Lidocaine attenuates cytokine-induced cell injury in endothelial and vascular smooth muscle cells.
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 microM for 30 min) and then exposed to the cytokines tumor necrosis factor-alpha, interferon-gamma, and interleukin-1beta 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 microM) increased cell survival by approximately 10%, whereas lidocaine (100 microM) 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.


CONCLUSIONS
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.
de Klaver
Manuela J M
MJM
Departments of *Anesthesiology and †Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia.
Buckingham
Mary-Gordon
MG
Rich
George F
GF
D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006880:Hydroxy Acids / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008012:Lidocaine / Q000494:pharmacology*; D008565:Membrane Proteins; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D013748:Tetracaine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000779:Anesthetics, Local; D001549:Benzamides; D016207:Cytokines; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D007375:Interleukin-1; D008565:Membrane Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014409:Tumor Necrosis Factor-alpha; C117780:mitochondrial K(ATP) channel; D013748:Tetracaine; C052853:5-hydroxydecanoic acid; D007371:Interferon-gamma; D008012:Lidocaine; C410297:HMR 1098; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C; D019311:Staurosporine