Tetrahydroaminoacridine blocks potassium channels and inhibits sodium inactivation in Myxicola.
In voltage-clamped Myxicola giant axons internally and externally applied tetrahydroaminoacridine (THA) blocked K+ channels with a dissociation constant of 100 microM and slowed their rate of activation. At a concentration of 10 microM, internal THA primarily slowed inactivation of conducting Na+ channels. At 100 microM the decline of the Na+ current during depolarizing pulses was biphasic, with an initial phase 2 to 3 times faster than in control axons. In the presence of THA there was a steady-state inward current accompanied by an increase in amplitude and time constant of Na+ tail currents, as if THA blocked Na+ channels by first entering them and then rendered THA-occluded channels resistant to fast inactivation. THA did not alter activation, prepulse-induced fast inactivation or slow inactivation. The effects of THA on voltage-dependent axonal ion channels might account for central nervous system hyperexcitability seen in some patients treated with THA. Because THA is a potent, centrally active anticholinesterase, even subtle ion channel-directed effects might contribute to its putative antidementia action in clinical states involving a central nervous system deficiency of acetylcholine by selective augmentation of acetylcholine release and/or negation of autoreceptor effects of endogeneous acetylcholine.
D000109:Acetylcholine / Q000378:metabolism; D000609:Aminoacridines / Q000494:pharmacology*; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D011077:Polychaeta; D011188:Potassium / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D013619:Tacrine / Q000494:pharmacology* / Q000627:therapeutic use
D000609:Aminoacridines; D007473:Ion Channels; D013619:Tacrine; D012964:Sodium; D000109:Acetylcholine; D011188:Potassium