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Anesth Analg 2006;102:1108-1113
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000200310.39031.1f

ANESTHETIC PHARMACOLOGY

Local Anesthetic-Induced Protection Against Lipopolysaccharide-Induced Injury in Endothelial Cells: The Role of Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channels

Manuela J. M. de Klaver, MD, Gregory S. Weingart, BS, Tom G. Obrig, PhD, and George F. Rich, MD, PhD

Department of Anesthesiology, Department of Medicine, Nephrology Division, Department of Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia

Address correspondence and reprint requests to George F. Rich, MD, PhD, Department of Anesthesiology, P.O Box 800710, University of Virginia Health System, Charlottesville, VA 22908-0710. Address e-mail to gfr2f{at}virginia.edu.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Lidocaine attenuates cell injury induced by ischemic-reperfusion and inflammation, although the protective mechanisms are not understood. We hypothesized that lidocaine and other amide local anesthetics protect against endothelial cell injury through activation of the mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels. We determined the effects of amide local anesthetics (lidocaine, ropivacaine, and bupivacaine), ester local anesthetics (tetracaine and procaine), one amide analog (YWI), and two non-amide local anesthetic analogs (JDA and ICM) on viability of human microvascular endothelial cells after exposure to lipopolysaccharide (LPS) in the absence or presence of the mitoKATP channel antagonist 5-hydroxydecaonate. Flavoprotein fluorescence was used to investigate the effects of local anesthetics on diazoxide-induced activation of mitoKATP channels. Lidocaine, ropivacaine, bupivicaine, YWI, JDA, and ICM attenuated by 60% to 70% the decrease in cell viability caused by LPS. Amide local anesthetics and YWI protection was inhibited by 5-hydroxydecaonate, whereas the protection induced by JDA and ICM was not. Tetracaine and procaine did not protect against LPS-induced injury. The amide local anesthetics and the amide analog (YWI) enhanced diazoxide-induced flavoprotein fluorescence by 5% to 20%, whereas ester local anesthetics decreased diazoxide-induced flavoprotein fluorescence by 5% to 60% and the non-amide local anesthetic analogs had no effect. In conclusion, amide local anesthetics and the amide analog (YWI) attenuate LPS-induced cell injury, in part, through activation of mitoKATP channels. In contrast, tetracaine and procaine had no protective effects and inhibited activation of mitoKATP channels. The non-amide local anesthetic analogs induced protection but through mechanisms independent of mitoKATP channels.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Regional anesthesia with local anesthetics has been reported by a meta-analysis study to decrease mortality by 33% after major surgery (1). Local anesthetics also decreased the incidence of postoperative complications, including deep vein thrombosis, pulmonary embolism, myocardial infarction, and renal failure (1). In addition, lidocaine has been reported to attenuate the ischemic-reperfusion (I/R) injury (2,3) and the I/R-induced inflammatory response (4,5). Because the endothelium plays a role in maintaining vascular tone and controlling permeability, protection of the endothelium during inflammatory injury is critically important. Mechanisms underlying the local anesthetic-induced protection against injury are not completely understood. Lidocaine has been demonstrated to enhance recovery of contractile cardiac function after I/R in isolated rat hearts. This recovery of cardiac function was correlated with a decrease in calcium and sodium overload (2). Lidocaine also improves biochemical stability and functional recovery of canine hearts after cardioplegia, which is associated with decreased calcium overload (6). Activation of mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels by diazoxide has been shown to decrease mitochondrial calcium overload, thereby protecting rabbit ventricular myocytes from I/R injury (7). Thus, regulation of calcium homeostasis by inducing the activation of mitoKATP channels may be a protective mechanism of local anesthetics.

Several studies have reported that volatile anesthetics enhance diazoxide-induced activation of myocardial mitoKATP channels (8,9). Conversely, lidocaine has been reported to inhibit activation of myocardial mitoKATP channels induced by diazoxide. However, the effects of local anesthetics in the absence or presence of diazoxide on activation of mitoKATP channels in endothelial cells have not been investigated. Our previous study showed that lidocaine, but not tetracaine, protected endothelial and vascular smooth muscle cells against cytokine-induced injury (10). The lidocaine-induced protection was abolished by the selective mitoKATP channel antagonist, 5-hydroxydecaonate (5-HD) (10). Therefore, we hypothesized that lidocaine and other amide local anesthetics, but not ester local anesthetics, exert their protective effects through opening of the mitoKATP channels in endothelial cells.

