Bupivacaine inhibits endothelin‐1‐evoked increases in intracellular calcium in model sensory neurons. Issue 7 (15th February 2015)

• Record Type: Journal Article
• Authors: Makdessi, M. J.; Barr, T. P.; Xue, W.; Strichartz, G. R.
• Is Part Of: Acta anaesthesiologica scandinavica. Volume 59:Issue 7(2015:Aug.)
• Page Start: 936
• Page End: 945
• Publication Date: 2015-02-15
• Subjects: Anesthesiology -- Periodicals; Critical care medicine -- Periodicals; 617.9605
• DOI: 10.1111/aas.12481
• Languages: English
• ISSNs: 0001-5172

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="aas12481-sec-0001" sec-type="section"> <title>Background</title> <p>Endothelin‐1 (ET‐1) induces pain‐like behavior in animals and man by activating the G<sub>q</sub> protein‐coupled receptor endothelin‐A (ET<sub>A</sub>). Activation of ET<sub>A</sub> receptors on nociceptor membranes evokes intracellular calcium transients and alters membrane Na<sup>+</sup> and K<sup>+</sup> 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<sub>q</sub> protein‐coupled signaling of several inflammatory and pro‐algesic mediators. In this study, we aimed to investigate the actions of local anesthetics on ET<sub>A</sub>‐mediated increases in intracellular calcium in ND7/104 model sensory neurons.</p> </sec> <sec id="aas12481-sec-0002" sec-type="section"> <title>Methods</title> <p>Increases in intracellular calcium were measured by the fluorescent indicator fura‐2 in a sensory neuron‐derived cell line (ND7/104), which endogenously expresses ET<sub>A</sub> 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.</p> </sec> <sec id="aas12481-sec-0003" sec-type="section"> <title>Results</title> <p>Bupivacaine suppressed ET‐1 responses in a concentration‐dependent and non‐competitive manner with an IC<sub>50</sub> of 3.79 ± 1.63 mM. Bupivacaine (6 mM) reduced the E<sub>max</sub> for ET‐1 from 50.07 ± 1.91 mM to 27.30 ± 2.92 mM. The actions of bupivacaine occurred quickly and were rapidly reversible. Membrane‐impermeant analogs of bupivacaine (LEA‐123 and LEA‐124, 6 mM) were without effect, as was lidocaine (10 mM) and its quaternary derivative QX‐314 (10 mM).</p> </sec> <sec id="aas12481-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Bupivacaine inhibits ET<sub>A</sub>‐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<sub>q</sub>‐coupled receptors, including ETA.</p> </sec> </abstract>