Lidocaine Increases Intracellular Sodium Concentration Through a Na+-H+ Exchanger in an Identified Lymnaea Neuron

BACKGROUND:The intracellular sodium concentration ([Na+]in) is related to neuron excitability. For [Na+]in, a Na+-H+ exchanger plays an important role, which is affected by intracellular pH ([pH]in). However, the effect of lidocaine on [pH]in and a Na+-H+ exchanger is unclear. We used neuron from Lymnaea stagnalis to determine how lidocaine affects [pH]in, Na+-H+ exchanger, and [Na+]in. METHODS:Intracellular sodium imaging by sodium-binding benzofuran isophthalate and intracellular pH imaging by 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein were used to measure [Na+]in and [pH]in. Measurements for [Na+]in were made in normal, Na+ free saline, with modified extracellular pH, and a Na+-H+ exchanger antagonist [(5-N-ethyl-N-isopropyl amiloride, N-methylisopropylamiloride, and 5-(N,N-hexamethylene)-amiloride) pretreatment trials. Furthermore, [Na+]in and [pH]in were recorded simultaneously. From 0.1 to 10 mM, lidocaine, mepivacaine, bupivacaine, prilocaine, and QX-314 were evaluated. RESULTS:Lidocaine, mepivacaine, and prilocaine increased the [Na+]in in a dose-dependent manner. In contrast, QX-314 did not change the [Na+]in at each dose. In the Na+ free saline or in the presence of each Na+-H+ exchanger antagonist, lidocaine failed to increase [Na+]in. Lidocaine, mepivacaine, and prilocaine induced a significant decrease in [pH]in below baseline with an increase in [Na+]in. In contrast, QX-314 did not change the [pH]in. These results demonstrated that lidocaine increases [Na+]in through Na+-H+ exchanger activated by intracellular acidification, which is induced by the proton trapping of lidocaine. This [Na+]in increase and [pH]in change induces cell toxicity. CONCLUSION:Lidocaine increases the [Na+] through a Na+-H+ exchanger by proton trapping.