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Anesth Analg 2003;97:1053-1058
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Effects of S(-)-, R(+)-, and Racemic Bupivacaine on Lysophosphatidate-Induced Priming of Human Neutrophils

Markus W. Hollmann, MD PhD*,{dagger},{ddagger}, Katrin Kurz, MS*,{dagger}, Susanne Herroeder, MS*,{dagger}, Danja Struemper, MD{dagger},{ddagger}, Klaus Hahnenkamp, MD{ddagger}, Noud S. Berkelmans, MS{dagger}, Christel G. den Bakker, MS{dagger}, and Marcel E. Durieux, MD PhD{dagger},{ddagger}

*Department of Anesthesiology, University of Heidelberg, Germany; {dagger}Department of Anesthesiology, University Hospital Maastricht, The Netherlands; and {ddagger}Department of Anesthesiology, University Hospital Muenster, Germany

Address correspondence and reprint requests to Marcel E. Durieux, MD, PhD, Department of Anesthesiology, University of Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Address e-mail to me.durieux{at}home.nl


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Local anesthetics modulate inflammatory responses and may therefore be potentially useful in mitigating perioperative inflammatory injury. The inflammatory modulating effects of S(-)-bupivacaine are not known. Therefore, we compared the effects of S(-)-bupivacaine, R(+)-bupivacaine, and racemic bupivacaine on neutrophil function and receptor signaling. Priming (by lysophosphatidic acid [LPA]) and activation (by N-formylmethionine-leucyl-phenylalanine) of superoxide release by isolated human neutrophils was studied by using a cytochrome c-reduction assay. LPA receptor signaling in Xenopus oocytes was studied by using voltage clamp. All three local anesthetics were without effect on activation. S(-)-Bupivacaine inhibited priming more than did racemic bupivacaine; R(+)-bupivacaine was without effect. At 10-4 M, S(-)-bupivacaine inhibited approximately 50%. Comparable results were obtained in our recombinant model, where S(-)-bupivacaine most effectively inhibited LPA signaling. Compared with racemic bupivacaine and other anesthetics, S(-)-bupivacaine appears particularly effective in suppressing neutrophil priming, a process responsible in part for the overactive neutrophil response.

IMPLICATIONS: Overactive inflammatory responses underlie several perioperative disorders. Compared with racemic bupivacaine and other anesthetics, S(-)-bupivacaine appears particularly effective in suppressing neutrophil priming, a process responsible in part for the overactive neutrophil response.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Local anesthetics (LA) possess potent inflammatory modulating actions (1), but the exact underlying mechanisms for these effects remain to be elucidated. We have shown recently that clinically relevant concentrations of LA inhibit several actions of the phospholipid mediator lysophosphatidic acid (LPA) on human polymorphonuclear neutrophils (hPMNs). Their selective inhibition of LPA-induced priming (2) is probably important, because the priming process is a critical component of hPMN-mediated tissue injury both in vitro and in vivo. (3) Furthermore, we have demonstrated that both stereoisomers of ropivacaine inhibited platelet-acti-vating factor-induced priming of hPMNs, with a modest but significant difference between S(-)-ropivacaine and the R(+)-isomer (4).

S(-)-Bupivacaine has been recently introduced to the market. In addition to its potential decreased cardiac toxicity (5), an improved separation of motor and sensory blockade has been shown for S(-)-bupivacaine (6–8). Thus, the use of S(-)-bupivacaine appears advantageous, because it showed similar local anesthetic potency but significantly fewer undesirable clinical effects compared with bupivacaine (9).

This study addressed the question of whether S(-)-bupivacaine might be of additional benefit regarding its inhibitory effect on priming of hPMNs compared with racemic bupivacaine. Several reports within the last few years have described additional pathways for the antiinflammatory potential of bupivacaine (10–12).

We studied the effects of S(-)-bupivacaine, racemic bupivacaine, and R(+)-bupivacaine on LPA-induced priming of hPMNs. To confirm their inhibitory potencies on LPA signaling, we also investigated the effects of those three compounds in a recombinant model by using Xenopus oocytes.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study protocol was approved by the University of Virginia IRB and the Animal Research Committee at the University of Virginia and was reapproved by the local authorities at the University of Maastricht. Human venous blood was obtained from healthy donors who had not taken any medications for at least 2 wk. Human PMNs were isolated according to the previously published protocol (4). The purity of our hPMN suspension, assessed by morphology, exceeded 98%. The viability of neutrophils was checked by trypan blue exclusion and was always found to be more than 94%. All preparation and assays were performed at room temperature.

