Local Anesthetics Inhibit the G Protein-Mediated Modulation of K+ and Ca++ Currents in Anterior Pituitary Cells

The effects of local anesthetics (LAs) on G protein-mediated responses of voltage-dependent K + ( I K ) and Ca ++ currents in rat anterior pituitary tumor (GH 3 ) cells were analyzed by using a whole-cell voltage clamp. Extracellular lidocaine inhibited I K with an IC 50 of 1.9 mM, comparable to 2.6 mM for I Ba but 10 times higher than the IC 50 for I Na (0.17 mM). Low concentrations of lidocaine (30–100 μM), which had no direct effect on basal I K , attenuated both the stimulatory and inhibitory modulation of K + channels by thyrotropin-releasing hormone (TRH). Both modulations had an IC 50 ∼40 μM independent of [TRH]. Intracellular QX314 (100 μM), a quaternary, charged form of lidocaine, also significantly attenuated the TRH effects; however, external QX314 and the neutral LA benzocaine (100 μM) did not. Lidocaine (≤100 μM) inhibited the TRH-induced increase in [Ca ++ ] but failed to block either the GTP-γ-S-induced increase in I K , the activation of I K by directly elevated [Ca ++ ] (ca. 3 × 10 −7 M), or the phorbol-12,13-dibutyrate-induced inhibition of Ca ++ -activated I K . Agonist binding assays revealed that none of the these LAs affected TRH receptor binding. Similar to its effect on TRH modulation of I K , lidocaine (100 μM) attenuated the inhibition of Ca ++ channels in GH 3 cells by somatostatin (1 μM). These results suggest that lidocaine’s action occurs between agonist binding and G protein activation. Such inhibition of G protein pathways may be an important component of the general action of LAs acting at spinal sites, or for i.v. therapeutics or during cardiotoxic episodes.