To test our hypothesis we compared the protective effects of the amide local anesthetics, lidocaine, bupivacaine, or ropivacaine, and the ester local anesthetics, tetracaine and procaine, against lipopolysaccharide (LPS)-induced injury by assessing cell viability in human endothelial cell culture. To investigate the role of mitoKATP channels in mediating the protective effects of local anesthetics, we evaluated cell viability after pretreatment with amide local anesthetics in the presence of 5-HD. These cell viability studies using a model of inflammation were performed in combination with flavoprotein fluorescence experiments in normal cells to evaluate the effects of amides and esters on diazoxide-induced activation of mitoKATP channels. Further, we evaluated one amide local anesthetic analog (YWI) and two non-amide local anesthetic analogs (JDA and ICM) to determine whether the amide linkage within the local anesthetic molecule facilitates the activation of mitoKATP channel and possibly leads to preservation of cell viability.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The human microvascular endothelial cells (HMEC) were grown in molecular cellular and developmental biology medium (MCDB 131, Gibco), supplemented with 29.2 mg/mL L-glutamine, 1 mg/mL hydrocortisone (Sigma, St Louis, MO), 10 mg/mL epidermal growth factor (BD Biosciences, Bedford, MA), and 15% fetal bovine serum. Confluent cell cultures of passages 7–12 were seeded with a density of 4 x 105/mL in 24-well plates and allowed to attach overnight. Stock solutions of the local anesthetics (Sigma) and analogs (gift from Dr. M. Patel at the University of Virginia) were made in dimethyl sulfoxide (Sigma) and phosphate-buffered saline (Gibco) and further diluted into the cell culture medium. The cells were pretreated for 30 min with amide local anesthetics (lidocaine, ropivacaine and bupivacaine, 0.01–1 mM), ester local anesthetics (tetracaine and procaine 0.01–1 mM), or analogs (YWI, JDA, ICM 10–100 µM), washed out with phosphate-buffered saline, and then incubated with fresh medium containing LPS (100 µg/mL) for 24 h. After LPS exposure, cell viability was determined with trypan blue exclusion. For control groups the cells were neither pretreated nor exposed to LPS. To determine whether mitoKATP channels mediate the effects on cell viability, the cells were also pretreated with amide local anesthetics or analogs in the presence of 5-HD (100 mM).

To evaluate whether amide local anesthetics activate mitoKATP channels we determined their effects on diazoxide-induced flavoprotein fluorescence. This method is based on the fact that the redox state of flavoproteins directly reflects the mitoKATP channels activity. Thus, activation of the mitoKATP channels can be demonstrated by monitoring the mitochondrial redox state as measured by autofluorescence of flavin adenine dinucleotide-linked enzymes in the mitochondria. The HMECs were grown on coverslips (2 cm2), which were placed in a cuvette containing 2 mL buffer solution (140 mM NaCl, 5 mM KCl, 1 mM MgCl2, 10 mM HEPES, and 2 mM CaCl2). Stock solutions of the used drugs were further diluted into this buffer to the final concentrations: for local anesthetics (0.01 mM, 0.10 mM, and 1 mM); for analogs (10, 50, and 100 µM); for diazoxide (0.01 mM, 0.1 mM, and 1 mM); for 5-HD (100 mM).

Excitation of flavoprotein was obtained from a Xenon arc lamp (every 5 s for 100 ms) and filtered at 480 nm. The emitted autofluorescence was passed through a 530-nm filter and recorded for 5 s on a computer (Felix Software; Photon Technology International, Canada). For each protocol flavoprotein fluorescence was measured during a stabilization period of 5 min (baseline) before adding diazoxide and/or local anesthetic/analog and recording flavoprotein fluorescence-induced by diazoxide and/or local anesthetic/analog.

Dinitrophenol (100 mM) an uncoupler of oxidative phosphorylation was used as a positive control for mitoKATP channel activation at the end of each protocol. Baseline values were subtracted from the local anesthetic-induced and dinitrophenol-induced flavoprotein fluorescence. The local anesthetic-induced flavoprotein fluorescence was compared with that induced by dinitrophenol and the results were expressed as percentage of dinitrophenol-induced flavoprotein fluorescence. The endothelial cells were exposed to diazoxide; diazoxide + local anesthetic/analog; local anesthetic or analog; 5-HD + local anesthetic/analog.

