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Anesth Analg 2003;97:465-70
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Lidocaine Attenuates Cytokine-Induced Cell Injury in Endothelial and Vascular Smooth Muscle Cells

Manuela J. M. de Klaver, MD*, Mary-Gordon Buckingham*, and George F. Rich, MD PhD*,{dagger}

Departments of *Anesthesiology and {dagger}Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia

Address correspondence to George F. Rich, MD, PhD, Department of Anesthesiology, PO 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
 
Local anesthetics have been reported to attenuate the inflammatory response and ischemia/reperfusion injury. Therefore, we hypothesized that pretreatment with local anesthetics may protect endothelial and vascular smooth muscle (VSM) cells from cytokine-induced injury. Human microvascular endothelial cells and rat VSM cells were pretreated with lidocaine or tetracaine (5–100 µM for 30 min) and then exposed to the cytokines tumor necrosis factor-{alpha}, interferon-{gamma}, and interleukin-1ß for 72 h. Cell survival and integrity were evaluated by trypan blue exclusion and lactate dehydrogenase release. The role of adenosine triphosphate-sensitive potassium (KATP) channels, protein kinase C, or both in modulating local anesthetic-induced protection was evaluated with the mitochondrial KATP antagonist 5-hydroxydecanoate, the cell-surface KATP antagonist 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea (HMR-1098), and the protein kinase C inhibitor staurosporine. Lidocaine attenuated cytokine-induced cell injury in a dose-dependent manner. Lidocaine (5 µM) increased cell survival by approximately 10%, whereas lidocaine (100 µM) increased cell survival by approximately 60% and induced a threefold decrease in lactate dehydrogenase release in both cell types. In contrast, tetracaine did not attenuate cytokine-induced cell injury. 5-hydroxydecanoate abolished the protective effects of lidocaine, but staurosporine and HMR-1098 had no effect on the lidocaine-induced protection. This study showed that lidocaine, but not tetracaine, attenuates cytokine-induced injury in endothelial and VSM cells. Lidocaine-induced protection appears to be modulated by mitochondrial KATP channels.

IMPLICATIONS: This study demonstrates that lidocaine attenuates cytokine-induced injury of endothelial and vascular smooth muscle cells via mechanisms involving adenosine triphosphate-sensitive potassium channels. Protection of the vasculature from cytokine-induced inflammation may preserve important physiological endothelial and vascular smooth muscle functions.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Reperfusion injury and systemic inflammation are associated with cytokine release and may result in cellular and organ damage (1,2). Local anesthetics have been reported to attenuate the inflammatory response during reperfusion injury in porcine myocardium (3). Furthermore, lidocaine inhibits the release of superoxide anions by human neutrophils in vitro (4) and decreases the release of interleukin (IL)-1ß from human mononuclear cells (5), which may protect cells from inflammation. These studies suggest that local anesthetics could potentially be protective of the cardiovascular system during inflammation.

We recently showed that isoflurane and halothane protect endothelial and vascular smooth muscle (VSM) cells against cytokine- and hydrogen peroxide-induced cell injury (6). Similarly, we demonstrated that isoflurane pretreatment attenuates the detrimental changes in endothelial function and pathology associated with lipopolysaccharide-induced inflammation in rats (7). Volatile anesthetics may also mimic ischemic myocardial preconditioning, as reported by several in vivo studies (8,9). Mitochondrial and sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels (10–12) and protein kinase C (PKC) (13) are thought to modulate the cardioprotection triggered by volatile anesthetics. We reported that PKC and KATP channels also appear to modulate the protective effect of volatile anesthetics in endothelial and smooth muscle cells against cytokine-induced cell death (6).

Volatile and local anesthetics appear to attenuate inflammation; however, the effect of local anesthetics on cytokine-induced cell injury remains unexplored. Furthermore, it is unknown whether the mechanisms by which local anesthetics decrease the effects of inflammation in endothelial and VSM cells are similar to the mechanisms associated with volatile anesthetic preconditioning. We hypothesized that local anesthetics would attenuate cytokine-induced cell injury in endothelial and VSM cells via mechanisms involving PKC, KATP channels, or both. To test this hypothesis, we evaluated the effects of lidocaine (amino-amide) and tetracaine (amino-ester) on cytokine-induced cell injury and the role of PKC and mitochondrial and cell-surface KATP channels in human microvascular endothelial cells (HMEC) and rat VSM cells.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The HMEC and rat VSM cells were gifts from L. Palmer and T. Obrig at the University of Virginia. Rat VSM cells were grown in Dulbecco’s minimal essential medium (HAM’s F12; Gibco, Rockville, MD) supplemented with 20% fetal bovine serum (Gibco). HMECs were grown in molecular cellular and developmental biology medium (131; Gibco) supplemented with 29.2 mg/mL of L-glutamine, 1 µg/mL of hydrocortisone (Sigma, St. Louis, MO), 10 µg/mL of 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 lidocaine and tetracaine (Sigma) were made in dimethyl sulfoxide (Sigma) and phosphate-buffered saline (PBS; Gibco) and further diluted into the medium.

