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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

The tricyclic antidepressants amitriptyline, nortriptyline and imipramine are weak antagonists of human and rat alpha(1B)-adrenoceptors

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Author(s):
Nojimoto, F. D. [1] ; Mueller, A. [1] ; Hebeler-Barbosa, F. [1] ; Akinaga, J. [1] ; Lima, V. [1] ; de A Kiguti, L. R. [1] ; Pupo, A. S. [1]
Total Authors: 7
Affiliation:
[1] UNESP, Inst Biociencias, Dept Pharmacol, BR-18618000 Botucatu, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: Neuropharmacology; v. 59, n. 1-2, p. 49-57, JUL-AUG 2010.
Web of Science Citations: 8
Abstract

Although it is long known that the tricyclic antidepressants amitriptyline, nortriptyline and imipramine inhibit the noradrenaline transporter and alpha(1)-adrenoceptors with similar affinities, which may lead to self-cancelling actions, the selectivity of these drugs for alpha(1)-adrenoceptor subtypes is unknown. The present study investigates the selectivity of amitriptyline, nortriptyline and imipramine for human recombinant and rat native alpha(1)-adrenoceptor subtypes. The selectivity of amitriptyline, nortriptyline and imipramine was investigated in HEK-293 cells expressing each of the human alpha(1)-subtypes and in rat native receptors from the vas deferens (alpha(1A)), spleen (alpha(1B)) and aorta (alpha(1D)) through {[}(3)H]prazosin binding, and noradrenaline-induced intracellular Ca(2+) increases and contraction assays. Amitriptyline, nortriptyline and imipramine showed considerably higher affinities for alpha(1A)- (similar to 25- to 80-fold) and alpha(1D)-adrenoceptors (similar to 10- to 25-fold) than for alpha(1B)-adrenoceptors in both contraction and {[}(3)H]prazosin binding assays with rat native and human receptors, respectively. In addition, amitriptyline, nortriptyline and imipramine were substantially more potent in the inhibition of noradrenaline-induced intracellular Ca(2+) increases in HEK-293 cells expressing alpha(1A)- or a truncated version of alpha(1D)-adrenoceptors which traffics more efficiently towards the cell membrane than in cells expressing alpha(1B)-adrenoceptors. Amitriptyline, nortriptyline and imipramine are much weaker antagonists of rat and human alpha(1B)-adrenoceptors than of alpha(1A)- and alpha(1D)-adrenoceptors. The differential affinities for these receptors indicate that the alpha(1)-adrenoceptor subtype which activation is most increased by the augmented noradrenaline availability resultant from the blockade of neuronal reuptake is the alpha(1B)-adrenoceptor. This may be important for the behavioural effects of these drugs. (C) 2010 Elsevier Ltd. All rights reserved. (AU)