For the cell viability experiments (n = 8) the cell counting was performed in a blinded manner. For both the viability and the flavoprotein fluorescence experiments (n = 5) comparisons among the control, the different local anesthetic pretreatment groups, the diazoxide treated group (at each concentration), and the effects of mitoKATP were made with a two-way analysis of variance and the Student Newman-Keuls post hoc test. Statistical analysis was performed with SigmaStat 2.0 (Jandel Scientific Software, San Rafael, CA). Data are presented as the mean ± sd. A value of P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
In control experiments, in which cells were not exposed to local anesthetics, local anesthetic-analogs, or LPS, there was 90% viability after 24 h, as determined by trypan blue exclusion. None of the local anesthetics influenced cell viability in controls in the absence of LPS (data not shown). In cell cultures exposed to only LPS for 24 h, viability decreased by more than 80%. Lidocaine and ropivacaine attenuated the decrease in cell viability caused by LPS in a dose-dependent manner (Fig. 1). The response to bupivacaine was dose-dependent at the smaller concentrations, but the protective effects were not greater for 1 mM compared with 0.1 mM. Tetracaine and procaine did not prevent the decrease in cell viability caused by LPS. All three local anesthetic analogs had protective effects in a dose dependent manner (Fig. 2).


Figure 123
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  		Figure 1. The effects of local anesthetics on cell viability after exposure to lipopolysaccharide (LPS). Human microvascular endothelial cells were pretreated with amide local anesthetics (lidocaine, bupivacaine, or ropivacaine) in absence and presence of 5-hydroxydecanoate (5-HD) or ester local anesthetics (tetracaine and procaine) in absence of 5-HD. Control is cells not pretreated with analogs nor exposed to LPS. LPS only are non-pretreated cell cultures, exposed to LPS. *Denotes that all 3 amide local anesthetics significantly increase cell viability compared to LPS at the smaller (0.01 to 0.1 mM) concentrations in a dose-dependent manner. **Denotes that 1 mM lidocaine and ropivacaine increased cell viability compared with 0.1 mM. #Denotes that 5-HD attenuated the protective effects of lidocaine and ropivacaine. {Psi}Denotes that 5-HD significantly inhibited the increase in cell viability induced by all 3 amide local anesthetics. Data are mean ± sd. Significance is stated for P < 0.05.

 

Figure 223
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  		Figure 2. The effects of local anesthetic analogs on cell viability in absence and presence of 5-hydroxydecanoate (5-HD) in human microvascular endothelial cells. Control is for cells not pretreated with analogs nor exposed to lipopolysaccharide (LPS). LPS only are non-pretreated cell cultures, exposed to LPS. *Denotes that cell viability is significantly increased compared to LPS only for all three analogs in a dose dependent manner. #Denotes that 5-HD significantly decreased cell viability induced by YMI (amide analog). Data are mean ± sd. Significance is stated for P < 0.05.

 

To evaluate whether mitoKATP channels are involved in the local anesthetic protective mechanisms, the cells were pretreated with lidocaine, bupivacaine, or ropivacaine in the presence of 5-HD. In control cultures in the absence of LPS or local anesthetics, 5-HD had no effect on cell viability (data not shown). However, 5-HD significantly inhibited the increased cell viability caused by the amide local anesthetics (Fig. 1). 5-HD inhibited the protective effects of the amide-like analog (YWI) but not the protective effects induced by the non-analogs JDA and ICM (Fig. 2).

Control flavoprotein fluorescence measurements with dimethyl sulfoxide (<0.1%) had no effect on baseline measurements (data not shown). Diazoxide 0.01–1 mM added in the absence of local anesthetics or analogs induced flavoprotein fluorescence in a dose-dependent manner; 0.01 mM diazoxide induced 4% flavoprotein fluorescence, 0.1 mM diazoxide-induced 56% flavoprotein fluorescence and 1 mM induced 73% flavoprotein fluorescence (data not shown). The amide local anesthetics enhanced diazoxide-induced flavoprotein fluorescence (Fig. 3A). Lidocaine and ropivacine caused dose-dependent protection, whereas bupivacaine caused protection but the effects of 1.0 mM were no greater than 0.1 mM. In contrast, tetracaine and procaine significantly decreased diazoxide-induced flavoprotein fluorescence. YWI, the amide analog, increased diazoxide-induced flavoprotein fluorescence, but the two non-amide analogs had no significant effect on diazoxide-induced flavoprotein fluorescence (Fig. 3B).