We used the cytochrome c-reduction assay to measure extracellular O2- production by activated hPMNs as described previously (13,14). O2- generation was measured spectrophotometrically as the superoxide dismutase-inhibitable reduction of cytochrome c.

Superoxide anion production was measured over time by the absorbance of cytochrome c at 550 nm. The reaction was performed in a spectrophotometer (Genesys 5; Spectronic Instruments, Rochester, NY). The reaction mixture was prepared according to the protocol previously published by our group (4) and was activated by adding N-formylmethionine-leucyl-phenylalanine (fMLP). The change in absorbance at 550 nm was observed over time. The reference sample was measured immediately afterward, and O2--dependent cytochrome c reduction was determined by subtracting the reference value from the study sample value. To test LA effects on priming, hPMNs were incubated for 60 min at 37°C in various concentrations of different LAs before hPMN activation with fMLP. LPA was used as a priming agent, and hPMNs were incubated for 10 min before activation with fMLP, because the priming effect by LPA has been shown to be maximal after 10 min (2). O2- generation at 0, 14, 16, and 18 min was measured. However, in this study, we report only O2- generation after 16 min, because we determined in prior studies that maximal superoxide anion production was achieved after this time period. (2,4) O2- production was calculated using a conversion factor of 47.4 µmol (1/21.1 mM-1 difference of extinction coefficient between oxidized and reduced cytochrome c at 550 nm) of O2- per unit change in absorbance. We measured extracellular (rather than total) PMN-mediated release of O2- because it is the release of oxygen metabolites into the extracellular milieu that may directly damage cells in the surrounding microenvironment.

Part of the study was performed in Xenopus oocytes. These cells express endogenous LPA receptors; intracellular Ca release as a response to receptor stimulation is easily assessed as Ca-activated Cl currents. Use of oocytes allowed comparison with our previous results obtained in this model. Oocyte harvesting, receptor expression, and electrophysiologic recording were performed as described previously (15,16).

LPA for activation of the endogenously expressed LPA receptors was diluted in Tyrode’s solution (150 mM NaCl, 5 mM KCl, 1 mM MgCl2 · 6H2O, 2 mM CaCl2 · 2H2O, 10 mM R(+)se, 10 mM HEPES) to the required concentration and was superfused (3 mL/min) over the oocyte for 10 s. The oocyte was positioned close to the inflow tubing, so that complete exposure to test solutions was obtained in 4.8 ± 0.4 s (n = 20). Control, treatment, and, at times, recovery responses were obtained from different oocytes to prevent the effects of receptor desensitization from obscuring the results.

Data are reported as mean ± SD. Leukocyte metabolic activity is reported as the percentage change from control. Blood from at least 12 donors was used for each data point. Groups were compared by using one-way repeated-measurements analysis of variance, followed by the Dunnett or Student-Newman-Keuls correction, if necessary.

For oocyte experiments, at least 20 oocytes were used to determine each data point. Because variability between batches of oocytes is common, responses were at times normalized to control response. Concentration-response curves were fit to the following logistic function, derived from the Hill equation:


where ymax and ymin are the maximum and minimum response obtained, n is the Hill coefficient, and x50 is the half-maximal effect concentration (EC50 for agonists) or the half-maximal inhibitory effect concentration (IC50 for antagonists). Differences in IC50 and the Hill coefficient for isomers of bupivacaine were compared by using Student’s t-test.

P < 0.05 was considered significant. SigmaStat 2.03 (Jandel Scientific Corp., San Rafael, CA) was used for all statistical analyses.

For neutrophil experiments, Hanks’ balanced salt solution (without phenol red and with Ca2+/Mg2+) was bought from Whittaker Bioproducts (Walkersville, MD); superoxide dismutase (from bovine liver), fMLP, cytochrome c (from horse heart), and catalase (from bovine liver), were obtained from Sigma Chemical Co. (St. Louis, MO). Ficoll-Hypaque and bovine serum albumin (protease-free bovine albumin fraction; fatty acid free) were from ICN Biomedicals, Inc. (Aurora, OH). Polymorph (Westbury, NY) neutrophil isolation medium was from Cardinal Associates (Santa Fe, NM). LPA was obtained from Avanti polar lipids (Alabaster, AL). Chemicals for oocyte experiments were obtained from Sigma. R(+)-bupivacaine and S(-)-bupivacaine were a gift from Abbott B.V.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Because hPMNs were to be incubated in LA for significant duration before the activation assay, we determined, in pilot experiments, the effect of incubation in buffer (37°C; 0–60 min) and the effect of movement (by a shaking waterbath) on O2- production. Neither treatment affected O2- production as compared with untreated control hPMNs (data not shown). We also determined any interference of LPA with the cytochrome c assay. LPA did not have any significant effect on absorbance in a neutrophil-free solution (data not shown).

