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The Effects of Levosimendan on Myocardial Function in Ropivacaine Toxicity in Isolated Guinea Pig Heart Preparations

Stehr, Sebastian N. MD*; Christ, Torsten MD; Rasche, Berit MD*; Rasche, Stefan MD*; Wettwer, Erich PhD; Deussen, Andreas MD; Ravens, Ursula MD; Koch, Thea MD*; Hübler, Matthias MD*

doi: 10.1213/01.ane.0000278146.15671.03
Anesthetic Pharmacology: Research Report
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BACKGROUND: Levosimendan is a novel drug used for inotropic support in heart failure, but its efficacy in local anesthetic-induced myocardial depression is not known. Therefore, we investigated the effects of levosimendan on the negative inotropic response to ropivacaine in isolated heart preparations of guinea pigs.

METHODS: Action potentials and force of contraction were studied with conventional techniques in guinea-pig papillary muscles. Heart rate, systolic pressure, the first derivative of left ventricular pressure (+dP/dtmax), coronary flow, and PR and QRS intervals were measured in isolated constant-pressure perfused, nonrecirculating Langendorff heart preparations. Single or cumulatively increasing concentrations of levosimendan and ropivacaine were used either alone or in combination.

RESULTS: In isolated papillary muscle, ropivacaine reduced force of contraction in a concentration-dependent manner. Exposure to 10 μM levosimendan in the presence of 10 μM ropivacaine almost completely reversed the negative inotropic response. Sensitivity to the positive inotropic effect of levosimendan was not altered by 10 μM ropivacaine (−logEC50 [M] = 7.03 without versus 6.9 with ropivacaine, respectively). Action potential parameters were influenced only at the highest concentration. In the Langendorff heart, levosimendan significantly reversed the ropivacaine-induced reduction in heart rate, systolic pressure, coronary flow, and +dP/dtmax to baseline values.

CONCLUSION: Levosimendan is an effective inotropic drug in ropivacaine-induced myocardial depression and levosimendan myocardial sensitivity, and efficacy was not affected by the local anesthetic. Our results suggest that the calcium-sensitizing action of levosimendan is effective in local anesthetic-induced cardiac depression.

IMPLICATIONS: The calcium-sensitizer, levosimendan, is an effective inotropic drug in ropivacaine-induced myocardial depression. Levosimendan myocardial sensitivity and efficacy were not affected by the local anesthetic. Our results suggest that levosimendan is effective in local anesthetic-induced cardiac depression.

From the Departments of *Anesthesiology and Intensive Care Medicine, †Pharmacology and Toxicology, and ‡Institute of Physiology, Medical Faculty Carl Gustav Carus, Dresden, Germany.

Accepted for publication June 1, 2007.

Supported by a grant from AstraZeneca.

The results of this study were presented in part at the Wissenschaftliche Arbeitstage der Deutschen Gesellschaft für Anästhesie und Intensivmedizin in Würzburg (February 2006) and at the 21st ASRA conference in Palm Springs (April 2006).

Address correspondence and reprint requests to Sebastian N. Stehr, MD, Department of Anesthesiology and Intensive Care Medicine, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscher Str. 74, 01307 Dresden, Germany. Address e-mail to sebastian.stehr@gmx.de.

Therapy of local anesthetic (LA)-induced myocardial depression must focus on inotropic support. In the clinical setting, catecholamines are the drugs of choice in acute myocardial collapse. However, marked arrhythmogenic effects of catecholamines, especially in LA-induced myocardial toxicity, have been described (1). As an alternative approach, phosphodiesterase (PDE) III inhibitors were shown to be effective in LA-induced myocardial depression (2) and were associated with a lower incidence of arrhythmia than catecholamines (3). Nevertheless, both catecholamines and PDE inhibitors have some arrhythmogenic potential as a result of increased intracellular calcium (4).

Calcium sensitizers are a novel class of inotropic drugs that increase the force of contraction by enhancing myofilamentary calcium sensitivity without an increase in intracellular calcium concentration (5,6). Levosimendan is a representative of this class of compounds, and large clinical trials have shown that it has positive effects in patients with heart failure (7,8). In the present study, we tested whether levosimendan maintains its positive inotropic effect in LA-induced myocardial toxicity. The aim of our study was to provide experimental evidence for a rationale of using levosimendan for treating LA-induced myocardial depression.

