The tricyclic antidepressants amitriptyline, nortriptyline and imipramine are weak antagonists of human and rat α1B-adrenoceptors

Abstract: Although it is long known that the tricyclic antidepressants amitriptyline, nortriptyline and imipramine inhibit the noradrenaline transporter and α1-adrenoceptors with similar affinities, which may lead to self-cancelling actions, the selectivity of these drugs for α1-adrenoceptor subtypes is unknown. The present study investigates the selectivity of amitriptyline, nortriptyline and imipramine for human recombinant and rat native α1-adrenoceptor subtypes. The selectivity of amitriptyline, nortriptyline and imipramine was investigated in HEK-293 cells expressing each of the human α1-subtypes and in rat native receptors from the vas deferens (α1A), spleen (α1B) and aorta (α1D) through [3H]prazosin binding, and noradrenaline-induced intracellular Ca2+ increases and contraction assays. Amitriptyline, nortriptyline and imipramine showed considerably higher affinities for α1A- (∼25- to 80-fold) and α1D-adrenoceptors (∼10- to 25-fold) than for α1B-adrenoceptors in both contraction and [3H]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 Ca2+ increases in HEK-293 cells expressing α1A- or a truncated version of α1D-adrenoceptors which traffics more efficiently towards the cell membrane than in cells expressing α1B-adrenoceptors. Amitriptyline, nortriptyline and imipramine are much weaker antagonists of rat and human α1B-adrenoceptors than of α1A- and α1D-adrenoceptors. The differential affinities for these receptors indicate that the α1-adrenoceptor subtype which activation is most increased by the augmented noradrenaline availability resultant from the blockade of neuronal reuptake is the α1B-adrenoceptor. This may be important for the behavioural effects of these drugs. [Copyright &y& Elsevier]