Racemic bupivacaine and S(-)-bupivacaine, but not R(+)-bupivacaine, concentration-dependently inhibit hPMN priming. After we confirmed the findings from our previous study (2) showing that LAs (in this study, racemic bupivacaine, S(-)-bupivacaine, and R(+)-bupivacaine) do not affect the activation process of hPMNs (data not shown), we investigated the effect of those LAs on hPMNs primed with LPA (10-4 M) and activated by fMLP (10-6 M). Human PMNs were incubated for 60 min in various concentrations (10-4 to 10-6 M) of the LAs before priming with LPA. Racemic bupivacaine and (more potently) S(-)-bupivacaine inhibited superoxide anion production in a concentration-dependent manner over the range tested (Fig. 1, A and B; n = 12). Even at an LA concentration (10-6 M) often attained in plasma after epidural or IV administration (17–20), O2- production was attenuated significantly (to 86.6% ± 4.2% of control response for racemic bupivacaine and 71.7% ± 5.9% of control response for S(-)-bupivacaine, as compared with the LPA [10-4 M]-primed/fMLP [10-6 M]-activated control response [10.8 ± 0.8 nmol/106 cells for racemic bupivacaine and 11.2 ± 1.1 nmol/106 cells for S(-)-bupivacaine experiments]).



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  		Figure 1. A–C, Concentration-dependent inhibition of superoxide anion production in human polymorphonuclear neutrophils (hPMNs) after 60 min of incubation in racemic bupivacaine (A; n = 12), S(-)-bupivacaine (B; n = 12), or R(+)-bupivacaine (C; n = 12) (10-4 to 10-6 M) followed by priming with lysophosphatidic acid (LPA) (10-4 M) and activation with N-formylmethionine-leucyl-phenylalanine (fMLP) (10-6 M). *Significant difference compared with LPA-primed and fMLP-activated control response. D, Effects of 60 min of preincubation of hPMNs with S(-)-bupivacaine, racemic bupivacaine, or R(+)-bupivacaine (all at 10-4 M) on LPA (10-4 M)-primed and fMLP (10-6 M)-activated hPMNs (n = 14). *Significant difference compared with LPA-primed and fMLP-activated control response; #significant difference com-pared with S(-)-bupivacaine; and +significant difference compared with racemic bupivacaine.

 
In contrast, R(+)-bupivacaine failed to inhibit superoxide anion production of LPA (10-4 M)-primed/fMLP (10-6 M)-activated hPMNs (Fig. 1C; n = 12). Even at the largest concentration tested (10-4 M), O2- production was not attenuated significantly (to 94.2% ± 7.3% of control response; 10.4 ± 0.6 nmol/106 cells) by R(+)-bupivacaine.

To exclude interindividual variability for the effects of racemic bupivacaine, S(-)-bupivacaine, and R(+)-bupivacaine on LPA-induced priming of hPMNs, we designed an experiment in which the largest concentration of each LA (10-4 M) was tested on hPMNs from blood of each volunteer (n = 14). Figure 1D shows that racemic bupivacaine and S(-)-bupivacaine significantly inhibit priming of hPMNs compared with the LPA (10-4 M)-primed/fMLP (10-6 M)-activated control group. At the largest concentration tested, S(-)-bupivacaine (58.1% ± 4.2% of control response) was found to inhibit O2- production more effectively than did racemic bupivacaine (80.6% ± 5.5% of control response). As expected from our previous experiments, R(+)-bupivacaine failed to significantly inhibit priming of hPMNs (97.8% ± 4.8% of control response). These findings demonstrate that, despite their identical physicochemical properties, isomers of bupivacaine exert different effects on LPA-induced priming of hPMNs, which could be explained by stereoselective interaction.

