Inhibition by local anesthetics of Ca2+ channels in rat anterior pituitary cells

Abstract The characteristics of local anesthetic inhibition of voltage-dependent Ca 2+ channels in a rat pituitary clonal cell line were investigated by whole-cell voltage clamp and compared with inhibition by the dihydropyridine Ca 2+ channel antagonist, nicardipine. With extracellular Ba 2+ (10 mM) as the current carrier, depolarization above −40 mV evoked a slowly inactivating I Ba . Extracellularly applied lidocaine inhibited I Ba without changing the activation threshold, the voltage of peak current, or the reversal potential. Inhibition was greater at a holding potential of −60 mV (IC 50 =1.2 mM) than at −80 mV (IC 50 =2.6 mM). This depolarization-induced potentiation in I Ba inhibition developed over 0.1–10 s after membrane depolarization began. Nicardipine also dose-dependently inhibited I Ba with an IC 50 =90 nM (at a holding potential=−80 mV). Both lidocaine and nicardipine shifted the I Ba steady-state inactivation (availability) curves to the left. Double-pulse protocols revealed that lidocaine (1 mM) accelerated the depolarization-induced inhibition (inactivation) of I Ba over the rate in drug-free solutions, but had no effect on the hyperpolarization-induced removal of channel inactivation. Nicardipine also accelerated the depolarization-induced inactivation of I Ba but, in addition, it slowed the hyperpolarization-induced inactivation removal. The relative inhibitory action of lidocaine in suppressing I Ba was unchanged in the presence of nicardipine. These results suggest that lidocaine has a direct action on membrane Ca 2+ channels, similar to the voltage-dependent action of dihydropyridine, but acting at a separate and independent site.