Abstract
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.
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|