The cells were pretreated with lidocaine or tetracaine (5–100 µM) for 30 min, followed by a washout with PBS. The cytokines (R&D Systems, Minneapolis, MN) were dissolved into PBS and further diluted into the medium at the following concentrations: 0.1 ng/mL of tumor necrosis factor-{alpha}, 5.0 ng/mL of interferon-{gamma}, and 5.0 ng/mL of IL-1ß. After the local anesthetic pretreatment and washout, the cells were exposed to cytokines for 72 h. For the control group, the cells were neither pretreated nor exposed to cytokines but were exposed to fresh medium for 72 h. Cells in the cytokine-only group were not pretreated with local anesthetics (Fig. 1).



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  		Figure 1. Protocols for (A) local anesthetic (LA) pretreatment and (B) lidocaine pretreatment in the absence or presence of 5-hydroxydecanoate (100 µM), 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea (100 µM), or staurosporine (5 nM) to determine the role of mitochondrial adenosine triphosphate-sensitive (KATP) channels, cell-surface KATP channels, and protein kinase C (PKC), respectively. LDH = lactate dehydrogenase.

 
Cell survival and integrity were evaluated after cytokine exposure. Dead cells are incapable of excluding trypan blue; therefore, the uptake of this dye was used as a marker of cell death. Trypan blue 10 µL (Sigma) was mixed with 50 µL of cell suspension. For each sample, at least 100 cells per field were counted with a hemocytometer under a light microscope. Cell survival was calculated as the number of total cells minus the number of dead cells and was expressed as percentage of the total number of cells per field.

Cell integrity was evaluated by measuring the release of lactate dehydrogenase (LDH) in the medium resulting from a disrupted cell plasma membrane. The LDH assay, performed according to the protocol provided by the vendor (Sigma), is based on the reduction of nicotinamide adenine dinucleotide (NAD) by the action of LDH. The resulting reduced form of NAD is used in the stoichiometric conversion of a tetrazolium dye. The absorbance was measured spectrophotometrically at 490 nm, and the background absorbance of the plates was measured at 690 nm. The resulting difference correlates with the extent of LDH release.

To evaluate whether PKC and/or KATP channels modulate the effects of local anesthetics, we examined the effects of the nonspecific PKC antagonist staurosporine (5 nM), the selective mitochondrial KATP inhibitor 5-hydroxydecanoate (5-HD; 100 µM), and the cell-surface KATP inhibitor 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea (HMR-1098).

Cell counting was performed in a blinded manner. Comparisons among the control group, the cytokine-only group, the groups pretreated with various concentrations of local anesthetics, and the effects of 5-HD, HMR-1098, and staurosporine were made with one-way analysis of variance and a Student-Newman-Keuls post hoc test. Statistical analysis was performed with SigmaStat 2.0 (Jandel Scientific Software, San Rafael, CA). Data (n = 6 for each group) are presented as the mean ± SD. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The objective of the first experiment was to evaluate the dose-response effects of lidocaine and tetracaine on cytokine-induced cell injury. Control cultures not exposed to local anesthetics or cytokines had <10% cell death, whereas cells in cultures exposed only to cytokines for 72 h had >80% cell death. Neither lidocaine nor tetracaine (100 µM) influenced cell survival or LDH release in controls not exposed to cytokines (data not shown). Figure 2 demonstrates that lidocaine attenuated cell death (Fig. 2A) and LDH release (Fig. 2B) in a dose-dependent manner. Lidocaine (5 µM) decreased cell death in both cell types and decreased LDH release in HMEC. The cell protection was significantly more at 10 µM, whereas 50 µM decreased cell death and LDH release significantly more than 10 µM. In rat VSM cells, 100 µM lidocaine had a greater protective effect compared with 50 µM, whereas in HMEC, survival and LDH release were equally decreased at 50 and 100 µM. In contrast to the protective effects of lidocaine, tetracaine did not have any significant effect on cell survival or LDH release at any concentration.



