Local anesthetics inhibit the G protein-mediated modulation of K+ and Ca++ currents in anterior pituitary cells.

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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 (GH3) cells were analyzed by using a whole-cell voltage clamp. Extracellular lidocaine inhibited I(K) with an IC50 of 1.9 mM, comparable to 2.6 mM for I(Ba) but 10 times higher than the IC50 for I(Na) (0.17 mM). Low concentrations of lidocaine (30-100 microM), 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 IC50 approximately 40 microM independent of [TRH]. Intracellular QX314 (100 microM), a quaternary, charged form of lidocaine, also significantly attenuated the TRH effects; however, external QX314 and the neutral LA benzocaine (100 microM) did not. Lidocaine (</=100 microM) inhibited the TRH-induced increase in [Ca++] but failed to block either the GTP-gamma-S-induced increase in I(K), the activation of I(K) by directly elevated [Ca++] (ca. 3 x 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 microM) attenuated the inhibition of Ca++ channels in GH3 cells by somatostatin (1 microM). 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.