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

Autor(es)

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]

Afiliação do(s) autor(es)

^[1] UNESP, Inst Biociencias, Dept Pharmacol, BR-18618000 Botucatu, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Neuropharmacology; v. 59, n. 1-2, p. 49-57, JUL-AUG 2010.
• Citações Web of Science: 8

Resumo

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)

• Processo FAPESP: 08/50423-7 - Adrenoceptores alfa-1A, seus ligantes e eficácias colaterais
• Beneficiário: André Sampaio Pupo
• Modalidade de apoio: Auxílio à Pesquisa - Regular