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METHODS

The investigation conformed to the Guide for the Care and Use of Laboratory Animals issued by the United States National Institutes of Health and was approved by the local government authority (AZ 24-9168.24-1-2005-1). Male Dunkin Hartley Crl: HA guinea pigs (Charles River, Sulzfeld, Germany) weighing 280–350 g were exposed to high concentrations of CO2 until complete loss of consciousness before decapitation.

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Guinea Pig Papillary Muscle

Hearts were rapidly excised, and thin papillary muscles were removed from the right ventricles. The muscles were mounted in an organ bath continuously perfused with oxygenated Tyrode solution of the following composition: NaCl 126.7 mM, KCl 5.4 mM, CaCl2 1.8 mM, MgCl2 1.05 mM, NaHCO3 22 mM, NaHPO4 0.42 mM, glucose 5 mM. After equilibration with carbogen (95% O2 and 5% CO2), the pH of the solution was 7.4 (37°C). One end of the muscle was pinned to the floor of the chamber; the free end was connected to a force transducer (AE 801, SensoNor, Dasing, Germany) with a loop of silk thread. The preparations were stimulated electrically via silver/ silver chloride electrodes at a frequency of 1 Hz. The muscles were allowed to equilibrate for at least 90 min before intracellular action potentials were recorded with conventional glass pipettes filled with 2–9 M KCl solution (tip resistance of 10–20 MΩ). Action potential signals were stored on a personal computer and the following parameters were analyzed off-line: resting membrane potential (RMP), action potential amplitude, action potential duration (APD) at 20%, 50%, and 90% of repolarization (APD20, APD50, and APD90), maximum upstroke velocity (dV/dtmax) and force of contraction (Fc). All data acquisition and analysis were performed with the ISO 2 system (MFK, Niedernhausen, Germany).

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Experimental Protocol Isolated Papillary Muscle

Ropivacaine and levosimendan were added to the superfusion solution from concentrated stock solutions to yield the final concentrations. Action potentials from stable preparations were recorded 30–45 min after drug addition before the individual drug concentrations were increased.

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Preparation of Isolated Hearts

The isolated perfused, nonrecirculating Langendorff guinea pig heart preparation was used in our study, as described previously (9). In brief, hearts were rapidly excised and perfused via the coronary arteries by tying the aorta onto a cannula. Constant perfusion pressure was 60 mm Hg, a modified Krebs– Henseleit buffer was used: NaCl 116 mmol/L, KCl 4.56 mmol/L, MgSO4 2.24 mmol/L, KH2PO4 1.18 mmol/L, NaHCO3 25.0 mmol/L, glucose 8.27 mmol/L, pyruvate 2.0 mmol/L, CaCl2 2.52 mmol/L. The solution was continuously bubbled with 95% O2 and 5% CO2, and pH was maintained at 7.35 ± 0.03. Arterial and venous Po2 and Pco2 (sampled via the inflow line or via a catheter placed in the pulmonary artery, respectively) were measured at 10, 15, and 20 min (AVL 990, Medical Instruments, Bad Homburg, Germany). Myocardial oxygen consumption (MvO2, μL · min−1 · g−1) was calculated from the arterial-venous difference of Po2 according to Fick's principle with the use of Bunsen's absorption coefficient (α = 0.036 μL · mm Hg−1 mL−1) and avDO2 (PartO2 − PvenO2) at 37°C as follows: MvO2 (μL · min−1 · g−1) = AvDO2 × α × F, where F denotes coronary flow (mL min−1 · g−1). All elements of the perfusion apparatus were water-jacketed and maintained at 37°C. In the spontaneously beating heart preparation, stable conditions were achieved in preliminary control hearts with minimal changes of inotropic parameters, left ventricular pressure and +dP/dtmax. Left ventricular systolic pressure (LVP) and its first derivative +dP/dtmax were continuously measured with a balloon catheter inserted into the left ventricle (Gould Inc. Instruments, Statham, USA) via the cut mitral valve. Diastolic left ventricular pressure was adjusted to 5 mm Hg. Coronary flow and coronary perfusion pressure were continuously measured by an in-line flow probe (Transonic Flowprobe, Transonic Systems Inc., NY, NY) and a pressure transducer (Gould Nicolet, Erlensee, Germany) connected to the perfusion cannula 2 cm above the orifices of the coronary vessels, respectively. Hemodynamic variables and derivatives (heart rate (HR), LVP, +dP/dt, coronary flow) and electrocardiogram (ECG) data (PR, QRS intervals) were continuously sampled and documented by a software system (PoNeMah, P3 plus Version 4, Gould LDS Test and Measurement LLC, OH). The ECG electrodes were consistently placed in a “lead II” position: one electrode in the right atrium and one epicardially at the apex of the heart. An indifferent electrode was connected to the Krebs–Henseleit buffer inflow-line. All ECG data were cross-checked manually offline to confirm correct assessment. All infused compounds were applied through a stainless steel cannula placed into the aortic inflow line approximately 2 cm above the coronary orifices at a rate of 200 μL/min or less (Precidor, Infors AG, Basel, Switzerland). The experimental protocol was started when LVP, +dP/dtmax, and HR had reached stable baseline values, i.e., 30 min after artificial perfusion had been commenced.

