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Bupivacaine inhibits endothelin-1-evoked increases in intracellular calcium in model sensory neurons
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2015 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 59, no 7, 936-945 p.Article in journal (Refereed) Published
Abstract [en]

BackgroundEndothelin-1 (ET-1) induces pain-like behavior in animals and man by activating the G(q) protein-coupled receptor endothelin-A (ETA). Activation of ETA receptors on nociceptor membranes evokes intracellular calcium transients and alters membrane Na+ and K+ channel and TRPV1 currents, leading to neuronal hyper-excitability manifested by spontaneous and evoked pain behaviors in vivo. In addition to blocking sodium channels, local anesthetics inhibit the G(q) protein-coupled signaling of several inflammatory and pro-algesic mediators. In this study, we aimed to investigate the actions of local anesthetics on ETA-mediated increases in intracellular calcium in ND7/104 model sensory neurons. MethodsIncreases in intracellular calcium were measured by the fluorescent indicator fura-2 in a sensory neuron-derived cell line (ND7/104), which endogenously expresses ETA receptors. Effects of lidocaine and bupivacaine, along with their respective membrane-impermeant derivatives QX-314, LEA-123 and LEA-124, on peak calcium responses to ET-1 were measured. ResultsBupivacaine suppressed ET-1 responses in a concentration-dependent and non-competitive manner with an IC50 of 3.791.63mM. Bupivacaine (6mM) reduced the E-max for ET-1 from 50.07 +/- 1.91mM to 27.30 +/- 2.92mM. The actions of bupivacaine occurred quickly and were rapidly reversible. Membrane-impermeant analogs of bupivacaine (LEA-123 and LEA-124, 6mM) were without effect, as was lidocaine (10mM) and its quaternary derivative QX-314 (10mM). ConclusionBupivacaine inhibits ETA-mediated calcium transients at clinically relevant concentrations through an intracellular target. The anti-inflammatory and analgesic actions of bupivacaine may be at least partially due to its inhibitory action on G(q)-coupled receptors, including ETA.

Place, publisher, year, edition, pages
2015. Vol. 59, no 7, 936-945 p.
National Category
Pharmaceutical Sciences Anesthesiology and Intensive Care
URN: urn:nbn:se:uu:diva-260268DOI: 10.1111/aas.12481ISI: 000357969800013PubMedID: 25684033OAI: oai:DiVA.org:uu-260268DiVA: diva2:847866
Available from: 2015-08-21 Created: 2015-08-18 Last updated: 2015-08-21Bibliographically approved

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