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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^*,

Departments of *Anesthesiology and 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

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-, interferon-, 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.

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