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Drugs

All chemicals were of analytical grade and were obtained from Sigma. Levosimendan was a gift of Abbott GmbH & Co. KG, Wiesbaden, Germany. Ropivacaine was a gift of AstraZeneca, GmbH, Wedel, Germany. Drugs were dissolved in dimethylsulfoxide as concentrated stock solutions and diluted directly into the superfusion solution to yield the final concentration. Time-matched control experiments without any drug addition were conducted in the presence of the maximum solvent concentration used, i.e., 0.3% dimethylsulfoxide.

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Statistical Analysis

All data are presented as means ± sd. For between-group comparison of hemodynamic variables in the isolated hearts values from 0 to 10 min were averaged (10 min) and 30 s averages at 15 and 20 min, respectively, were used. Statistical analyses were performed using SPSS software for MS Windows (Release 11.0, SPSS Inc., Chicago, IL) using ANOVA and Bonferroni post hoc adjustment or Student's t-test if appropriate. P < 0.05 was considered as statistical significance.

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RESULTS

Isolated Guinea Pig Papillary Muscle

Under control conditions RMP was −86.3 ± 0.2 mV, dV/dtmax was 198 ± 10 V/s and APD90 amounted to 164.4 ± 3.4 ms (n = 22). In time-matched controls, these three variables remained stable over 4 h. In contrast, Fc showed a small but significant decline over time from 156 ± 26 to 101 ± 13 μN (n = 6, P < 0.05).

Ropivacaine clearly suppressed Fc in a concentration-dependent manner from 155 ± 48 to 24 ± 3 μN (P < 0.05, −logEC50 [M] = 5.3, Fig. 1A). The RMP remained unaffected (Fig. 1B). Ropivacaine shortened APD mainly by shortening plateau duration (APD20 from 93 ± 7 to 66 ± 3 ms, Fig. 1C). As expected for a sodium channel blocking drug, dV/dtmax significantly decreased, but only at concentrations larger than 10 μM (−logEC50 [M] = 3.8, Fig. 1D).

Figure 1

Figure 1

Levosimendan increased Fc in a concentration-dependent manner from 73 ± 14 to 120 ± 24 μN (P < 0.05, n = 5, −logEC50 [M] = 7.03, Fig. 2A). The action potential parameters dV/dtmax, APD, and RMP and were not affected (Figs. 2B–D).

Figure 2

Figure 2

To evaluate the effects of levosimendan in ropivacaine-induced myocardial depression, we measured the concentration-dependent effects of levosimendan in papillary muscles pretreated with one single concentration of ropivacaine (10 μM). Fc decreased by about one-third (from 102 ± 10 to 66 ± 13 μN, n = 7, P < 0.05, Fig. 3A). Exposure to levosimendan in the continuous presence of 10 μM ropivacaine reversed the reduction in Fc almost completely to 91 ± 21 μN (Fig. 3A). As found in the absence of ropivacaine, no significant change in APD was noted when levosimendan was applied in the presence of ropivacaine (Fig. 3B). Sensitivity to levosimendan was not changed by 10 μM ropivacaine (−logEC50 [M] = 6.9). The efficacy of levosimendan was also not affected by 10 μM ropivacaine (levosimendan 144% ± 23% versus levosimendan and ropivacaine 154% ± 16%).

Figure 3

Figure 3

To study the interaction of contractile function and potential coronary vascular effects of levosimendan and ropivacaine, additional experiments were performed in the Langendorff preparation.

