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

Nojimoto, Fernanda D.; Mueller, André N.; Hebeler-Barbosa, Flávia; Akinaga, Juliana; Lima, Vinícius; Kiguti, Luiz Ricardo de Almeida; Pupo, André S.

doi:10.1016/j.neuropharm.2010.03.015

Cited by 18 publications

(32 citation statements)

References 45 publications

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“…This suggestion is consistent with the affinity profile of imipramine and other tricyclic antidepressants for α 1 -adrenoceptor subtypes as these drugs behave as competitive antagonists with much higher affinity for α 1A -and α 1D -adrenoceptors than for α 1B -adrenoceptors (Nojimoto et al, 2010). Hence, the α 1B -adrenoceptor is the subtype more likely to be targeted by the mechanisms triggered by the chronically elevated α 1A -and α 1B -adrenoceptor signalling take place in the manifestation of these two phenotypes.…”

Section: Discussionsupporting

confidence: 84%

“…It was recently found that imipramine, amitriptyline and nortriptyline are much weaker antagonists of α 1B -adrenoceptors than of α 1A -and α 1D -subtypes; the affinities of these tricyclic antidepressants for α 1B -adrenoceptors were approximately 10-to 80-fold lower than the affinities for the other two subtypes (Nojimoto et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…As far as the noradrenergic neurotransmission is concerned, drugs such as imipramine that in the same concentration range increase the synaptic levels of noradrenaline and antagonise α 1 -adrenoceptors are likely to produce self-cancelling effects because the α 1 -adrenoceptor antagonism counteracts the sensitising influence of the inhibition of noradrenaline reuptake (Nojimoto et al, 2010;Pupo et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of α1B-adrenoceptors in the anti-immobility effect of imipramine in the tail suspension test

Ribeiro

Pupo

2015

European Journal of Pharmacology

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Imipramine is a tricyclic antidepressant inhibitor of norepinephrine and serotonin neuronal reuptake. The roles of specific α1-adrenoceptor subtypes that might be targeted by the increased synaptic levels of noradrenaline induced by imipramine are not well understood. This study investigates the α1-adrenoceptor subtypes involved in the anti-immobility effect of imipramine in the mouse tail suspension test. The anti-immobility effect of imipramine (32mg/kg, i.p.) was significantly antagonised by the non-subtype-selective α1-adrenoceptor antagonist prazosin (0.5 and 1.0mg/kg, i.p.). Neither the selective α1A-adrenoceptor antagonist 5-methyl-3-[3-[3-[4-[2-(2,2,2,-trifluroethoxy)phenyl]-1-piperazinyl]propyl]-2,4-(1H,3H)-pyrimidinedione (RS-100329, 0.5 and 1.0mg/kg) nor the selective α1D-adrenoceptor antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride, (BMY-7378, up to 1.0mg/kg, i.p.) affected the anti-immobility effect of imipramine. However, the anti-immobility effect of imipramine was significantly antagonised by the selective α1B-adrenoceptor antagonist (2S)-4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinecarboxylate (L-765,314). In addition, mice treated only with RS-100329 or BMY-7378, but not with L-765,314, showed reduced immobility times in comparison to mice treated with vehicle. These results indicate that the selective antagonism of α1A- and α1D-adrenoceptors results in antidepressant-like effects and that the α1B-subtype is the main target for the increased levels of noradrenaline caused by imipramine.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Involvement of α1B-adrenoceptors in the anti-immobility effect of imipramine in the tail suspension test

Ribeiro

Pupo

2015

European Journal of Pharmacology

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“…2B) pre-exposed to OXY (10 mM/5 minutes), PE and NE were 20-fold less potent than in time controls that had been treated with vehicle (Table 2). OXY (10 mM/5 minutes) was unable to induce tachyphylaxis to PE or NE if the treatment was performed in the presence of prazosin a1D-AR, which traffics efficiently to the cell membrane) Hague et al, 2004;Nojimoto et al, 2010). All the ligands competed for the binding of a1D-ARs.…”

