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ANESTHETIC PHARMACOLOGY

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

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.

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 (mitoK_ATP) 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 mitoK_ATP channel antagonist 5-hydroxydecaonate. Flavoprotein fluorescence was used to investigate the effects of local anesthetics on diazoxide-induced activation of mitoK_ATP 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 mitoK_ATP channels. In contrast, tetracaine and procaine had no protective effects and inhibited activation of mitoK_ATP channels. The non-amide local anesthetic analogs induced protection but through mechanisms independent of mitoK_ATP channels.

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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