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Isolated Guinea Pig Heart

Baseline variables of all experimental groups for HR (247 ± 22 bpm), coronary flow (17.2 ± 4.2 mL/min), systolic pressure (96 ± 11.3 mm Hg), +dP/dtmax (1542 ± 197 mm Hg/s), PR (62 ± 6 ms), QRS (32 ± 5 ms), and QTc (261 ± 11 ms) were similar and showed no significant between-group differences. Furthermore, perfusate oxygenation values and pH were similar in the different groups at baseline (data not shown).

In a group of six hearts exposed to 10 μM ropivacaine, HR significantly decreased from 248 ± 11 to 207 ± 10 bpm (P < 0.05). PR and QRS intervals were prolonged by ropivacaine from 63 ± 1 to 81 ± 6 and 32 ± 3 to 38 ± 3 ms, respectively (P < 0.05), indicating significant delay in conduction at a concentration of 10 μM ropivacaine. QTc was slowed from 261 ± 9 to 280 ± 16 ms. Contractility was also significantly impaired from 1450 ± 250 to 980 ± 131 mm Hg/s (+dP/dtmax, P < 0.05) and systolic pressure decreased from 90 ± 12 to 76 ± 10 mm Hg (P < 0.05). Coronary flow was significantly reduced from 15.8 ± 2.6 to 12.0 ± 1.3 mL/min (P < 0.05). All changes induced by ropivacaine remained stable over the time of ropivacaine application (10 min).

In seven hearts receiving 10 μM levosimendan HR (258 ± 14 to 298 ± 17 bpm), +dP/dtmax (1597 ± 248 to 1802 ± 328 mm Hg/s), systolic pressure (86 ± 8.4–98 ± 7 mm Hg), and coronary flow (16 ± 4.3–17.4 ± 4 mL/min, Figs. 4A and C, P < 0.05) were significantly increased.

Figure 4

Figure 4

In a further series of experiments, the effects of 10 μM levosimendan in the continuous presence of 10 μM ropivacaine (n = 6) were evaluated. Ropivacaine 10 μM alone resulted in similar changes as reported above. After addition of 10 μM levosimendan HR increased significantly from 202 ± 27 to 238 ± 23 bpm, systolic pressure from 73 ± 9 to 87 ± 11 mm Hg, +dP/dtmax from 983 ± 120 to 1335 ± 155 mm Hg/s, and coronary flow from 15.7 ± 2.6 to 18.7 ± 2.4 mL/min (P < 0.05, Figs. 4B and D, Figs. 5 and 6). ECG parameters were not affected by levosimendan, neither in control experiments nor in the presence of 10 μM ropivacaine (data not shown).

Figure 5

Figure 5

Figure 6

Figure 6

Coronary flow is crucial for myocardial oxygen and substrate supply. We used a Langendorff constant pressure model. Therefore, any change in coronary flow indicates a change in coronary resistance. Levosimendan significantly increased avDO2 from 353 ± 30 to 387 ± 27 mm Hg (P < 0.05) and MvO2 from 198 ± 14 to 241 ± 20 μL min−1 g−1 (P < 0.05). Ropivacaine alone significantly decreased MvO2 from 238 ± 38 to 166 ± 24 μL min−1 g−1 (P < 0.05). In hearts receiving levosimendan after ropivacaine MvO2 and avDO2 were increased by levosimendan to 224 ± 31 μL min−1 g−1 and 355 ± 36 mm Hg, respectively (P < 0.05).

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DISCUSSION

In our experiments, ropivacaine had a negative inotropic effect, reducing Fc in isolated papillary muscles, as well as systolic pressure and +dP/dtmax, in the Langendorff preparation. Maximum upstroke velocity as an indirect measure of sodium channel conductance was reduced, reflected as a prolongation of atrioventricular conductance in isolated heart ECG recordings. At concentrations of 10 μM, ropivacaine did not prolong APD in right ventricular papillary muscles. PR, QRS intervals were prolonged and QTc was slightly increased. Ropivacaine 10 μM resulted in a decrease of spontaneous HR of 18% with occurrence of first-degree atrioventricular block (defined as PR interval >70 ms), but not of higher degree blocks, as also previously described for ropivacaine and isolated guinea pig hearts (10). Levosimendan increased contractility in a dose-dependent manner and did not affect action potential shape. In the Langendorff preparation, 10 μM levosimendan significantly increased HR, systolic pressure, +dP/dtmax and coronary flow, and could completely reverse the negative inotropic effect induced by 10 μM ropivacaine.

