Pharmacological Characteristics of Anxiolytics on Acetylcholine-Induced Contractions in Rat Detrusor Smooth Muscle

Abstract

Introduction: Benzodiazepine anxiolytics are believed to cause urination disorders due to their anticholinergic effects. Objective: This study was carried out to investigate the potential inhibitory effects of 15 clinically available anxiolytics in Japan on acetylcholine (ACh)-induced contractions in rat detrusor smooth muscle (DSM) to predict whether these anxiolytics could induce urination disorders. Methods: Effects of anxiolytics on contractions induced by ACh and 80 mmol/L KCl solution in rat DSM and effects of anxiolytics on specific binding of [N-methyl-3 H]scopolamine ([ 3 H]NMS) in mouse cerebral cortex were investigated. Results and Conclusions: ACh-induced contractions in rat DSM were inhibited by clotiazepam and diazepam (benzodiazepine anxiolytics) at concentrations that were clinically relevant. These contractions were also significantly inhibited by paroxetine, escitalopram (selective serotonin reuptake inhibitors [SSRIs]), and hydroxyzine (a histamine H 1 receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. At a concentration of 10-5 mol/L, paroxetine, escitalopram, and hydroxyzine inhibited 80 mmol/L high-KCl solution-induced rat DSM contractions but not clotiazepam and diazepam. Paroxetine, escitalopram, and hydroxyzine also inhibited specific binding of [ 3 H]NMS in mouse cerebral cortex but clotiazepam and diazepam did not. In contrast to the effects of the abovementioned anxiolytics, ACh-induced contractions were not significantly affected by tofisopam, alprazolam, lorazepam, bromazepam, oxazolam, chlordiazepoxide, clonazepam, ethyl loflazepate (benzodiazepine anxiolytics), fluvoxamine (an SSRI), or tandospirone (a serotonin 5-HT 1A receptor agonist). These findings suggest that most clinically used anxiolytics are not likely to result in anticholinergic-induced urination disorders within their clinically achievable blood concentration ranges. However, clotiazepam and diazepam may induce urination disorders within their clinical dose ranges via nonanticholinergic inhibition of DSM contractility.

Inhibitory Effects of Antipsychotics on the Contractile Response to Acetylcholine in Rat Urinary Bladder Smooth Muscles

“…The effects of antipsychotics on UBSM contraction were assessed as previously described. 21,22) Briefly, isolated rat UBSM strips were equilibrated under a 0.5 g resting tone for 20 min in a 20 mL organ bath containing Locke-Ringer solution equilibrated with 95% O 2 and 5% CO 2 at 32 ± 1°C; the solution was comprised of the following (mM): NaCl, 154; KCl, 5.6; CaCl 2 , 2.2; MgCl 2 , 2.1; NaHCO 3 , 5.9; and glucose, 2.8. The UBSM preparation was contracted using 10 −4 M ACh at least three times at 20 min intervals (preliminary procedures).…”

“…Data Analysis and Statistics CRCs for ACh-induced contractions and Schild plot analysis of anxiolytics versus ACh concentrations were performed using GraphPad Prism (GraphPad Software Inc., San Diego, CA, U.S.A.), as previously described. 21,22) All values are presented as mean ± standard error of the mean (S.E.M.) or mean with 95% confidence intervals (CIs) for different numbers (n) of preparations.…”