To confirm stereoselective inhibition of LPA signaling by isomers of bupivacaine and to narrow down the site of action, we next determined the inhibitory potency of all three LAs on LPA signaling in Xenopus oocytes. To provide baseline measurements and to ensure that our model behaved similarly to our previous studies, we determined the concentration-response relationship for LPA. LPA induced inward currents as described previously by us (21–23) and others (24–28) (Fig. 2A). As shown in Figure 2B, the response to LPA was concentration dependent. The EC50 was 143 ± 85 nM. Maximal responses of 1.8 ± 0.2 µA were obtained at an LPA concentration of 10 µM. The calculated Emax was 1.8 ± 0.3 µA, and the Hill coefficient was 0.64 ± 0.26. These findings compare closely with data reported in our previous studies (29–32).



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  		Figure 2. A, Sample trace of a Ca-activated Cl current (ICl(Ca)) induced by a 10-s administration of 1 µM lysophosphatidic acid (LPA) in an oocyte endogenously expressing LPA receptors. The peak current is 1.83 µA. B, LPA evokes ICl(Ca) in a concentration-dependent manner. Curve fitting by using the Hill equation revealed a half-maximal effect concentration (EC50) of 143 ± 85 nM. C, Example trace of LPA (at EC50 143 nM)-induced ICl(Ca), under control conditions (top) and 10 min after the administration of S(-)-bupivacaine (1 mM) (bottom). D, Racemic bupivacaine and both stereoisomers concentration-dependently inhibit the functioning of LPA receptors activated by LPA at EC50 (143 nM), but with different half-maximal inhibition concentrations (IC50). Calculated IC50 values were 1.5 ± 0.3 mM for racemic bupivacaine, 23.6 ± 5.0 mM for R(+)-bupivacaine, and 0.18 ± 0.03 mM for S(-)-bupivacaine. The mean ± SD of control responses was 1.1 ± 0.3 µA for racemic bupivacaine, 1.0 ± 0.2 µA for R(+)-bupivacaine, and 1.3 ± 0.3 µA for S(-)-bupivacaine. LA = local anesthetic.

 
Both stereoisomers and the racemic mixture concentration-dependently inhibited the functioning of LPA receptors (e.g., Fig. 2C) activated by LPA at EC50 (143 nM) (Fig. 2D). The calculated IC50 for the clinically relevant S(-)-enantiomer of bupivacaine was 0.18 ± 0.03 mM. R(+)-bupivacaine showed an approximately 14-fold less inhibitory potency than did S(-)-bupivacaine (IC50, 23.6 ± 5.0 mM); the difference in IC50 between S(-) and R(+) was significant, but we observed no statistically significant difference in the Hill coefficients of both curves (0.9 ± 0.2 for R(+) versus 0.6 ± 0.2 for S(-)). Racemic bupivacaine showed, as anticipated, an intermediate inhibitory potency (IC50, 1.5 ± 0.3 mM). These results confirm that the more profound inhibitory action on LPA signaling could be attributed to the S(-)-isomer of racemic bupivacaine.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, we have shown that the most recently introduced LA, S(-)-bupivacaine, is an inhibitor of LPA-induced priming of human neutrophils. In contrast, its stereoisomer, R(+)-bupivacaine, was found to completely lack this effect. Further experiments in Xenopus oocytes confirmed this stereoselective action and suggest that it takes place proximally in the LPA signaling cascade. Although an action on an organized (and, hence, stereoselective) lipid membrane cannot be excluded by these experiments, the data are compatible with a protein interaction underlying the inhibition of hPMN priming by LA, as suggested in our previous studies (4). This study demonstrates an important role for stereoselectivity in the inhibitory effect on hPMN priming. The important implications are as follows: 1) this lessens the likelihood that the observed effect is a "nonspecific" action on the membrane, but instead makes a direct protein interaction more likely; and 2) because the stereoselectivity profile is different from that of the "classic" LA action, it is likely that another part of the LA molecule is involved as compared with Na channel block.

LPA is an intercellular phospholipid mediator known to induce a variety of biological responses (e.g., cell proliferation, platelet aggregation, smooth muscle cell contraction, chemotaxis, and inhibition of differentiation) (33). LPA influences target cells by activating several specific G protein-coupled membrane receptors present in numerous cell types. These, in turn, activate a number of intracellular signaling cascades. Although the physiological functions of the compound remain to be determined, LPA can be generated by platelets, leukocytes, and other cells challenged with inflammatory stimuli (34,35), suggesting that it may stimulate responses at sites of inflammation and can act as an inflammatory mediator. In fact, we have shown previously that LPA can act as a chemoattractant and priming agent in hPMNs (2).

