Potent block of potassium currents in rat isolated sympathetic neurones by the uncharged form of amitriptyline and related tricyclic compounds

摘要

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 μM) 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 μM. Dizocilpine (30 μM) 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 μM) where the ratio of charged to uncharged drug was 50:50 compared with pH 7.4 (K_D= 11.9 μM) where the ratio was 99:1. 4 N-methyLamitriptyLine (10 μM), the permanently charged analogue of amitriptyline, inhibited K_V by only 2% whereas in the same cells amitriptyline (10 μM) 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.