Inhibitory Effects of Antidepressants on Acetylcholine-Induced Contractions in Isolated Guinea Pig Urinary Bladder Smooth Muscle

Abstract

Background/Aims: To investigate the potential inhibitory effects of 18 clinically available antidepressants on acetylcholine (ACh)-induced contractions in guinea pig urinary bladder smooth muscle (UBSM) in order to predict whether they may induce voiding impairment. Methods: Concentration-response curves for ACh-induced contractions in guinea pig UBSM strips were obtained in the absence or presence of selected antidepressants. When inhibitory effects indicated competitive antagonism, pA₂ values against ACh were calculated and compared to plausible antidepressant blood concentrations. Results: ACh-induced contraction was antagonized competitively within clinical dose ranges by tricyclic antidepressants (imipramine, amitriptyline, trimipramine, clomipramine, nortriptyline, and amoxapine), maprotiline (a tetracyclic antidepressant), and mirtazapine (a noradrenergic and specific serotonergic antidepressant). ACh-induced contraction was also significantly inhibited by mianserin (a tetracyclic antidepressant), paroxetine and sertraline (serotonin-selective reuptake inhibitors, SSRIs), and duloxetine (a serotonin noradrenaline (norepinephrine) reuptake inhibitor, SNRI), albeit at concentrations that substantially exceeded clinically achievable blood levels. However, ACh-induced contractions were not significantly affected by fluvoxamine and escitalopram (SSRIs), milnacipran (an SNRI), trazodone (a serotonin 5-HT_2A receptor antagonist), sulpiride (a dopamine D₂ receptor antagonist), or aripiprazole (a dopamine partial agonist). Conclusion: These findings suggest that in addition to tricyclics, some relatively novel antidepressants such as mirtazapine can induce voiding impairment, attributed to diminished UBSM contractility from the inhibition of muscarinic receptors in the UBSM.

Evaluation of Antidepressant Effects on Recovery of Electrical Field Stimulation-Induced Contractions that have been Suppressed by Clonidine in Isolated Rat Vas Deferens

“…We were unable to find prior literature on the binding properties of sertraline toward α 2 -AR. However, the concentration (10 -5 mol/L) of sertraline exhibiting this physiological effect in our study was beyond clinically achievable blood concentrations (the negative logarithm of blood concentration is 6.84-7.14) [7]. Therefore, the possibility that sertraline causes incremental urethral resistance-induced dysuria due to α 2 -AR antagonism is unlikely.…”

“…6A, C). Clinically achievable blood concentrations, expressed as negative logarithms, range from 6.13-6.91 and 5.41-5.71 for mirtazapine and trazodone, respectively [7]. This information suggests that both mirtazapine and trazodone within their clinical ranges induce dysuria by increasing urethral resistance.…”

“…-5 mol/L, this concentration is outside the range of clinically achievable blood concentrations; the negative logarithm of blood concentration is 6.10-6.50 for amitriptyline, 6.14-6.61 for trimipramine, and 6.30-6.70 for clomipramine [7]. Therefore, the possibility of these 3 tricyclics inducing dysuria due to increased urethral resistance via α 2 -AR antagonism is deemed low.…”

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

“…After incubating for 30 min in the presence of an arbitrary antidepressant (10 −6 mol/L), NA (10 −8 ‐10 −4 mol/L) was again cumulatively applied to construct the third concentration‐response curve, which was compared with the second (control) concentration‐response curve. A concentration of 10 −6 mol/L was used for all antidepressants in this study, as this concentration was estimated to be achieved in the blood at clinical dose ranges …”

“…In addition to tricyclic antidepressants, it has been shown that maprotiline, a tetracyclic, and mirtazapine, a NaSSA, competitively inhibit ACh‐induced contraction at clinically used dose ranges. Thus, these antidepressants may cause anti‐cholinergic action‐derived urination disorders as well …”