Figure 323
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  		Figure 3. The effects of A) local anesthetics and B) local anesthetic-analogs on diazoxide-induced flavoprotein fluorescence. Flavoprotein fluorescence is expressed as percentage increase or decrease compared with flavoprotein fluorescence induced by diazoxide only. *Denotes that for each concentration of diazoxide, the flavoprotein fluorescence induced by the amide local anesthetics or analog is dose-dependently increased compared with flavoprotein fluorescence induced by diazoxide alone. #Denotes 1.0 mM is not more than 0.1 mM. **Denotes that the flavoprotein fluorescence is decreased equally compared to diazoxide alone. Data are mean ± sd. Significance is stated for P < 0.05.

 

To evaluate whether amide local anesthetics and the amide-analog (YWI) alone would activate mitoKATP channels, lidocaine, bupivacaine, ropivacaine, and YWI were administrated in the absence of diazoxide. Lidocaine and ropivacaine (0.01–1 mM) induced flavoprotein fluorescence in a dose-dependent manner, whereas there was no difference between the two larger concentrations (Fig. 4). 5-HD had no effect on control measurements (data not shown); however, 5-HD significantly decreased the flavoprotein fluorescence levels induced by all amide local anesthetics and YMI (Fig. 4).


Figure 423
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  		Figure 4. The effects of amide local anesthetics and analog on flavoprotein fluorescence, expressed as percentage of dinitrophenol-induced flavoprotein fluorescence. *Denotes that each local anesthetic/analog dose-dependently increased flavoprotein fluorescence. #Denotes that for each local anesthetic/analog, the effect on flavoprotein fluorescence was not more than the smaller concentration. +Denotes that for each concentration of local anesthetic, flavoprotein fluorescence was significantly decreased by 5-hydroxydecaonate (5-HD). Data are mean ± sd. Significance is stated for P < 0.05.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Based on our previous study, we hypothesized that lidocaine and other amide local anesthetics preserve cell viability during LPS-induced injury, in part through the activation of mitoKATP channels. To investigate the role of mitoKATP as a possible protective mechanism, we evaluated cell viability and the extent of flavoprotein fluorescence using amide and ester local anesthetics in addition to several newly designed analogs. This study showed that amide local anesthetics and the amide-analog (YWI) attenuated LPS-induced decrease in cell viability and that this protection was inhibited by 5-HD. Esters did not provide any protection against the LPS-induced decrease of cell viability. In addition, amide local anesthetics and the amide analog enhanced diazoxide-induced flavoprotein fluorescence and flavoprotein fluorescence in the absence of diazoxide, whereas ester local anesthetics decreased the diazoxide-induced flavoprotein fluorescence.

This study demonstrates that amide local anesthetics are protective against LPS-induced injury in cultured HMEC. These in vitro results are consistent with other studies showing that lidocaine is cardioprotective by decreasing infarct size using in vivo animal models (12,13) and decreasing human mortality (1). Our results show that the protection resulting from clinically relevant concentrations of ropivacaine and bupivacaine are comparable to that of lidocaine, suggesting that the protective effects of amide local anesthetics are not limited to lidocaine. On the other hand, tetracaine and procaine did not show any protection against the LPS-induced injury. This is consistent with our previous study demonstrating that tetracaine did not provide any protection against the cytokine-induced decrease in cell viability (10). Tetracaine (1.5 mM) has been reported to cause morphological changes in leukocytes, preventing leukocyte adhesion to the endothelium, which is a possible protective effect (14). Nevertheless, there are no other studies that have reported that ester local anesthetics provide protection against cell injury. Our results suggest that local anesthetic protection is limited to amides.

When 5-HD was administered with the amide local anesthetics and the amide analog (YWI), the preservation of cell viability was significantly decreased. These results are consistent with our previous lidocaine study and support evidence that the protective effects are, in part, mediated through activation of mitoKATP channels. The observation that esters have no protective effect and that the protective effects of amide local anesthetics are inhibited by 5-HD suggests the amide linkage might be necessary for activation of mitoKATP channels and preservation of cell viability. The protective effects of the amide analog (YWI) further support this hypothesis. However, the two non-amide analogs (JDA and ICM) have protective effects that were not altered by 5-HD, implicating the involvement of other mechanisms in preserving cell viability. The inhibition of G-coupled proteins may be one mechanism of local anesthetic-induced protection because most inflammatory mediators cause injury through activation of G-coupled protein receptors (15). Furthermore, in vivo another mechanism of local anesthetic-induced protection may involve the scavenging of oxygen radicals and reduction of neutrophil adhesion (16,17).

