Inhibition by local anesthetics of Ca2+ channels in rat anterior pituitary cells.
The characteristics of local anesthetic inhibition of voltage-dependent Ca2+ channels in a rat pituitary clonal cell line were investigated by whole-cell voltage clamp and compared with inhibition by the dihydropyridine Ca2+ channel antagonist, nicardipine. With extracellular Ba2+ (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 (IC50 = 1.2 mM) than at -80 mV (IC50 = 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 IC50 = 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 Ca2+ channels, similar to the voltage-dependent action of dihydropyridine, but acting at a separate and independent site.
Xiong
Z
Z
Pain Research Center, Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Strichartz
G R
GR
D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002999:Clone Cells; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008012:Lidocaine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009529:Nicardipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010903:Pituitary Gland, Anterior / Q000187:drug effects*; D051381:Rats
D000779:Anesthetics, Local; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C038806:1,4-dihydropyridine; D008012:Lidocaine; D009529:Nicardipine; D002045:Bupivacaine