotropic effect under isotonic and isometric conditions whereas mepivacaine did not (Fig. 1). When 10−3 M of lidocaine or mepivacaine (bolus dose) was added directly to the bath in a separate group of muscle, both drugs induced a significant negative inotropic effect which was greatest with lidocaine in isotonic (Vmax: 71 ± 11 vs. 84 ± 8% of baseline value, P < 0.05) and isometric conditions (AF: 63 ± 10 vs. 84 ± 10% of baseline value, P < 0.05). This result did not significantly differ from those observed with cumulative concentrations of local anaesthetics (Fig. 1).

Figure 1.

Figure 1.

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Lusitropic effects

Under isotonic condition, lidocaine and mepivacaine impaired relaxation and significantly decreased maxVr (e.g. and at 10−3 M, maxVr was 74 ± 19 in the lidocaine vs. 82 ± 8% of baseline in the mepivacaine group, NS) but only mepivacaine significantly impaired the coupling between contraction and relaxation (R1) suggesting an impairment of the SR function (Fig. 2).

Figure 2.

Figure 2.

Under isometric condition, we observed that only lidocaine impaired relaxation. For example and at the highest concentration, −dF dt−1 was 76 ± 14% of baseline in the lidocaine group (P < 0.05 vs. baseline) vs. 92 ± 8% of baseline in the mepivacaine group (NS). Lidocaine induced a significant improvement of the contraction–relaxation coupling (R2) whereas mepivacaine had no significant effect (Fig. 2). However, because a decrease in AF per se induces a decrease in R2 [18,25], we compared the change in R2 observed with 10−3 M of lidocaine with that induced by lowering [Ca2+]o in order to obtain the same decrease in AF. Thus, we found no significant difference in the decrease of R2 with lidocaine (72 ± 12% of baseline) and lowering [Ca2+]o (80 ± 15% of baseline) suggesting that myofilament calcium sensitivity was not modified by lidocaine.

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Effects on postrest potentiation

Postrest potentiation was not significantly modified by 10−4 M of lidocaine or mepivacaine (Table 1).

Table 1

Table 1

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Inotropic response to increased [Ca2+]o

The bolus dose of 10−4 M added in the bath for this experiment induced a significant negative inotropic effect both in the lidocaine and mepivacaine group (AF: 84 ± 8 vs. 79 ± 9% of baseline value, NS). Increasing [Ca2+]o from 0.5 to 1 mmol induced a significant positive inotropic effect under isotonic and isometric conditions in the control and anaesthetic groups (Fig. 3). However, this effect was significantly diminished in the lidocaine group (Fig. 3).

Figure 3.

Figure 3.

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Effects on FFR

Increasing frequency from 0.1 to 5 Hz resulted in a negative FFR in the control group. An FFR was further impaired with local anaesthetics (Fig. 4). At 5 Hz, AF was 18 ± 10% in control group, 4 ± 2% in lidocaine group (P < 0.05, vs. control group) and 2 ± 2% of baseline value in mepivacaine group (P < 0.05, vs. control group). At the end of the experiment, we verified that after 30 min recovery at 0.2 Hz, AF was not significantly different that baseline value at 0.2 Hz (Fig. 4).

Figure 4.

Figure 4.

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Discussion

In the present study, we observed the following:(1) lidocaine and mepivacaine induced a negative inotropic effect that was significantly greater with lidocaine whatever the loading conditions; (2) lidocaine depressed the contractile response to increased [Ca2+]o whereas mepivacaine did not; (3) lidocaine impaired relaxation process in isotonic and isometric conditions whereas mepivacaine impaired contraction–relaxation coupling in isotonic conditions; (4) postrest potentiation was not modified by lidocaine or mepivacaine; (5) both lidocaine and mepivacaine induced similar impairments of the FFR.

Several investigators have reported a depressant effect of lidocaine and mepivacaine in isolated ventricular myocardium of various species including guinea pig and rat [4], dog [26] and human beings [27]. Among the mechanisms responsible for the negative inotropic effect of the local anaesthetics, the direct inhibition of the sodium channel as well as the potassium channel play an important role [3,6]. Brau and colleagues have shown, in enzymatically dissociated sciatic nerve fibers of Xenopus laevis, that mepivacaine and lidocaine could have a different effect on sodium and potassium channels as demonstrated by a lower IC50 of mepivacaine to induce tonic block for sodium channel and a lower IC50 of lidocaine to induce tonic block for potassium channel [6]. Direct inhibition of the sodium channel is responsible for a fall in [Na+]i activity that leads to a decrease in the activity of the Na+–Ca2+ exchanger in turn leading to a decrease in the amount of available intracellular calcium [8]. However, despite the fact that both local anaesthetics have almost the same clinical effects and potency [4], we observed that the negative inotropic effect of lidocaine was significantly greater than that of mepivacaine in isotonic and isometric conditions (Fig. 1). Xu and colleagues [9] suggested in neuronal cell suspensions that lidocaine inhibited both KCl- and carbachol-evoked [Ca2+]i transients with a greater potency than mepivacaine. Moreover, Desai and colleagues [28] have suggested that lidocaine has at least one locus of action at a site other than a tetrodotoxin blockade site (i.e. sodium channel) as they observed that in the presence of tetrodotoxin blockade, lidocaine produces a further decrease in amplitude of contraction. Among the mechanisms involved in the negative inotropic effect of mepivacaine and lidocaine, one may expect that calcium channels (ICaL), myofilaments or SR play a role. We also observed that the positive inotropic response induced by increasing extracellular calcium concentration was significantly diminished in the lidocaine group (Fig. 3) and might be in relation with the known inhibitory effect of lidocaine on calcium channel [10,11]. Lack of modification of postrest potentiation suggested that lidocaine and mepivacaine had no significant effect on the calcium release channel of the SR [15]. However, postrest potentiation is a complex process reflecting SR Ca2+ content and restitution of SR Ca2+ release mechanism. It is also probable that myofilament calcium sensitivity was not modified as demonstrated by the n.s. (after correction) decrease of R2 by lidocaine [14]. Therefore, we cannot exclude that the greater effect of lidocaine on contractility was mainly in relation to a direct inhibitory effect of lidocaine on ICaL [10,11]. Reduction of the action potential duration may have also contributed to the negative inotropic effect of lidocaine and mepivacaine, as previously shown [4,29].

