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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 (α_1A), spleen (α_1B) and aorta (α_1D) through [³H]prazosin binding, and noradrenaline-induced intracellular Ca²⁺ increases and contraction assays. Amitriptyline, nortriptyline and imipramine showed considerably higher affinities for α_1A- (∼25- to 80-fold) and α_1D-adrenoceptors (∼10 …