Vol. 55, Issue 1, 150-158, January 1999

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

Zhiling Xiong, Cuneyt Bukusoglu, and Gary R. Strichartz

Department of Anesthesia, Pain Research Center , Brigham and Women's Hospital (Z.X., C.B., G.R.S.) and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School (G.R.S.), Boston, Massachusetts

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 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 IC₅₀ ~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--S-induced increase in I_K, the activation of I_K by directly elevated [Ca⁺⁺] (ca. 3 × 10⁷ 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 GH₃ 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.