Local anesthetics are known to inhibit the voltage-dependent sodium channels. The present study reports an inhibitory effect of the local anesthetics on the carbachol (CCh)-induced Ca²⁺ responses in HSY, human salivary ductal cell line. Lidocaine (150 μM =~0.0035%) suppressed the CCh (50 µM)-induced increase in the intracellular Ca²⁺ concentration ([Ca²⁺]i). Similar inhibitory effects on the CCh-induced Ca²⁺ responses were observed with propitocaine, mepibacaine, procaine, and a cell-impermeable analogue of lidocaine QX314 (QX).  EC50 values of lidocaine, procaine, and QX on reducing CCh-induced Ca²⁺ responses were 123.9 μM, 20.4 μM, 36.4 μM, respectively. QX also reduced CCh-induced Ca²⁺ responses in the absence of extracellular Ca²⁺, indicating the reduction of Ca²⁺ release from intracellular stores. On the other hand, QX had no effect on the rise in [Ca²⁺]i by SERCA inhibitor, thapsigargin, had a very weak inhibitory effect on ATP-induced Ca²⁺response. These results suggest that QX and local anesthetics have a relatively specific inhibitory effect on muscarinic receptors. We also found that procaine and QX had strong inhibitory effects on the muscarinic receptor-mediated recruitment of beta-arrestin. The results suggest a possibility that local anesthetics and their derivatives may act as allosteric modulators for certain G protein coupled receptors.