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REGIONAL ANESTHESIA

Local Anesthetics Inhibit Thromboxane A₂ Signaling in Xenopus Oocytes and Human K562 Cells

Christian W. Hönemann, MD, Klaus Hahnenkamp, MD^*, Tobias Podranski^*, Danja Strumper, MD^*, Markus W. Hollmann, MD PhD, and Marcel E. Durieux, MD PhD

*Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, University Hospital, Münster; Department of Anesthesiology, St. Marienhospital, Vechta; Department of Anesthesiology, University of Heidelberg, Germany; and Department of Anesthesiology, University of Virginia, Charlottesville

Address correspondence to Marcel E. Durieux, MD, PhD, Department of Anesthesiology, University of Virginia, PO Box 800710, Charlottesville, VA 22908-0710. Address e-mail to durieux{at}virginia.edu

Thromboxane A₂ (TXA₂) has been proposed as a mediator of perioperative myocardial ischemia, vasoconstriction, and thrombosis. As these adverse events are minimized with epidural anesthesia, rather than general anesthesia, we hypothesized that local anesthetics would inhibit TXA₂-receptor signaling. We used fluorometric determination of intracellular [Ca²⁺] in human K562 cells and 2-electrode voltage clamp measurements in Xenopus laevis oocytes expressing TXA₂ receptors. After 10-min incubation, lidocaine (IC₅₀: 1.02 ± 0.2 x 10^–3 M), ropivacaine (IC₅₀: ropivacaine 6.3 ± 0.9 x 10^–5 M), or bupivacaine (IC₅₀: 1.42 ± 0.08 x 10^–7 M) inhibited TXA₂-induced [Ca²⁺]_i in K562 cells. These data were confirmed in Xenopus oocytes recombinantly expressing TXA₂ receptors, with IC₅₀s of bupivacaine 1.2 ± 0.2 x 10^–5 M, R(+) ropivacaine 4.9 ± 1.7 x 10^–4 M, S(-) ropivacaine 5.3 ± 0.9 x 10^–5 M, and lidocaine 6.4 ± 2.8 x 10^–4 M. Intracellular pathways activated by IP₃ and GTPS were not significantly affected by the local anesthetics tested. QX314, a positively charged lidocaine analog, inhibited only if injected intracellularly (IC₅₀: 5.3 ± 1.7 x 10^–4 M), indicating one local anesthetic target is most likely inside the cell. Benzocaine (largely uncharged) inhibited with an IC₅₀ of 8.7 ± 1.8 x 10^–4 M. This suggests that some of the beneficial effects of regional anesthesia techniques might be due to direct interaction of local anesthetics with the functioning of membrane proteins.

IMPLICATIONS: We demonstrated, using two different models, that thromboxane receptor functioning is inhibited by commonly used local anesthetics. One site of action seems to be inside the cell. This suggests that some of the beneficial effects of regional anesthesia techniques might be due to direct interaction of local anesthetics with the functioning of membrane proteins.

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