To investigate if local anesthetics influence mitoKATP channel activation, their effects on diazoxide-induced mitoKATP channel activation were evaluated using flavoprotein fluorescence. Our data show that lidocaine, ropivacaine, and bupivacaine increased diazoxide-induced flavoprotein fluorescence, whereas tetracaine and procaine decreased the diazoxide-induced flavoprotein fluorescence. In addition, the amide analog (YWI) increased diazoxide-induced flavoprotein fluorescence, whereas the two non-amide analogs did not alter flavoprotein fluorescence. These effects of amide local anesthetics and analog support evidence from our cell viability experiments that activation of mitoKATP channels plays a role in the mechanistic pathway leading to protection against injury. In contrast, the two non-amide analogs (JDA and ICM) and the esters did not increase flavoprotein fluorescence. This may imply that the amide intermediate structure within the local anesthetic or analog molecule is, in part, responsible for the activation of mitoKATP channels.

Our results are in contrast with findings by Tsutsumi et al. (18), who reported that lidocaine (0.1–10 mM) decreased diazoxide-induced mitochondrial oxidation in rat ventricular myocytes. Although volatile anesthetics have similar effects on mitoKATP channel activity in cardiomyocytes (8,9) and endothelial cells (unpublished data), it is possible that local anesthetics activate mitoKATP channels differently in rat myocytes versus HMEC. Our results indicating that amide local anesthetics increase mitoKATP channel activity are consistent with our results demonstrating that local anesthetic-induced protection is inhibited by 5-HD.

We also evaluated whether amide local anesthetics and analog (YWI) could induce mitoKATP activation in the absence of diazoxide. Lidocaine, ropivacaine, bupivacaine, and the amide analog enhanced flavoprotein fluorescence indicating that amide local anesthetics have the ability to independently activate mitoKATP channel. These effects were significantly inhibited by 5-HD, confirming that the increase in flavoprotein fluorescence was induced by the activation of mitoKATP channels. Notably, the increase in diazoxide-induced flavoprotein fluorescence is comparable to the extent to which the amide local anesthetics and analogs enhance flavoprotein fluorescence in the absence of diazoxide. This suggests that amide local anesthetics and diazoxide facilitate opening of mitoKATP channels through different mechanisms. Mechanisms of local anesthetic protection have been shown to be related to oxidative stress induced by a large concentration of reactive oxygen species (19,20).

The inhibitory effects of tetracaine and procaine on diazoxide-induced flavoprotein fluorescence support our findings that ester local anesthetics do not activate mitoKATP channels and do not provide protection against LPS-induced injury. In fact, it has been reported that preservation of mitochondrial bioenergetic function, which is critically important for protection against I/R or inflammatory injury, is a consequence of the mitoKATP channels activation (21). Studies showed that decreasing the activation of these channels may impair mitochondrial function and could even cause more extensive cellular injury (22–24).

Understanding the mechanisms through which local anesthetics provide protection against cell injury is essential to developing therapeutic strategies to control the inflammatory response and prevent postoperative complications. Although activation of the inflammatory system is crucial for structural and functional repair, an inappropriate and extensive inflammatory response in certain populations of patients may lead to increased mortality and morbidity (1). In this study, amide local anesthetics inhibited cell injury in cell culture using a model of inflammation. Although LPS is commonly used to induce inflammatory injury, we cannot exclude that LPS caused direct toxicity independent of inflammation. Furthermore, although we used clinically relevant concentrations of local anesthetics, we cannot confirm that cellular concentrations are similar as those used clinically or that our in vitro results may be altered in vivo by neutrophils or other inflammatory mediators.

In conclusion, this study indicates that lidocaine, ropivacaine, bupivacaine, and an amide analog attenuate LPS-induced cell injury in endothelial cells. The preservation of viability by amide local anesthetics and the amide analog appear to be, in part, mediated through activation of mitoKATP channels. Tetracaine and procaine had no protective effects and inhibited activation of mitoKATP channels. The non-amide analogs of local anesthetics facilitated protection through mechanisms that appear to be independent of mitoKATP channel activation.


   Footnotes
 
Supported, in part, by the Department of Anesthesiology, University of Virginia Health System.

Accepted for publication December 1, 2005.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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