Modulation of nerve-evoked contractions by β3-adrenoceptor agonism in human and rat isolated urinary bladder

Pharmacol Res. 2014 Feb:80:14-20. doi: 10.1016/j.phrs.2013.12.006. Epub 2013 Dec 28.

Abstract

Activation of β3-adrenoceptors has been shown to have a direct relaxant effect on urinary bladder smooth muscle from both rats and humans, however there are very few studies investigating the effects of β3-adrenoceptor agonists on nerve-evoked bladder contractions. Therefore in the current study, the role of β3-adrenoceptors in modulating efferent neurotransmission was evaluated. The effects of β3-adrenoceptor agonism on neurogenic contractions induced by electrical field stimulation (EFS) were compared with effects on contractions induced by exogenous acetylcholine (Ach) and αβ-methylene adenosine triphosphate (αβ-meATP) in order to determine the site of action. Isoproterenol inhibited EFS-induced neurogenic contractions of human bladder (pD2=6.79; Emax=65%). The effect of isoproterenol was selectively inhibited by the β3-adrenoceptor antagonist L-748,337 (pKB=7.34). Contractions induced by exogenous Ach (0.5-1μM) were inhibited 25% by isoproterenol (3μM) while contractions to 10Hz in the same strip were inhibited 67%. The selective β3-adrenoceptor agonist CL-316,243 inhibited EFS-induced neurogenic contractions of rat bladder (pD2=7.83; Emax=65%). The effects of CL-316,243 were inhibited in a concentration dependent manner by L-748,337 (pA2=6.42). Contractions induced by exogenous Ach and αβ-meATP were significantly inhibited by CL-316,243, 29% and 40%, respectively. These results demonstrate that the activation of β3-adrenoceptors inhibits neurogenic contractions of both rat and human urinary bladder. Contractions induced by exogenously applied parasympathetic neurotransmitters are also inhibited by β3-agonism however the effect is clearly less than on neurogenic contractions (particularly in human), suggesting that in addition to a direct effect on smooth muscle, activation of prejunctional β3-adrenoceptors may inhibit neurotransmitter release.

Keywords: CL-316,243; Human urinary bladder; Isoproterenol; Neurogenic contractions; Rat urinary bladder; β-Adrenoceptors.

MeSH terms

  • Acetylcholine / antagonists & inhibitors
  • Acetylcholine / pharmacology
  • Adenosine Triphosphate / analogs & derivatives
  • Adenosine Triphosphate / antagonists & inhibitors
  • Adenosine Triphosphate / pharmacology
  • Adrenergic beta-3 Receptor Agonists / pharmacology*
  • Adrenergic beta-3 Receptor Antagonists / pharmacology
  • Aminophenols / pharmacology
  • Animals
  • Dioxoles / antagonists & inhibitors
  • Dioxoles / pharmacology
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Female
  • Humans
  • In Vitro Techniques
  • Isoproterenol / antagonists & inhibitors
  • Isoproterenol / pharmacology
  • Male
  • Muscle Contraction / drug effects*
  • Muscle Contraction / physiology
  • Muscle, Smooth / drug effects*
  • Muscle, Smooth / physiology*
  • Rats
  • Receptors, Adrenergic, beta-3 / physiology*
  • Sulfonamides / pharmacology
  • Urinary Bladder / drug effects*
  • Urinary Bladder / innervation*
  • Urinary Bladder / physiology

Substances

  • Adrenergic beta-3 Receptor Agonists
  • Adrenergic beta-3 Receptor Antagonists
  • Aminophenols
  • Dioxoles
  • L 748,337
  • Receptors, Adrenergic, beta-3
  • Sulfonamides
  • disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate
  • Adenosine Triphosphate
  • Isoproterenol
  • Acetylcholine
  • alpha,beta-methyleneadenosine 5'-triphosphate