Both local anaesthetics induced impairment of the relaxation process. However, that impairment was observed only in isotonic condition for mepivacaine and in isotonic and isometric conditions with lidocaine. Mepivacaine also induced an impairment of contraction–relaxation coupling under isotonic condition (Fig. 2) but only at the highest concentration (10−3 M). In rat myocardium, the SR accounts for the nearly total removal of the Ca2+ from the cytoplasm during the relaxation process [30]. Thus, the alteration of R1 and maxVr (isotonic condition) that may reflect the rapid uptake of calcium by SR [19] suggests a direct effect of mepivacaine on the SR. This effect on SR might have also contributed to the negative inotropic effect observed for mepivacaine because contraction and relaxation are interdependent. Our results are in conflict with those reported by Park and Suh [4] since they proposed that local anaesthetics induce an inhibition of calcium release from the SR. However, the fact that in our experiment postrest potentiation was not significantly modified by mepivacaine or by lidocaine suggests that calcium efflux from the SR was not significantly modified [15]. Our results are in agreement with those of Mitchell and Plant who described a lack of effect of lidocaine on the Ca2+-induced release of Ca2+ from the SR [31].

Impairment in FFR suggests alteration in Ca2+ handling and excitation–contraction coupling. Na+–Ca2+ exchanger and [Na+]i play a role in the mechanism involved in the FFR [32,33]. It has been shown that inhibition of sodium channels by antidysrhythmic drugs alters Na+–Ca2+ exchanger and that intracellular sodium is modified when frequency of stimulation is increased [32,34,35]. However, the negative effect on the FFR was the same for mepivacaine and lidocaine suggesting that the effect of local anaesthetics on sodium handling was probably the same.

The following points must be considered in the assessment of the clinical relevance of our results. First, because this study was conducted in vitro, it only dealt with intrinsic myocardial contractility. Observed changes in cardiac function after in vivo lidocaine or mepivacaine administration also depend on modifications in venous return, afterload and compensatory mechanism. Moreover, it has been shown that local anaesthetics had an effect on the conducting tissue [1]. Second, this study was conducted at 29°C and at a low-stimulation frequency. However, papillary muscles must be studied at this temperature because stability of mechanical parameters is not sufficient at 37°C, and at a low frequency because high-stimulation frequency induces core hypoxia [36]. Third, it was performed in rat myocardium, which differs from human myocardium. Lastly, in vivo a large amount of local anaesthetics can bind to albumin, and thus the concentrations of 10−3 M which result in a toxic myocardial effect would rarely be achieved clinically [1]. However, cardiac contractile depression might be observed in clinical practice as blood concentration as high as 128 μmol L−1 when 3 mg kg−1 of lidocaine was injected intravenously [37] or superior to 25 μmol L−1 for mepivacaine have been observed [38].

In conclusion, in isolated rat myocardium, the negative inotropic and lusitropic effects effect induced by lidocaine were more important than that induced by mepivacaine. This was probably related to a more important effect of lidocaine on intracellular Ca2+ handling including an inhibitory effect on calcium channel and an impairment of the SR.

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Acknowledgements

We thank Dr. Claude Tousignant (St Michael's Hospital, Toronto) for reviewing the manuscript, Dr. Joelle Goudable (Department of Biochemistry, CHU Edouard Herriot, Lyon, France) for measurement of ionized calcium and electrolytes and Florence Arnal, laboratory technician (EA 1896, Claude Bernard University, Lyon) for the management and care of the animals. This study was supported by EA 1896 (Université Claude Bernard, Lyon) and EA 3975 (Université Pierre et Marie Curie, Paris) all in France. Dr. C Duracher and Dr. J Amour received a fellowship grant from the Fondation pour la Recherche Médicale (Paris, France).

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Keywords:

MYOCARDIAL CONTRACTION; ANAESTHETICS LOCAL, lidocaine, mepivacaine; RATS; HEART

© 2007 European Society of Anaesthesiology