Assessment of Inhibitory Effects of Hypnotics on Acetylcholine-Induced Contractions in Isolated Rat Urinary Bladder Smooth Muscle

Biol Pharm Bull. 2019;42(2):280-288. doi: 10.1248/bpb.b18-00829.

Abstract

The present study aimed to investigate the potential inhibitory effects of 21 clinically available hypnotics on acetylcholine (ACh)-induced contractions in rat urinary bladder smooth muscle (UBSM) in order to predict whether these hypnotics could induce voiding impairment. ACh-induced contraction in rat UBSM was inhibited only by diphenhydramine (a histamine H1 receptor antagonist) at a concentration that was clinically relevant. ACh-induced contraction was also significantly inhibited by flurazepam (a benzodiazepine hypnotic) and suvorexant (an orexin receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. These three drugs (at 10-5 M) also inhibited high-KCl (80 mM) Locke-Ringer solution-induced contractions. In contrast to the effects of the abovementioned hypnotics, ACh-induced contractions were not significantly affected by triazolam, etizolam, brotizolam, lormetazepam, estazolam, flunitrazepam, nitrazepam (benzodiazepine hypnotics), thiopental, thiamylal, pentobarbital, amobarbital, secobarbital, phenobarbital (barbiturate hypnotics), zolpidem (an imidazopyridine hypnotic), zopiclone (a cyclopyrrolone hypnotic), ramelteon (a melatonin receptor agonist), bromovalerylurea, and chloral hydrate. These findings suggest that most clinically used hypnotics are not likely to result in anticholinergic-induced dysuria within their clinically achievable blood concentration ranges. Diphenhydramine may, however, induce voiding impairment, an action attributable to diminished UBSM contractility within its clinical dose range.

Keywords: acetylcholine; hypnotic; rat urinary bladder smooth muscle.

MeSH terms

  • Acetylcholine / antagonists & inhibitors*
  • Acetylcholine / pharmacology*
  • Animals
  • Atropine / pharmacology
  • Barbiturates / pharmacology
  • Benzodiazepines / pharmacology
  • Drug Interactions
  • Hypnotics and Sedatives / pharmacology*
  • Male
  • Muscle Contraction / drug effects*
  • Muscle Contraction / physiology
  • Muscle, Smooth / drug effects*
  • Rats
  • Rats, Wistar
  • Urinary Bladder / drug effects*
  • Urinary Bladder / physiology

Substances

  • Barbiturates
  • Hypnotics and Sedatives
  • Benzodiazepines
  • Atropine
  • Acetylcholine