title: The tricyclic antidepressants amitriptyline, nortriptyline and imipramine are weak antagonists of human and rat alpha1B-adrenoceptors.
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)- (approximately 25- to 80-fold) and alpha(1D)-adrenoceptors (approximately 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.
authors.affiliation: Department of Pharmacology, Instituto de Biociências, UNESP, Botucatu, SP, Brazil.
authors.forename: F D
authors.initials: FD
authors.lastname: Nojimoto
authors.forename: A
authors.initials: A
authors.lastname: Mueller
authors.forename: F
authors.initials: F
authors.lastname: Hebeler-Barbosa
authors.forename: J
authors.initials: J
authors.lastname: Akinaga
authors.forename: V
authors.initials: V
authors.lastname: Lima
authors.forename: L R de A
authors.initials: LR
authors.lastname: Kiguti
authors.forename: A S
authors.initials: AS
authors.lastname: Pupo
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000639:Amitriptyline / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007099:Imipramine / Q000493:pharmacokinetics / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009661:Nortriptyline / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism
chemical_list: C547713:ADRA1A protein, human; C547716:ADRA1B protein, human; C547715:Adra1a protein, rat; C547718:Adra1b protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000929:Antidepressive Agents, Tricyclic; D018340:Receptors, Adrenergic, alpha-1; D000639:Amitriptyline; D009661:Nortriptyline; D007099:Imipramine; D002118:Calcium