Clinically, myocardial collapse is the result of two main cardiac toxic mechanisms of LA: arrhythmias as a result of sodium (11) and Ik (HERG) channel blockade (12) and contractile failure because of negative inotropic effects (13). Presently no rational, clinically effective approach is known for the treatment of LA-induced arrhythmia. To the contrary, several drugs with proven efficacy in treating LA-induced cardiotoxicity possess severe unwanted side effects. Epinephrine is effective in counteracting LA-induced hypotension (14), but has marked arrhythmogenic potential (15). PDE inhibitors significantly increase cardiac output (16) and have been shown to reverse LA-induced myocardial depression in vitro in animal cardiac preparations (2). However, they also induce arrhythmias (17). The common basis for the arrhythmogenic effects of catecholamines and PDE inhibitors is a marked increase in intracellular calcium concentrations, leading to intracellular calcium overload (4). Therefore, considerable effort has been directed towards the development of compounds that lack this potentially life-threatening side effect.

The novel calcium-sensitizers exert their positive inotropic effects by increasing myofilamentary calcium sensitivity (5). Among these inotropic drugs, levosimendan seems to be unique with respect to enhancing contractility without concomitantly increasing myocardial oxygen demand, and has therefore been successfully used in patients with heart failure (7,8). Levosimendan is given as an initial loading dose of 6–24 μg/kg, followed by a continuous infusion of 0.05–0.2 μg kg−1 min−1. This dosage results in plasma concentrations of 10–100 ng/mL (18). In experimental (19) and clinical studies (20), no significant arrhythmogenic effect of levosimendan was noted. Myocardial depression in LA-induced toxicity differs from impaired force development in heart failure. We therefore evaluated whether levosimendan is capable of enhancing contractile force in LA-induced myocardial toxicity.

In the isolated papillary muscle, ropivacaine concentration-dependently decreased Fc as published by Wulf et al. (21), and this result was confirmed in the Langendorff preparation. With 10 μM ropivacaine L-type calcium current is decreased only by 10% (22), suggesting that ropivacaine probably impairs intracellular calcium handling. As expected from sodium channel blockade, dV/dtmax was decreased and atrioventricular conduction times were prolonged at a concentration of 10 μM ropivacaine. An extensive literature has shown clinical torsades de points tachycardia in LA cardiac toxicity and, in recent years, HERG channel inhibition has served as a possible explanation for arrhythmogenesis (12). In contrast to an earlier study in atria papillary muscles (21), we found no evidence for disturbance of late repolarization in right ventricular papillary muscle preparations. QTc, which reflects left ventricular repolarization, was prolonged by ropivacaine. The discrepancy between lack of effect on repolarization in the isolated right papillary muscle and in prolonged QTc interval in the isolated heart can be attributed to regional differences in potassium current density, leading to differences in repolarization reserve (23). Levosimendan led to a concentration-dependant increase in Fc. Neither effect size nor sensitivity of levosimendan was reduced in the presence of ropivacaine toxicity. This finding indicates that the calcium-sensitizing effect of levosimendan is not impaired by ropivacaine-induced myocardial toxicity. Furthermore, sinusbradycardia was reversed by levosimendan application in the isolated guinea pig heart. The increase in coronary blood flow induced by levosimendan was also preserved in ropivacaine toxicity.

As mentioned above, levosimendan has been clinically evaluated in chronic heart failure. In a study performed during cardiac catheterization and quantitative angiography in humans receiving a 24 μg/kg IV bolus over 10 min, levosimendan resulted in a significant increase in HR, cardiac output, and ejection fraction, and reduced aortic mean pressure and systemic vascular resistance (24). Considering the inodilatory effects of levosimendan, we cannot predict the systemic effects in a whole animal model of LA toxicity.

Levosimendan is an effective inotropic drug in ropivacaine-induced myocardial depression and is capable of reversing the Fc effects of 10 μM ropivacaine. Disturbance of conductance and repolarization was not affected, but sinus bradycardia was reversed. Most importantly, myocardial sensitivity and efficacy for levosimendan did not differ from control conditions in ropivacaine-induced depression, indicating that the calcium-sensitizing effects of levosimendan are still effective in LA-induced contractile depression.

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ACKNOWLEDGMENTS

The authors thank Konstanze Fischer (Department of Pharmacology and Toxicology) and Bianca Müller (Institute of Physiology) for excellent technical assistance.

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