Antagonism by local anesthetics of sodium channel activators in the presence of scorpion toxins: two mechanisms for competitive inhibition.
1. The interaction of veratridine (VTD), a Na+ channel activator, scorpion alpha-toxin (LQ), an open state Na+ channel stabilizer, and the local anesthetic, lidocaine (LID), a channel inhibitor, at the neuronal sodium channel was assessed by measuring VTD-dependent slow depolarizations of frog sciatic nerve using the sucrose-gap method. 2. The slow depolarizing action of veratridine was potentiated more than 10-fold by the peptide LQ toxin, whereas its competitive inhibition by lidocaine was unchanged by LQ. 3. We conclude that the antagonism between VTD and a LID molecule during slow depolarization is allosteric, involving a trapping of the Na+ channel by LID in the inactivated state that has a very low affinity for VTD. 4. The binding of VTD to the open state of the channel, which is stabilized by LQ, may be inhibited by orthosteric competition at overlapping sites since both LID and VTD bind avidly and rapidly to open channels.
Son
Stanley Lee
SL
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115-6110, USA.
Wong
Kin
K
Strichartz
Gary
G
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D011892:Rana catesbeiana; D012584:Sciatic Nerve / Q000187:drug effects* / Q000378:metabolism; D012604:Scorpion Venoms / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D014701:Veratridine / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000779:Anesthetics, Local; D012604:Scorpion Venoms; D015222:Sodium Channels; D014701:Veratridine; D008012:Lidocaine