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Potent block of potassium currents in rat isolated sympathetic neurones by the uncharged form of amitriptyline and related tricyclic compounds
Author(s) -
Wooltorton Julian R.A.,
Mathie Alistair
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15053.x
Subject(s) - amitriptyline , cyproheptadine , chemistry , tricyclic , desipramine , intracellular , pharmacology , biophysics , stereochemistry , endocrinology , biochemistry , serotonin , medicine , hippocampus , receptor , biology , antidepressant
1 The block of K + currents by amitriptyline and the related tricyclic compounds cyproheptadine and dizocilpine was studied in dissociated rat sympathetic neurones by whole‐cell voltage‐clamp recording. 2 Cyproheptadine (30 μ m ) inhibited the delayed‐rectifier current (K v ) by 92% and the transient current (K A ) by 43%. For inhibition of K V , cyproheptadine had a K D of 2.2 μ m . Dizocilpine (30 μ m ) inhibited K V by 26% and K A by 22%. The stereoisomers of dizocilpine were equally potent at blocking K V and K A . 3 Amitriptyline, a weak base, was significantly more effective in blocking K V at pH 9.4 ( K D =0.46 μ m ) where the ratio of charged to uncharged drug was 50:50 compared with pH 7.4 ( K D =11.9 μ m ) where the ratio was 99:1. 4 N‐methylamitriptyline (10 μ m ), the permanently charged analogue of amitriptyline, inhibited K v by only 2% whereas in the same cells amitriptyline (10 μ m ) inhibited K v by 36%. 5 Neither amitriptyline nor N‐methylamitriptyline had a detectable effect on K v when added to the intracellular solution. 6 It is concluded that the uncharged form of amitriptyline is approximately one hundred times more potent in blocking K v than the charged form. However, this does not seem to be due to uncharged amitriptyline having better access to an intracellular binding site.