Section: Resultsmentioning

confidence: 99%

Differential Phosphorylation, Desensitization, and Internalization ofα1A−Adrenoceptors Activated by Norepinephrine and Oxymetazoline

et al. 2013

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Loss of response on repetitive drug exposure (i.e., tachyphylaxis) is a particular problem for the vasoconstrictor effects of medications containing oxymetazoline (OXY), an a1-adrenoceptor (AR) agonist of the imidazoline class. One cause of tachyphylaxis is receptor desensitization, usually accompanied by phosphorylation and internalization. It is well established that a1A-ARs are less phosphorylated, desensitized, and internalized on exposure to the phenethylamines norepinephrine (NE), epinephrine, or phenylephrine (PE) than are the a1B and a1D subtypes. However, here we show in human embryonic kidney-293 cells that the low-efficacy agonist OXY induces G protein-coupled receptor kinase 2-dependent a1A-AR phosphorylation, followed by rapid desensitization and internalization (∼40% internalization after 5 minutes of stimulation), whereas phosphorylation of a1A-ARs exposed to NE depends to a large extent on protein kinase C activity and is not followed by desensitization, and the receptors undergo delayed internalization (∼35% after 60 minutes of stimulation). Native a1A-ARs from rat tail artery and vas deferens are also desensitized by OXY, but not by NE or PE, indicating that this property of OXY is not limited to recombinant receptors expressed in cell systems. The results of the present study are clearly indicative of agonist-directed a1A-AR regulation. OXY shows functional selectivity relative to NE and PE at a1A-ARs, leading to significant receptor desensitization and internalization, which is important in view of the therapeutic vasoconstrictor effects of this drug and the varied biologic process regulated by a1A-ARs.

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“…Nortriptyline, a tricyclic, potentiated NA‐induced contraction at the distal site but suppressed it at the proximal site. Suppression of NA‐induced contraction by nortriptyline is likely attributable to α 1 ‐AR antagonist properties . Nortriptyline should suppress NA‐induced contraction even at the distal site; however, nortriptyline potentiated NA‐induced contraction at the distal site rather than suppressing it.…”

Section: Discussionmentioning

confidence: 96%

Evaluation of the potentiating effects of antidepressants on the contractile response to noradrenaline in guinea pig urethra smooth muscles

Obara

Imanaka

Fukuhara

et al. 2019

Clin Exp Pharma Physio

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Summary We investigated the potential augmenting effects of 19 clinically available antidepressants on noradrenaline (NA)‐induced contractions in guinea pig urethra smooth muscle (USM). Concentration‐response curves for NA‐induced contractions in guinea pig USM strips were obtained in the absence or presence of selected antidepressants. Desipramine, an active metabolite of imipramine, produced a contraction and potentiated NA‐induced contraction at the distal urethra without affecting the proximal urethra. Further, nortriptyline and amoxapine, tricyclic antidepressants, produced a contraction and potentiated NA‐induced contraction at the distal urethra. NA‐induced contraction was unaffected or reduced by imipramine, clomipramine, trimipramine, and amitriptyline at the proximal and distal urethra. Maprotiline, a tetracyclic antidepressant, potentiated NA‐induced contraction at the distal urethra. NA‐induced contraction was unaffected by mianserin at the proximal and distal urethra. Paroxetine, a selective serotonin reuptake inhibitor (SSRI), potentiated NA‐induced contraction at the distal urethra, while NA‐induced contraction was unaffected by fluvoxamine, sertraline, and escitalopram at the proximal and distal urethra. Milnacipran, a serotonin‐noradrenaline reuptake inhibitor (SNRI), potentiated NA‐induced contraction at the proximal and distal urethra, whereas duloxetine potentiated it at the distal urethra. Mirtazapine slightly inhibited NA‐induced contraction at the distal urethra. Aripiprazole and sulpiride did not affect NA‐induced contractions at the proximal nor distal urethra. Trazodone inhibited NA‐induced contraction at both urethras. Desipramine, nortriptyline, amoxapine, maprotiline, paroxetine, milnacipran, and duloxetine likely induce urinary disturbance by increasing urethral resistance and augmenting NA‐induced contraction, which should be carefully considered when delivering guidance for drug administration to patients.

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

Cited by 18 publications

References 45 publications

Involvement of α1B-adrenoceptors in the anti-immobility effect of imipramine in the tail suspension test

Involvement of α1B-adrenoceptors in the anti-immobility effect of imipramine in the tail suspension test

Differential Phosphorylation, Desensitization, and Internalization ofα1A−Adrenoceptors Activated by Norepinephrine and Oxymetazoline

Evaluation of the potentiating effects of antidepressants on the contractile response to noradrenaline in guinea pig urethra smooth muscles

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