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

Klaver, Manuela J. M. de; Weingart, Gregory S.; Obrig, Tom G.; Rich, George F.

doi:10.1213/01.ane.0000200310.39031.1f

Cited by 26 publications

(19 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…32,33 However, these studies primarily focused on the inhibition of effects of prolonged (>24 h) cytokine exposure and used concentrations of local anesthetics up to 100,000 times higher than that used in the current study 32,33 although still much lower than concentrations required to achieve effective blockade of voltage-gated sodium channels (IC 50 of 50 to 100 μM). 34,35 Interestingly, in an earlier study, we observed that inhibition of TNFα-induced Src activation by local anesthetics occurs independently of sodium channel blockade.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Barrier Protection by Local Anesthetics

et al. 2014

View full text Add to dashboard Cite

Background Pulmonary endothelial barrier dysfunction mediated in part by Src-kinase activation plays a crucial role in acute inflammatory disease. Proinflammatory cytokines, such as tumor necrosis factor-α (TNFα), activate Src via phosphatidylinositide 3-kinase/Akt-dependent nitric oxide generation, a process initiated by recruitment of phosphatidylinositide 3-kinase regulatory subunit p85 to TNF-receptor-1. Because amide-linked local anesthetics have well-established anti-inflammatory effects, the authors hypothesized that ropivacaine and lidocaine attenuate inflammatory Src signaling by disrupting the phosphatidylinositide 3-kinase–Akt–nitric oxide pathway, thus blocking Src-dependent neutrophil adhesion and endothelial hyperpermeability. Methods Human lung microvascular endothelial cells, incubated with TNFα in the absence or presence of clinically relevant concentrations of ropivacaine and lidocaine, were analyzed by Western blot, probing for phosphorylated/activated Src, endothelial nitric oxide synthase, Akt, intercellular adhesion molecule-1, and caveolin-1. The effect of ropivacaine on TNFα-induced nitric oxide generation, co-immunoprecipitation of TNF-receptor-1 with p85, neutrophil adhesion, and endothelial barrier disruption were assessed. Results Ropivacaine and lidocaine attenuated TNFα-induced Src activation (half-maximal inhibitory concentration [IC50] = 8.611 × 10−10 M for ropivacaine; IC50 = 5.864 × 10−10 M for lidocaine) and endothelial nitric oxide synthase phosphorylation (IC50 = 7.572 × 10−10 M for ropivacaine; IC50 = 6.377 × 10−10 M for lidocaine). Akt activation (n = 7; P = 0.006) and stimulus-dependent binding of TNF-receptor-1 and p85 (n = 6; P = 0.043) were blocked by 1 nM of ropivacaine. TNFα-induced neutrophil adhesion and disruption of endothelial monolayers via Src-dependent intercellular adhesion molecule-1- and caveolin-1-phosphorylation, respectively, were also attenuated. Conclusions Ropivacaine and lidocaine effectively blocked inflammatory TNFα signaling in endothelial cells by attenuating p85 recruitment to TNF-receptor-1. The resultant decrease in Akt, endothelial nitric oxide synthase, and Src phosphorylation reduced neutrophil adhesion and endothelial hyperpermeability. This novel anti-inflammatory “side-effect” of ropivacaine and lidocaine may provide therapeutic benefit in acute inflammatory disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Endothelial Barrier Protection by Local Anesthetics

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The postoperative analgesia associated with lidocaine's intraoperative administration compliments this action (12)(13)(14)(15)(16). Further advantages to the clinical intraoperative use of lidocaine include the protection of vital tissues, such as the brain, against periods of hypoxia (20), perhaps by activation of mitochondrial potassium ATP channels (21).…”

Section: Discussionmentioning

confidence: 99%

Lidocaine, MK-801, and MAC

Zhang

Laster²,

Eger³

et al. 2007

Anesthesia &Amp; Analgesia

View full text Add to dashboard Cite

show abstract

“…In addition, they have also been demonstrated to exhibit significant anti-inflammatory properties [9-11]. In an earlier study of bacterial endotoxin-induced lung injury, it was shown that administration of the long-acting amide-linked local anesthetic ropivacaine attenuated endothelial cell NFκB activation and inflammatory lung injury in vivo and lung epithelial cell activation in vitro [9].…”

Section: Introductionmentioning

confidence: 99%

Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling

Piegeler

Dull

et al. 2014

BMC Anesthesiol

View full text Add to dashboard Cite

BackgroundAcute lung injury (ALI) is associated with high mortality due to the lack of effective therapeutic strategies. Mechanical ventilation itself can cause ventilator-induced lung injury. Pulmonary vascular barrier function, regulated in part by Src kinase-dependent phosphorylation of caveolin-1 and intercellular adhesion molecule-1 (ICAM-1), plays a crucial role in the development of protein-/neutrophil-rich pulmonary edema, the hallmark of ALI. Amide-linked local anesthetics, such as ropivacaine, have anti-inflammatory properties in experimental ALI. We hypothesized ropivacaine may attenuate inflammation in a “double-hit” model of ALI triggered by bacterial endotoxin plus hyperinflation via inhibition of Src-dependent signaling.MethodsC57BL/6 (WT) and ICAM-1 −/− mice were exposed to either nebulized normal saline (NS) or lipopolysaccharide (LPS, 10 mg) for 1 hour. An intravenous bolus of 0.33 mg/kg ropivacaine or vehicle was followed by mechanical ventilation with normal (7 ml/kg, NTV) or high tidal volume (28 ml/kg, HTV) for 2 hours. Measures of ALI (excess lung water (ELW), extravascular plasma equivalents, permeability index, myeloperoxidase activity) were assessed and lungs were homogenized for Western blot analysis of phosphorylated and total Src, ICAM-1 and caveolin-1. Additional experiments evaluated effects of ropivacaine on LPS-induced phosphorylation/expression of Src, ICAM-1 and caveolin-1 in human lung microvascular endothelial cells (HLMVEC).ResultsWT mice treated with LPS alone showed a 49% increase in ELW compared to control animals (p = 0.001), which was attenuated by ropivacaine (p = 0.001). HTV ventilation alone increased measures of ALI even more than LPS, an effect which was not altered by ropivacaine. LPS plus hyperinflation (“double-hit”) increased all ALI parameters (ELW, EVPE, permeability index, MPO activity) by 3–4 fold compared to control, which were again decreased by ropivacaine. Western blot analyses of lung homogenates as well as HLMVEC treated in culture with LPS alone showed a reduction in Src activation/expression, as well as ICAM-1 expression and caveolin-1 phosphorylation. In ICAM-1 −/− mice, neither addition of LPS to HTV ventilation alone nor ropivacaine had an effect on the development of ALI.ConclusionsRopivacaine may be a promising therapeutic agent for treating the cause of pulmonary edema by blocking inflammatory Src signaling, ICAM-1 expression, leukocyte infiltration, and vascular hyperpermeability.

show abstract

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

Cited by 26 publications

References 22 publications

Endothelial Barrier Protection by Local Anesthetics

Endothelial Barrier Protection by Local Anesthetics

Lidocaine, MK-801, and MAC

Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling

Contact Info

Product

Resources

About