Human PMNs are of great importance in host defense, because they move actively to the site of inflammation (chemotaxis), where a multicomponent enzyme complex, nicotinamide adenine dinucleotide phosphate oxidase, generates toxic oxygen metabolites (O2-, H2O2, HOCl, and OH-). Human PMNs exist in one of three states: quiescent, primed, or active. Priming refers to a process whereby the response of hPMNs to a subsequent activating stimulus is potentiated. Release of oxygen metabolites is markedly enhanced when hPMNs have previously been primed (3). The priming process is a critical component of hPMN-mediated tissue injury both in vitro and in vivo. (3) Primed hPMNs have been identified in the peripheral blood of patients after blunt trauma (36), adult respiratory distress syndrome (37), and bacterial or fungal infections (38). Human PMN priming is critical for the induction of endothelial injury (39) and lung damage (40) in vivo.

The effect of S(-)-bupivacaine (approximately 50% inhibition at 10-4 M) is remarkable, not only compared with its rather ineffective R(+)-counterpart, but also as compared with other LAs. For example, S(-)-ropivacaine (100 µM) inhibited LPA-induced priming by only 25%, lidocaine by 32%, and etidocaine by 38% (2) (Hollmann MW, unpublished data, 2001). Only the ester-linked LAs, such as benzocaine (approximately 60% inhibition) (4), seem to exert an inhibitory action on hPMN priming as potent as that of S(-)-bupivacaine.

The concentrations at which this effect takes place are much less than those required to block Na channels. S(-)-Bupivacaine and also the racemic mixture showed significant inhibitory effects on priming, even at concentrations often obtained in plasma of patients after epidural or IV administration (approximately 0.5–5 µg/mL, corresponding to 2–20 µM) (17); for example, IV administration of lidocaine at 2–4 mg/min leads to plasma concentrations of 1–3 µg/mL (4–12 µM) after 150 minutes (18). A 2 mg/kg IV bolus of lidocaine results in peak plasma levels of 1.5–1.9 µg/mL (6–8 µM) after 15 minutes (19). Similar plasma concentrations are obtained after epidural administration (20).

We observed significant inhibitory effects of the compounds at concentrations of 10-6 M. In the clinical situation, we would anticipate free concentrations to be approximately 10-fold less because of protein binding. We did not study this concentration directly, but certainly the trend of the S(-)-bupivacaine concentration-response relationship suggests that at this concentration, an appreciable inhibitory effect would still be observed. However, our study was intended to compare the pharmacologic actions of the various compounds, not to determine the likely clinical effects at these concentrations. In addition, the in vitro assay is of course a greatly artificial environment, and concentrations as obtained in this assay cannot be extrapolated directly to the clinical setting.

The duration of LA incubation (60 minutes) was chosen for two reasons: first, because it has been proven to be effective in our previous studies (2,4), and second, because we believe that this mimics the clinical setting more closely, in contrast to most other in vitro studies, where incubation times are mostly between 10 and 30 minutes.

In conclusion, our study has shown that S(-)-bupivacaine, but not R(+)-bupivacaine, is a potent inhibitor of LPA-induced priming in hPMNs. Therefore, this recently introduced LA might provide, in addition to a potential decrease in cardiac toxicity and improved separation of motor and sensory blockade, further benefits because of its inflammatory modulating action, as compared with racemic bupivacaine. Further research should address the question of how much inflammatory modulation is necessary to prevent an overactive inflammatory response and determine structure-function relationships for this effect. If the active part within the LA molecule could be discovered, it might be possible to develop new drugs, on the basis of LA, with stronger inhibition of priming but lacking the sodium channel-blocking property.


   Acknowledgments
 
Dr. Hollmann is supported in part by the Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany, and by a grant of the German Research Society (DFG HO 2199/1-1), Bonn, Germany. This study was supported in part by a grant from Abbott B.V.; the 2000 and 2002 Ben Covino Research Award (MWH) sponsored by AstraZeneca Pain Control, Sweden; National Institutes of Health Grant GMS 52387, Bethesda, MD (MED); and American Heart Association Grant VHA 9920345U (Mid-Atlantic Affiliation), Baltimore, MD (MWH).

We gratefully acknowledge Prof. Dr. Med. Eike Martin (Ruprecht-Karls-Universität Heidelberg, Germany) for his support.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 16, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press