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  		Figure 2. The local anesthetic (LA) effects of lidocaine and tetracaine on cell survival (A) and lactate dehydrogenase (LDH) release (B) in human microvascular endothelial cells (HMEC) and rat vascular smooth muscle (RVSM) cells. *Cell death and LDH release after pretreatment with 5 µM LA were significantly attenuated compared with no pretreatment. #Cell death and LDH release after pretreatment with 10 µM LA were significantly attenuated compared with pretreatment with 5 µM local anesthetic. {psi}Cell death and LDH release after pretreatment with 50 µM LA were significantly attenuated compared with pretreatment with 10 µM LA. @Cell death and LDH release after pretreatment with 100 µM local anesthetic were significantly attenuated compared with pretreatment with 50 µM local anesthetic. Data are mean ± SD (n = 6). Significance was considered as P < 0.05.

 
We evaluated the effects of staurosporine, 5-HD (100 µM), and HMR-1098 (100 µM) on the lidocaine-induced protection to determine whether PKC and/or KATP channels modulate the protective effects of lidocaine. 5-HD, HMR-1098, and staurosporine had no effect on cell survival and LDH release in cell cultures not pretreated with lidocaine or exposed to cytokines (data not shown) or cell cultures exposed to only cytokines (0 µM lidocaine). 5-HD abolished the lidocaine-induced increase in cell survival and decrease in LDH release at all concentrations of lidocaine in HMEC (Fig. 3) and rat VSM cells (Fig. 4). In contrast, HMR-1098 and staurosporine did not inhibit the lidocaine-induced decrease in cell death and LDH release at any lidocaine concentration in either cell type.



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  		Figure 3. Cell survival (A) and lactate dehydrogenase (LDH) release (B) in human microvascular endothelial cells (HMEC) after lidocaine pretreatment in the presence or absence of 5-hydroxydecanoate (5-HD;100 µM), 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea (HMR-1098; 100 µM), or staurosporine (5 nM). *5-HD significantly decreased cell survival or significantly increased LDH release compared with lidocaine alone. Data are mean ± SD (n = 6). Significance was considered as P < 0.05.

 


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  		Figure 4. Cell survival (A) and lactate dehydrogenase (LDH) release (B) in rat vascular smooth muscle (RVSM) cells after lidocaine pretreatment in the presence or absence of 5-hydroxydecanoate (5-HD; 100 µM), 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea (HMR-1098; 100 µM), or staurosporine (5 nM). *5-HD significantly decreased cell survival or significantly increased LDH release compared with lidocaine alone. Data are mean ± SD (n = 6). Significance was considered as P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We previously showed that isoflurane and halothane are protective against cytokine- and hydrogen peroxide-induced cell injury (6). Other studies have reported protective effects of local anesthetics from inflammatory injury (3–5), and we therefore hypothesized that local anesthetics would protect against cytokine-induced injury in HMEC and rat VSM cells. This study demonstrates that lidocaine dose-dependently decreased cytokine-induced cell injury via mechanisms involving KATP channels.

Our results demonstrating that lidocaine attenuated cell death and LDH release in a model of cytokine-induced cell injury are consistent with previous studies reporting the protective effects of lidocaine. The neutrophil superoxide anion release was decreased in myocardial infarct patients who received prolonged (>12 hours) lidocaine infusion compared with patients who did not receive lidocaine treatment. The same study also showed in vitro that incubation of human (phorbol myristate acetate-stimulated) neutrophils with lidocaine (1–10 mg/mL) for 60 minutes dose-dependently decreased the superoxide anion release (4). In an in vitro cell culture model, the IL-1ß release was attenuated by lidocaine (0.05%–0.5%) and bupivacaine (0.00125%–0.125%) incubated for 24 hours with lipopolysaccharide-stimulated human leukocytes (5). In addition, lidocaine (plasma level, 1.16 µg/mL) administered locally before three hours of reperfusion decreased the myocardial infarct size by approximately 20% in an in vivo porcine model (3).

Tetracaine did not have any effect on cytokine-induced cell injury. There has been very little investigation into the antiinflammatory effects of ester local anesthetics; however, in vitro incubation of leukocytes with tetracaine (0.25–1.0 mM) for 15 minutes during stimulation with zymosan has been reported to significantly decrease (by 37%) superoxide anion release (14). Although our study suggests that there may be differences in antiinflammatory effects between amino-amides and amino-esters, further studies may be necessary to determine whether these differences are apparent in other models of inflammation and what specific mechanisms may explain the different antiinflammatory effects.

