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

Abstract Although it is long known that the tricyclic antidepressants amitriptyline, nortriptyline and imipramine inhibit the noradrenaline transporter and α 1 -adrenoceptors with similar affinities, which may lead to self-cancelling actions, the selectivity of these drugs for α 1 -adrenoceptor subtypes is unknown. The present study investigates the selectivity of amitriptyline, nortriptyline and imipramine for human recombinant and rat native α 1 -adrenoceptor subtypes. The selectivity of amitriptyline, nortriptyline and imipramine was investigated in HEK-293 cells expressing each of the human α 1 -subtypes and in rat native receptors from the vas deferens (α 1A ), spleen (α 1B ) and aorta (α 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 α 1A - (∼25- to 80-fold) and α 1D -adrenoceptors (∼10- to 25-fold) than for α 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 α 1A - or a truncated version of α 1D -adrenoceptors which traffics more efficiently towards the cell membrane than in cells expressing α 1B -adrenoceptors. Amitriptyline, nortriptyline and imipramine are much weaker antagonists of rat and human α 1B -adrenoceptors than of α 1A - and α 1D -adrenoceptors. The differential affinities for these receptors indicate that the α 1 -adrenoceptor subtype which activation is most increased by the augmented noradrenaline availability resultant from the blockade of neuronal reuptake is the α 1B -adrenoceptor. This may be important for the behavioural effects of these drugs.