We evaluated the role of mitochondrial KATP channels because these channels appear to modulate volatile anesthetic-induced cellular protection and cardioprotection, as has been shown by several other studies (10,15). The opening of the mitochondrial KATP channels by the selective agonist diazoxide mimics anesthetic and ischemic preconditioning (16). The selective mitochondrial KATP inhibitor 5-HD blocked or attenuated the lidocaine-induced decrease in injury of endothelial and VSM cells, suggesting a modulating role of these channels in lidocaine-induced protection. The precise mechanism by which the opening of the mitochondrial KATP channels mediates protective effects remains unclear. Opening of mitochondrial KATP channels has been suggested to result in membrane depolarization, matrix swelling, slowing of ATP synthesis, accelerated respiration, and reduced calcium overload (17). It has also been hypothesized that the opening of mitochondrial KATP channels may maintain the tight apposition of the inner and outer membranes of the mitochondria, thereby preserving the structure and function of the mitochondria (18). In addition, activation of mitochondrial KATP channels may have antiapoptotic effects by inhibiting cytochrome c release and the loss of mitochondrial membrane potential (19), both of which are early events in the cell death cascade (20). Our results suggest that lidocaine may preserve or increase KATP activity as a mechanism of cellular protection, which is in contradiction to a study indicating that lidocaine (10 µM to 10 mM) inhibits diazoxide-induced (25 µM) mitochondrial KATP channel activation in rat myocytes (21). This discrepancy might be due to the different investigational models or cell types.

HMR-1098 did not inhibit the decrease in cell death and decrease in LDH release associated with lidocaine, suggesting that the cell-surface KATP channels may not be involved in modulating the protective effects of lidocaine. This result is consistent with our data that show that the protective effects of isoflurane are not blocked by HMR-1098 (unpublished data) and with in vitro and in vivo studies demonstrating that anesthetic and ischemic preconditioning of the myocardium are unaffected by inhibition of the sarcolemmal KATP channels (12,22,23).

A nonspecific PKC antagonist, staurosporine, did not inhibit the lidocaine-induced protection in either cell line. This result is in contrast with our previous study that showed that staurosporine (4 nM) blocked the isoflurane-induced increase in cell survival (6) and with a study that showed that isoflurane blocks ischemia/reperfusion-induced apoptosis via PKC in myocytes (24). Another study investigating the inhibitory effects of local anesthetics on human polymorphonuclear neutrophil functions in vitro showed that PKC is involved in the pathway of local anesthetic-induced inhibitory effects but that the target site for local anesthetics is located upstream of PKC (25). Our results cannot exclude a role for PKC in the lidocaine-induced protective pathways in endothelial and VSM cells. It might be possible that PKC is involved but that it is not a direct target for lidocaine or that other mediators that play a more prominent role in mediating the protective effects are activated by lidocaine.

The concentration of lidocaine at which cell survival is maximally increased is 50 µM (corresponding with 12.5 µg/mL plasma levels) in rat VSM cells and 100 µM (25 µg/mL) in HMEC. These concentrations are in a similar range as the plasma levels (1.0–5.6 µg/mL, corresponding to 4–23 µM) at which lidocaine decreases free-radical production by neutrophils (4) and are less than the concentrations at which lidocaine inhibits IL-1ß release (0.2–20 mM, corresponding to 50 µg/mL to 5 mg/mL) (5). Clinically, the smaller concentrations of lidocaine that induced protection in our study (5–10 µM, corresponding to 1.2–2.5 µg/mL) are similar to plasma concentrations present after epidural infusion (2.0 ± 0.4 µg/mL) and IV administration (1.9 ± 0.8 µg/mL) (26).

Protection of the endothelium and VSM may have significant clinical implications and important physiological consequences. The endothelium produces modulators responsible for vasodilation, provides an antithrombogenic surface, and also plays an important role in the regulation of adhesion and migration of leukocytes (27). Protection of the endothelium may be important not only during ischemia/reperfusion injury, but also during the systemic inflammatory response associated with cardiopulmonary bypass and during other vascular diseases involving inflammation (1).

In conclusion, this study showed that lidocaine, but not tetracaine, attenuates cytokine-induced injury in endothelial and VSM cells. The antiinflammatory effect of lidocaine appears to be modulated by mitochondrial KATP channels.


   Acknowledgments
 
Funded by the Department of Anesthesiology, University of Virginia Health System.

We would like to thank Tom G. Obrig, PhD, Professor of Internal Medicine and Immunology, University of Virginia Health System, and Lisa A. Palmer, PhD, Associate Professor of Anesthesiology, for their gift of cells and their help. We also would like to thank Professor H. Gögelein, Aventis Pharma Deutschland GmbH, Germany, for providing HMR-1098.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 3, 2003.




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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